WashU weekly Neuroscience publications

Gut microbial dysbiosis after traumatic brain injury modulates the immune response and impairs neurogenesis
(2021) Acta Neuropathologica Communications, 9 (1), art. no. 40, . 

Celorrio, M.^a , Abellanas, M.A.^a c d , Rhodes, J.^a , Goodwin, V.^a , Moritz, J.^a , Vadivelu, S.^a , Wang, L.^b , Rodgers, R.^b , Xiao, S.^a , Anabayan, I.^a , Payne, C.^a , Perry, A.M.^a , Baldridge, M.T.^b , Aymerich, M.S.^c d e , Steed, A.^a , Friess, S.H.^a

^a Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, United States
^b Division of Infectious Diseases, Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, United States
^c Departamento de Bioquímica Y Genética, Facultad de Ciencias, Universidad de Navarra, Pamplona, Spain
^d CIMA, Programa de Neurociencias, Universidad de Navarra, Pamplona, Spain
^e IdiSNA, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain

Abstract
The influence of the gut microbiota on traumatic brain injury (TBI) is presently unknown. This knowledge gap is of paramount clinical significance as TBI patients are highly susceptible to alterations in the gut microbiota by antibiotic exposure. Antibiotic-induced gut microbial dysbiosis established prior to TBI significantly worsened neuronal loss and reduced microglia activation in the injured hippocampus with concomitant changes in fear memory response. Importantly, antibiotic exposure for 1 week after TBI reduced cortical infiltration of Ly6Chigh monocytes, increased microglial pro-inflammatory markers, and decreased T lymphocyte infiltration, which persisted through 1 month post-injury. Moreover, microbial dysbiosis was associated with reduced neurogenesis in the dentate gyrus 1 week after TBI. By 3 months after injury (11 weeks after discontinuation of the antibiotics), we observed increased microglial proliferation, increased hippocampal neuronal loss, and modulation of fear memory response. These data demonstrate that antibiotic-induced gut microbial dysbiosis after TBI impacts neuroinflammation, neurogenesis, and fear memory and implicate gut microbial modulation as a potential therapeutic intervention for TBI. © 2021, The Author(s).

Author Keywords
Antibiotics;  Fear conditioning;  Gut microbial dysbiosis;  Microglia;  Monocytes;  Neurogenesis;  T cells;  Traumatic brain injury

Funding details
CDI-CORE-2015-505, CDI-CORE-2019-813
National Institutes of HealthNIHOD021629, R01NS097721
Foundation for Barnes-Jewish Hospital3770, 4642
Washington University School of Medicine in St. Louis
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH

Loss of Quaking RNA binding protein disrupts the expression of genes associated with astrocyte maturation in mouse brain
(2021) Nature Communications, 12 (1), art. no. 1537, . 

Sakers, K.^a b , Liu, Y.^a b , Llaci, L.^c , Lee, S.M.^a b , Vasek, M.J.^a b , Rieger, M.A.^a b , Brophy, S.^a b , Tycksen, E.^d , Lewis, R.^e , Maloney, S.E.^b , Dougherty, J.D.^a b

^a Department of Genetics, Washington University School of Medicine, Saint Louis, MO 63110, United States
^b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^c Division of Biomedical and Biological Sciences, Washington University School of Medicine, Saint Louis, MO, United States
^d Genome Technology Access Center, McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, MO, United States
^e Hope Center, Washington University School of Medicine and Saint Louis University, Saint Louis, MO, United States

Abstract
Quaking RNA binding protein (QKI) is essential for oligodendrocyte development as myelination requires myelin basic protein mRNA regulation and localization by the cytoplasmic isoforms (e.g., QKI-6). QKI-6 is also highly expressed in astrocytes, which were recently demonstrated to have regulated mRNA localization. Here, we define the targets of QKI in the mouse brain via CLIPseq and we show that QKI-6 binds 3′UTRs of a subset of astrocytic mRNAs. Binding is also enriched near stop codons, mediated partially by QKI-binding motifs (QBMs), yet spreads to adjacent sequences. Using a viral approach for mosaic, astrocyte-specific gene mutation with simultaneous translating RNA sequencing (CRISPR-TRAPseq), we profile ribosome associated mRNA from QKI-null astrocytes in the mouse brain. This demonstrates a role for QKI in stabilizing CLIP-defined direct targets in astrocytes in vivo and further shows that QKI mutation disrupts the transcriptional changes for a discrete subset of genes associated with astrocyte maturation. © 2021, The Author(s).

Task-generic and task-specific connectivity modulations in the ADHD brain: an integrated analysis across multiple tasks
(2021) Translational Psychiatry, 11 (1), art. no. 159, . 

Chauvin, R.J.^a b c , Buitelaar, J.K.^a b d , Sprooten, E.^a b , Oldehinkel, M.^a b e , Franke, B.^b f , Hartman, C.^g , Heslenfeld, D.J.^h , Hoekstra, P.J.^g , Oosterlaan, J.^h i , Beckmann, C.F.^a b j , Mennes, M.^b

^a Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
^b Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
^c Department of Neurology, Washington University School of Medicine, St Louis, United States
^d Karakter Child and Adolescent Psychiatry University Centre, Nijmegen, Netherlands
^e School of Psychological Sciences, Monash Institute of Cognitive and Clinical Neurosciences, Monash University, Melbourne, VIC, Australia
^f Departments of Human Genetics and Psychiatry, Radboud University Medical Center, Nijmegen, Netherlands
^g University of Groningen, University Medical Center Groningen, Department of Psychiatry, Groningen, Netherlands
^h Amsterdam UMC, University of Amsterdam & Vrije Universiteit Amsterdam, Emma Neuroscience Group at Emma Children’s Hospital, department of Pediatrics, Amsterdam Reproduction & Development, Amsterdam, Netherlands
ⁱ Clinical Neuropsychology section, Vrije Universiteit, Van der Boechortstraat 7, Amsterdam, 1081 BT, Netherlands
^j Centre for Functional MRI of the Brain (FMRIB), University of Oxford, Oxford, United Kingdom

Abstract
Attention-deficit/hyperactivity disorder (ADHD) is associated with altered functioning in multiple cognitive domains and neural networks. This paper offers an overarching biological perspective across these. We applied a novel strategy that extracts functional connectivity modulations in the brain across one (Psingle), two (Pmix) or three (Pall) cognitive tasks and compared the pattern of modulations between participants with ADHD (n-89), unaffected siblings (n = 93) and controls (n = 84; total N = 266; age range = 8–27 years). Participants with ADHD had significantly fewer Pall connections (modulated regardless of task), but significantly more task-specific (Psingle) connectivity modulations than the other groups. The amplitude of these Psingle modulations was significantly higher in ADHD. Unaffected siblings showed a similar degree of Pall connectivity modulation as controls but a similar degree of Psingle connectivity modulation as ADHD probands. Pall connections were strongly reproducible at the individual level in controls, but showed marked heterogeneity in both participants with ADHD and unaffected siblings. The pattern of reduced task-generic and increased task-specific connectivity modulations in ADHD may be interpreted as reflecting a less efficient functional brain architecture due to a reduction in the ability to generalise processing pathways across multiple cognitive domains. The higher amplitude of unique task-specific connectivity modulations in ADHD may index a more “effortful” coping strategy. Unaffected siblings displayed a task connectivity profile in between that of controls and ADHD probands, supporting an endophenotype view. Our approach provides a new perspective on the core neural underpinnings of ADHD. © 2021, The Author(s).

Funding details
Wellcome TrustWT098369/Z/12/Z
ZonMw60-60600-97-193
Horizon 2020 Framework ProgrammeH2020667302 (CoCA)
Horizon 2020 Framework ProgrammeH2020728018 (Eat2beNICE)
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO864-12-003 /016-130-669/ 1750102007010 / 056-13-015 /433-09-242
Center for Information TechnologyCITR01MH62873

Spontaneous Beta Band Rhythms in the Predictive Coding of Natural Stimuli
(2021) Neuroscientist, 27 (2), pp. 184-201. 

Betti, V.^a b , Della Penna, S.^c , de Pasquale, F.^d , Corbetta, M.^e f g

^a Department of Psychology, Sapienza University of Rome, Rome, Italy
^b IRCCS Fondazione Santa Lucia, Rome, Italy
^c Institute for Advanced Biomedical Technologies and Department of Neuroscience, Imaging and Clinical Sciences, “G. D’Annunzio” University, Chieti, Italy
^d Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy
^e Department of Neuroscience and Padova Neuroscience Center (PNC), University of Padua, Padua, Italy
^f Venetian Institute of Molecular Medicine (VIMM), Padua, Italy
^g Department of Neurology, Radiology, and Neuroscience, Washington University in St. Louis, St. LouisMO, United States

Abstract
The regularity of the physical world and the biomechanics of the human body movements generate distributions of highly probable states that are internalized by the brain in the course of a lifetime. In Bayesian terms, the brain exploits prior knowledge, especially under conditions when sensory input is unavailable or uncertain, to predictively anticipate the most likely outcome of upcoming stimuli and movements. These internal models, formed during development, yet still malleable in adults, continuously adapt through the learning of novel stimuli and movements. Traditionally, neural beta (β) oscillations are considered essential for maintaining sensorimotor and cognitive representations, and for temporal coding of expectations. However, recent findings show that fluctuations of β band power in the resting state strongly correlate between cortical association regions. Moreover, central (hub) regions form strong interactions over time with different brain regions/networks (dynamic core). β band centrality fluctuations of regions of the dynamic core predict global efficiency peaks suggesting a mechanism for network integration. Furthermore, this temporal architecture is surprisingly stable, both in topology and dynamics, during the observation of ecological natural visual scenes, whereas synthetic temporally scrambled stimuli modify it. We propose that spontaneous β rhythms may function as a long-term “prior” of frequent environmental stimuli and behaviors. © The Author(s) 2020.

Author Keywords
beta band;  natural vision;  neural oscillations;  priors;  spontaneous activity

Funding details
759651
National Institutes of HealthNIHRO1 NS095741
European Research CouncilERC
Ministero dell’Istruzione, dell’Università e della RicercaMIUR
Fundação Bial

Plasma amyloid‐beta levels in a pre‐symptomatic dutch‐type hereditary cerebral amyloid angiopathy pedigree: A cross‐sectional and longitudinal investigation
(2021) International Journal of Molecular Sciences, 22 (6), art. no. 2931, pp. 1-12. 

Chatterjee, P.^a b , Tegg, M.^b , Pedrini, S.^b , Fagan, A.M.^c d , Xiong, C.^d e , Singh, A.K.^f , Taddei, K.^b g , Gardener, S.^b , Masters, C.L.^h , Schofield, P.R.^i j , Multhaup, G.^k , Benzinger, T.L.S.^d l , Morris, J.C.^c d , Bateman, R.J.^c d , Greenberg, S.M.^m , van Buchem, M.A.ⁿ , Stoops, E.^o , Vanderstichele, H.^p , Teunissen, C.E.^q , Hankey, G.J.^r , Wermer, M.J.H.^s , Sohrabi, H.R.^{a b g t u} , Martins, R.N.^{a b g u v} , the Dominantly Inherited Alzheimer Network^w

^a Department of Biomedical Sciences, Macquarie University, North Ryde, NSW 2109, Australia
^b School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA 6027, Australia
^c Department of Neurology, Washington University, St. Louis, MO 63130, United States
^d Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63130, United States
^e Division of Biostatistics, Washington University, St. Louis, MO 63130, United States
^f Macquarie Business School, Macquarie University, North Ryde, NSW 2109, Australia
^g Australian Alzheimer’s Research Foundation, Nedlands, WA 6009, Australia
^h The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC 3052, Australia
ⁱ Neuroscience Research Australia, Sydney, NSW 2031, Australia
^j School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia
^k Department of Pharmacology and Therapeutics, McGill University, Montreal, QC H3G 1Y6, Canada
^l Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^m Department of Neurology, Massachusetts General Hospital Stroke Research Center, Harvard Medical School, Boston, MA 02114, United States
ⁿ Department of Radiology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
^o ADx NeuroSciences, Gent, 9052, Belgium
^p Biomarkable, Gent, 9000, Belgium
^q Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam University Medical Centers, Amsterdam, 1007 MB, Netherlands
^r Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, WA 6009, Australia
^s Department of Neurology, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
^t Centre for Healthy Ageing, College of Science, Health, Engineering and Education, Murdoch University, Murdoch, WA 6150, Australia
^u School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, WA 6009, Australia
^v The KaRa Institute of Neurological Disease, Macquarie Park, NSW 2113, Australia

Abstract
Plasma amyloid‐beta (Aβ) has long been investigated as a blood biomarker candidate for Cerebral Amyloid Angiopathy (CAA), however previous findings have been inconsistent which could be attributed to the use of less sensitive assays. This study investigates plasma Aβ alterations between pre‐symptomatic Dutch‐type hereditary CAA (D‐CAA) mutation‐carriers (MC) and non-carriers (NC) using two Aβ measurement platforms. Seventeen pre‐symptomatic members of a D‐ CAA pedigree were assembled and followed up 3–4 years later (NC = 8;MC = 9). Plasma Aβ1‐40 and Aβ1‐42 were cross‐sectionally and longitudinally analysed at baseline (T1) and follow‐up (T2) and were found to be lower in MCs compared to NCs, cross‐sectionally after adjusting for covari-ates, at both T1(Aβ1‐40: p = 0.001; Aβ1‐42: p = 0.0004) and T2 (Aβ1‐40: p = 0.001; Aβ1‐42: p = 0.016) employing the Single Molecule Array (Simoa) platform, however no significant differences were observed using the xMAP platform. Further, pairwise longitudinal analyses of plasma Aβ1‐40 revealed decreased levels in MCs using data from the Simoa platform (p = 0.041) and pairwise longitudinal analyses of plasma Aβ1‐42 revealed decreased levels in MCs using data from the xMAP platform (p = 0.041). Findings from the Simoa platform suggest that plasma Aβ may add value to a panel of biomarkers for the diagnosis of pre‐symptomatic CAA, however, further validation studies in larger sample sets are required. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Amyloid‐beta;  Blood biomarkers;  Cerebral amyloid angiopathy;  Early diagnosis;  Hereditary cerebral haemorrhage with amyloidosis—Dutch type;  Plasma amyloid‐beta;  Single molecule array platform

Funding details
National Health and Medical Research CouncilNHMRCAPP1129627
National Institutes of HealthNIHU19AG032438

Cerebral expression of metabotropic glutamate receptor subtype 5 in idiopathic autism spectrum disorder and fragile x syndrome: A pilot study
(2021) International Journal of Molecular Sciences, 22 (6), art. no. 2863, pp. 1-16. 

Brašić, J.R.^a , Nandi, A.^a , Russell, D.S.^b c , Jennings, D.^b c d , Barret, O.^b c e , Martin, S.D.^a f , Slifer, K.^g h , Sedlak, T.^a i , Seibyl, J.P.^b c , Wong, D.F.^a j , Budimirovic, D.B.^g k

^a Section of High Resolution Brain Positron Emission Tomography Imaging, Division of Nuclear Medicine and Molecular Imaging, The Russell H. Morgan, Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
^b Institute for Neurodegenerative Disorders, New Haven, CT 06510, United States
^c Research Clinic, Invicro, New Haven, CT 06510, United States
^d Denali Therapeutics, Inc, South San Francisco, CA 94080, United States
^e Laboratoire des Maladies Neurodégénératives, Molecular Imaging Research Center (MIRCen), Institut de Biologie François Jacob, Centre National de la Recherche Scientifique (CNRS), Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA), Université Paris-Saclay, Fontenay-aux-Roses CEDEX, 92265, France
^f Department of Neuroscience, Zanvyl Krieger School of Arts and Sciences, The Johns Hopkins University, Baltimore, MD 21218, United States
^g Department of Psychiatry and Behavioral Sciences-Child Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^h Department of Behavioral Psychology, Kennedy Krieger Institute, Baltimore, MD 21205, United States
ⁱ Department of Psychiatry and Behavioral Sciences-General Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^j Laboratory of Central Nervous System (CNS) Neuropsychopharmacology and Multimodal Imaging (CNAMI), Mallinckrodt Institute of Radiology, Washington University, Saint Louis, MO 63110, United States
^k Department of Psychiatry, Kennedy Krieger Institute, Baltimore, MD 21205, United States

Abstract
Multiple lines of evidence suggest that dysfunction of the metabotropic glutamate receptor subtype 5 (mGluR5) plays a role in the pathogenesis of autism spectrum disorder (ASD). Yet animal and human investigations of mGluR5 expression provide conflicting findings about the nature of dysregulation of cerebral mGluR5 pathways in sub-types of ASD. The demonstration of reduced mGluR5 expression throughout the living brains of men with fragile X syndrome (FXS), the most common known single-gene cause of ASD, provides a clue to examine mGluR5 expression in ASD. We aimed to (A) compare and contrast mGluR5 expression in idiopathic autism spectrum disorder (IASD), FXS, and typical development (TD) and (B) show the value of positron emission tomography (PET) for the application of precision medicine for the diagnosis and treatment of individuals with IASD, FXS, and related conditions. Two teams of investigators independently ad-ministered 3-[18F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([18 F]FPEB), a novel, specific mGluR5 PET ligand to quantitatively measure the density and the distribution of mGluR5s in the brain regions, to participants of both sexes with IASD and TD and men with FXS. In contrast to participants with TD, mGluR5 expression was significantly increased in the cortical regions of participants with IASD and significantly reduced in all regions of men with FXS. These results suggest the feasibility of this protocol as a valuable tool to measure mGluR5 expression in clinical trials of individuals with IASD and FXS and related condi-tions. © 2021 by the authors.

Author Keywords
Binding potential;  Caudate nucleus;  Cingulate;  Cortex;  Fragile X mental retardation 1 gene (FMR1);  Neurodevelopmental disorders;  Positron emission tomography (PET);  Putamen;  Radiotracer;  Thalamus

Funding details
National Institutes of HealthNIH
Institute for Clinical and Translational Research, University of Wisconsin, MadisonUW ICTRUL1 TR003098
National Center for Advancing Translational SciencesNCATS
Intellectual and Developmental Disabilities Research CenterIDDRCU54 HD079123

The role of SPECT and PET in epilepsy
(2021) American Journal of Roentgenology, 216 (3), pp. 759-768. 

Ponisio, M.R.^a , Zempel, J.M.^b , Day, B.K.^b , Eisenman, L.N.^b , Miller-Thomas, M.M.^a , Smyth, M.D.^c , Hogan, R.E.^b

^a Mallinckrodt Institute of Radiology, Washington University, School of Medicine, CB 8225, 510 S Kingshighway Blvd, St. Louis, MO 63110, United States
^b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE. The purpose of this article is to summarize the role of molecular imaging of the brain by use of SPECT, FDG PET, and non-FDG PET radiotracers in epilepsy. CONCLUSION. Quantitative image analysis with PET and SPECT has increased the diagnostic utility of these modalities in localizing epileptogenic onset zones. A multimodal platform approach integrating the functional imaging of PET and SPECT with the morphologic information from MRI in presurgical evaluation of epilepsy can greatly improve outcomes. © American Roentgen Ray Society

Author Keywords
Epilepsy;  MRI;  PET;  SPECT

Opioid Use among Adolescents Undergoing Surgical Repair of Facial Trauma
(2021) Plastic and Reconstructive Surgery, 147 (3), pp. 690-698. 

Som, A., Santosa, K.B., Skolnick, G.B., Lapidus, J.B., Waljee, J.F., Patel, K.B.

From the Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine; and the Section of Plastic Surgery, Department of Surgery, University of Michigan

Abstract
BACKGROUND: New persistent opioid use has been quantified among adults undergoing surgery; less is known about the risk among adolescents. The authors examine new persistent opioid use in opioid-naive adolescent patients who underwent operative repair of facial fractures. METHODS: Using the IBM MarketScan Commercial Database, the authors performed a retrospective analysis of patients aged 11 to 17 years who underwent facial fracture repair between 2006 and 2015. The incidences of prolonged opioid use and potentially inappropriate opioid prescriptions were determined. RESULTS: Of 4892 patients, 78.5 percent filled a prescription. Among these patients, 7.9 percent had prolonged opioid use. Significant risk factors included older age (i.e., age 15 to 17 years) (OR, 1.579; 95 percent CI, 1.173 to 2.126 compared to younger patients), multiple comorbidities (OR, 3.005; 95 percent CI, 1.193 to 7.568), mandible fracture (OR, 1.614; 95 percent CI, 1.213 to 2.146), and multiple fractures (OR, 1.542; 95 percent CI, 1.002 to 2.372). Overall, 24.1 percent received a potentially inappropriate opioid prescription. Mandible fracture repair was associated with increased risk (OR, 2.753; 95 percent CI, 2.275 to 3.331) of potentially inappropriate opioid prescription. CONCLUSIONS: Nearly one in 12 adolescents met criteria for prolonged opioid use; nearly one in four received a potentially inappropriate opioid prescription. Significant risk factors included mandible fracture, older age, multiple comorbidities, and multiple fractures. Like adults, many adolescents are at high risk for potentially inappropriate opioid prescriptions and prolonged opioid use following surgical repair. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. Copyright © 2021 by the American Society of Plastic Surgeons.

Can proton therapy reduce radiation-related lymphopenia in glioblastoma?
(2021) Neuro-oncology, 23 (2), pp. 179-181. 

Huang, J.^a , Mehta, M.^b

^a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^b Miami Cancer Institute and Florida International University, Miami, FL, United States

Strategies and Tools for Studying Microglial-Mediated Synapse Elimination and Refinement
(2021) Frontiers in Immunology, 12, art. no. 640937, . 

Morini, R.^a , Bizzotto, M.^a b , Perrucci, F.^a b , Filipello, F.^a b c , Matteoli, M.^a d

^a Laboratory of Pharmacology and Brain Pathology, Neurocenter, Humanitas Clinical and Research Center – IRCCS, Rozzano, Italy
^b Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Consiglio Nazionale Delle Ricerche (CNR), Institute of Neuroscience – URT Humanitas, Rozzano, Italy

Abstract
The role of microglia in controlling synapse homeostasis is becoming increasingly recognized by the scientific community. In particular, the microglia-mediated elimination of supernumerary synapses during development lays the basis for the correct formation of neuronal circuits in adulthood, while the possible reactivation of this process in pathological conditions, such as schizophrenia or Alzheimer’s Disease, provides a promising target for future therapeutic strategies. The methodological approaches to investigate microglial synaptic engulfment include different in vitro and in vivo settings. Basic in vitro assays, employing isolated microglia and microbeads, apoptotic membranes, liposomes or synaptosomes allow the quantification of the microglia phagocytic abilities, while co-cultures of microglia and neurons, deriving from either WT or genetically modified mice models, provide a relatively manageable setting to investigate the involvement of specific molecular pathways. Further detailed analysis in mice brain is then mandatory to validate the in vitro assays as representative for the in vivo situation. The present review aims to dissect the main technical approaches to investigate microglia-mediated phagocytosis of neuronal and synaptic substrates in critical developmental time windows. © Copyright © 2021 Morini, Bizzotto, Perrucci, Filipello and Matteoli.

Author Keywords
confocal microscopy;  flow cytometry;  microglia;  phagocytosis;  synaptic pruning

Funding details
-201602361571, 2017A9MK4R
Fondazione Cariplo2018-0364
Fondazione Umberto Veronesi

Ontogenetic Oxycodone Exposure Affects Early Life Communicative Behaviors, Sensorimotor Reflexes, and Weight Trajectory in Mice
(2021) Frontiers in Behavioral Neuroscience, 15, art. no. 615798, . 

Minakova, E.^a , Sarafinovska, S.^b c d , Mikati, M.O.^{c e f g h} , Barclay, K.M.^e f g h , McCullough, K.B.^b c , Dougherty, J.D.^b c i , Al-Hasani, R.^e f g h , Maloney, S.E.^c i

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^d Medical Scientist Training Program, Washington University in St. Louis, St. Louis, MO, United States
^e Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^g Washington University Pain Center, Washington University in St. Louis, St. Louis, MO, United States
^h Center for Clinical Pharmacology, St. Louis College of Pharmacy, University of Health Sciences and Pharmacy, St. Louis, MO, United States
ⁱ Intellectual and Developmental Disabilities Research Center, Washington University In St. Louis, St. Louis, MO, United States

Abstract
Nationwide, opioid misuse among pregnant women has risen four-fold from 1999 to 2014, with commensurate increase in neonates hospitalized for neonatal abstinence syndrome (NAS). NAS occurs when a fetus exposed to opioids in utero goes into rapid withdrawal after birth. NAS treatment via continued post-natal opioid exposure has been suggested to worsen neurodevelopmental outcomes. We developed a novel model to characterize the impact of in utero and prolonged post-natal oxycodone (Oxy) exposure on early behavior and development. Via subcutaneous pump implanted before breeding, C57BL/6J dams were infused with Oxy at 10 mg/kg/day from conception through pup-weaning. At birth, in utero oxy-exposed pups were either cross-fostered (paired with non-Oxy exposed dams) to model opioid abstinence (in utero Oxy) or reared by their biological dams still receiving Oxy to model continued post-natal opioid exposure (prolonged Oxy). Offspring from vehicle-exposed dams served as cross-fostered (in utero Veh) or biologically reared (prolonged Veh) controls. In utero Oxy exposure resulted in sex-dependent weight reductions and altered spectrotemporal features of isolation-induced ultrasonic vocalization (USV). Meanwhile, prolonged Oxy pups exhibited reduced weight and sex-differential delays in righting reflex. Specifically, prolonged Oxy female offspring exhibited increased latency to righting. Prolonged Oxy pups also showed decreases in number of USV calls and changes to spectrotemporal USV features. Overall, ontogenetic Oxy exposure was associated with impaired attainment of gross and sensorimotor milestones, as well as alterations in communication and affective behaviors, indicating a need for therapeutic interventions. The model developed here will enable studies of withdrawal physiology and opioid-mediated mechanisms underlying these neurodevelopmental deficits. © Copyright © 2021 Minakova, Sarafinovska, Mikati, Barclay, McCullough, Dougherty, Al-Hasani and Maloney.

Author Keywords
behavior;  in utero;  neonatal abstinence syndrome;  opioid;  oxycodone;  post-natal

Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATSULITR002345
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50 HD103525
Washington University School of Medicine in St. Louis20-186-9770

Machine Learning Analytics of Resting-State Functional Connectivity Predicts Survival Outcomes of Glioblastoma Multiforme Patients
(2021) Frontiers in Neurology, 12, art. no. 642241, . 

Lamichhane, B.^a , Daniel, A.G.S.^b , Lee, J.J.^c , Marcus, D.S.^c , Shimony, J.S.^c , Leuthardt, E.C.^{a b d e f g}

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States
^f Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO, United States
^g Brain Laser Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Glioblastoma multiforme (GBM) is the most frequently occurring brain malignancy. Due to its poor prognosis with currently available treatments, there is a pressing need for easily accessible, non-invasive techniques to help inform pre-treatment planning, patient counseling, and improve outcomes. In this study we determined the feasibility of resting-state functional connectivity (rsFC) to classify GBM patients into short-term and long-term survival groups with respect to reported median survival (14.6 months). We used a support vector machine with rsFC between regions of interest as predictive features. We employed a novel hybrid feature selection method whereby features were first filtered using correlations between rsFC and OS, and then using the established method of recursive feature elimination (RFE) to select the optimal feature subset. Leave-one-subject-out cross-validation evaluated the performance of models. Classification between short- and long-term survival accuracy was 71.9%. Sensitivity and specificity were 77.1 and 65.5%, respectively. The area under the receiver operating characteristic curve was 0.752 (95% CI, 0.62–0.88). These findings suggest that highly specific features of rsFC may predict GBM survival. Taken together, the findings of this study support that resting-state fMRI and machine learning analytics could enable a radiomic biomarker for GBM, augmenting care and planning for individual patients. © Copyright © 2021 Lamichhane, Daniel, Lee, Marcus, Shimony and Leuthardt.

Author Keywords
biomarker;  brain tumor;  classification;  overall survival;  resting state functional connectivity;  short and long-term survival;  support vector machine

Funding details
National Cancer InstituteNCI
National Institute for Health ResearchNIHRR01CA203861

Association of Opioid Use Disorder Treatment With Alcohol-Related Acute Events
(2021) JAMA Network Open, 4 (2), p. e210061. 

Xu, K.Y.^a , Presnall, N.^a , Mintz, C.M.^a , Borodovsky, J.T.^a b , Bhat, N.R.^a , Bierut, L.J.^a c , Grucza, R.A.^a d e

^a Health and Behavior Research Center, Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Now with Center for Technology and Behavioral Health, Department of Biomedical Data Science, Geisel School of Medicine at DartmouthNH, Lebanon
^c Alvin J Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine in St Louis, St Louis, MO, United States
^d Department of Family and Community Medicine, St Louis University, St Louis, MO, United States
^e Department of Health and Clinical Outcomes Research, St Louis University, St Louis, MO, United States

Abstract
Importance: Persons with opioid use disorder (OUD) and co-occurring alcohol use disorder (AUD) are understudied and undertreated. It is unknown whether the use of medications to treat OUD is associated with reduced risk of alcohol-related morbidity. Objective: To determine whether the use of OUD medications is associated with decreased risk for alcohol-related falls, injuries, and poisonings in persons with OUD with and without co-occurring AUD. Design, Setting, and Participants: This recurrent-event, case-control, cohort study used prescription claims from IBM MarketScan insurance databases from January 1, 2006, to December 31, 2016. The sample included persons aged 12 to 64 years in the US with an OUD diagnosis and taking OUD medication who had at least 1 alcohol-related admission. The unit of observation was person-day. Data analysis was performed from June 26 through September 28, 2020. Exposures: Days of active OUD medication prescriptions, with either agonist (ie, buprenorphine or methadone) or antagonist (ie, oral or extended-release naltrexone) treatments compared with days without OUD prescriptions. Main Outcomes and Measures: The primary outcome was admission for any acute alcohol-related event defined by International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Conditional logistic regression was used to compare OUD medication use between days with and without an alcohol-related event. Stratified analyses were conducted between patients with OUD with and without a recent AUD diagnostic code. Results: There were 8 424 214 person-days of observation time among 13 335 participants who received OUD medications and experienced an alcohol-related admission (mean [SD] age, 33.1 [13.1] years; 5884 female participants [44.1%]). Agonist treatments (buprenorphine and methadone) were associated with reductions in the odds of any alcohol-related acute event compared with nontreatment days, with a 43% reduction for buprenorphine (odds ratio [OR], 0.57; 95% CI, 0.52-0.61) and a 66% reduction for methadone (OR, 0.34; 95% CI, 0.26-0.45). The antagonist treatment naltrexone was associated with reductions in alcohol-related acute events compared with nonmedication days, with a 37% reduction for extended-release naltrexone (OR, 0.63; 95% CI, 0.52-0.76) and a 16% reduction for oral naltrexone (OR, 0.84; 95% CI, 0.76-0.93). Naltrexone use was more prevalent among patients with OUD with recent AUD claims than their peers without AUD claims. Conclusions and Relevance: These findings suggest that OUD medication is associated with fewer admissions for alcohol-related acute events in patients with OUD with co-occurring AUD.

Pain, the immune system and opioids are cross-talking: Are we just listening in, or can we shape the conversation?
(2021) Minerva Anestesiologica, 87 (2), pp. 150-152. 

Cavallone, L.F.^a b , Montana, M.C.^b

^a Department of Anesthesiology, University of Mississippi Medical Center, Jackson, MS, United States
^b Department of Anesthesiology, Washington University in St. Louis, Medical Center, St. Louis, MO, United States

Profiles and Predictors of Treatment-Resistant Opioid Use Disorder (TROUD): A Secondary Data Analysis of Treatment Episode Data Set’s 2017 Admissions
(2021) Alcoholism Treatment Quarterly, . 

Patterson Silver Wolf, D.A.^a , Dulmus, C.^b , Wilding, G.^c , Barczykowski, A.^c , Yu, J.^c , Beeler-Stinn, S.^a , Asher Blackdeer, A.^a , Harvey, S.^d , Rodriguez, N.M.^d

^a Brown School, Washington University in St. Louis, St. Louis, MO, United States
^b School of Social Work, University at Buffalo, Buffalo, NY, United States
^c Biostatistics, University at Buffalo, Buffalo, NY, United States
^d Integrity Partners for Behavioral Health, IPA, Inc, Batavia, United States

Abstract
Though behavioral interventions and medications have shown efficacy for individuals suffering from an opioid use disorder (OUD), there is a substantial sub-population that does not respond to currently available treatments. Through a secondary data analysis, this study finds evidence for the existence of treatment-resistant opioid use disorder (TROUD) by determining and examining factors associated with low and high treatment groups. This study provides evidence that failure to successfully complete treatment is related to the disorder’s resistance, thereby opening new clinical and research paths that can help in designing personalized therapies to treat TROUD. © 2021 Taylor & Francis.

Author Keywords
opioid use disorder;  predictive models;  risk factors;  Substance use disorder;  treatment resistance

Early Surgical Intervention in Amniotic Band Sequence for Upper Extremity Motor Nerve Palsies: A Case Report
(2021) Hand, . 

Mohan, A.S., Russo, S.A., Pet, M.A.

Washington University School of Medicine, St. Louis, MO, United States

Abstract
Urgent surgical intervention for amniotic band sequence (ABS) is currently indicated for concerns of vascular compromise and progressive lymphedema. Peripheral motor nerve palsies are rare, and reports of surgical intervention in these cases describe persistent motor dysfunction. We report band release and ulnar, median, and radial nerve decompression in a 1-week-old with a severe upper extremity constriction band and signs of ulnar nerve motor dysfunction. A literature review on nerve exploration and outcomes of patients with motor nerve palsy from ABS was performed. Early evidence of ulnar motor function was observed at 5.5-month follow-up. Previous reports of nerve decompression for upper extremity constriction bands with motor nerve palsy document poor recovery after interventions beginning at 3 months of age. In this case, band release and nerve decompression were undertaken at 7 days of age, and we observed early motor recovery. This finding suggests that very early surgical intervention in the neonate may facilitate nerve recovery in appropriate candidates. © The Author(s) 2021.

Author Keywords
amniotic band sequence;  band release;  constriction band;  nerve decompression;  peripheral motor palsy;  ulnar nerve

Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults
(2021) Brain, Behavior, and Immunity, . 

Albrecht, D.S.^a , Sagare, A.^b , Pachicano, M.^b , Sweeney, M.D.^b , Toga, A.^a , Zlokovic, B.^b , Chui, H.^c , Joe, E.^c , Schneider, L.^c , Morris, J.C.^d , Benzinger, T.^d , Pa, J.^a c

^a Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States
^b Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States
^c Alzheimer Disease Research Center, Department of Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, United States
^d Department of Neurology, Department of Radiology, and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults. Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [18F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [18F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions. Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships. Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate. © 2021

Author Keywords
Amyloid-β;  Chemokine;  Cytokine;  Glial activation;  Neuroinflammation;  PET imaging;  Tau

Funding details
National Institute on AgingNIAP01AG03991, P01AG052350, P50AG05681, R01AG054617, P01AG026276

Bivariate Latent-Change-Score Analysis of Peer Relations From Early Childhood to Adolescence: Leading or Lagging Indicators of Psychopathology
(2021) Clinical Psychological Science, . 

Rappaport, B.I.^a , Jackson, J.J.^a , Whalen, D.J.^b , Pagliaccio, D.^c , Luby, J.L.^b , Barch, D.M.^a b d

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
^b Department of Psychiatry, Washington University School of Medicine, United States
^c New York State Psychiatric Institute and College of Physicians and Surgeons, Columbia University, United States
^d Department of Radiology, Washington University School of Medicine, United States

Abstract
Understanding longitudinal associations between problematic peer relations and psychopathology is needed to inform public health. Three models have been proposed: Poor peer relations (a) lead or are a risk factor for psychopathology, (b) lag or are a consequence of psychopathology, or (c) both lead and lag psychopathology. Another model is that poor peer relations lead or lag psychopathology depending on the developmental period. To test these models, youths’ peer relations and clinical symptoms were assessed up to six times between ages 3 and 11 in 306 children. Bivariate latent-change-score models tested leading and lagging longitudinal relationships between children’s peer relations (peer victimization/rejection, peer-directed aggression, social withdrawal, prosocial behavior) and psychopathology (depression, anxiety, and externalizing symptoms). Peer victimization/rejection was a leading indicator of depression from early childhood into preadolescence. Peer-directed aggression was a leading indicator of externalizing symptoms (in late childhood). © The Author(s) 2021.

Author Keywords
aggressive behaviors;  depression;  latent change score;  peer relations;  peer victimization

High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial
(2021) Molecular Neurobiology, .

Moran, M.^a b , Blum, K.^{b c d e f g h i j} , Ponce, J.V.^b , Lott, L.^b , Gondré–Lewis, M.C.^k , Badgaiyan, S.^b , Brewer, R.^b h , Downs, B.W.ⁱ , Fynman, P.^l , Weingarten, A.^l m , Cadet, J.L.ⁿ , Smith, D.E.^o , Baron, D.^e , Thanos, P.K.^p , Modestino, E.J.^q , Badgaiyan, R.D.^{r s t u v} , Elman, I.^w , Gold, M.S.^x

^a Pain Consultants of San Antonio, San Antonio, TX, United States
^b Department of Nutrigenomics, Geneus Health, LLC, San Antonio, TX, United States
^c Department of Psychiatry, University of Vermont, Burlington, VT, United States
^d Division of Addiction Services, Dominion Diagnostics, North Kingston, RI, United States
^e Western University Health Science Centers, Graduate College, Pompano, CA, United States
^f Institute of Psychology, Eotvos Loránd University, Budapest, Hungary
^g Department of Psychiatry, Wright University Boonshoft School of Medicine, Dayton, OH, United States
^h The Kenneth Blum Behavioral and Neurogenetic Institute, (Division of Ivitalize Inc), Austin, TX, United States
ⁱ Division of Nutrigenomics, Victory Nutrition International, LLC, Lederoch, PA, United States
^j Division of Clinical Neurology, Path Foundation NY, New York, NY, United States
^k Department of Anatomy, Developmental Neuro-Psycho-Pharmacology Laboratory, Howard University College of Medicine, Washington, DC, United States
^l Comprehensive Pain Management, Syosset, NY, United States
^m Department of Psychiatry, New York Medical College, Valhalla, NY, United States
ⁿ Molecular Neuropsychiatry Branch, National Institutes of Health, Bethesda, MD, United States
^o Department of Pharmacology, College of Medicine, University of San Francisco, San Francisco, CA, United States
^p Department of Psychology & Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, University at Buffalo, Buffalo, NY, United States
^q Department of Psychology, Curry College, Milton, MA, United States
^r Department of Psychiatry, Icahn School of Medicine Mt Sinai, New York, NY, United States
^s Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, United States
^t Long School of Medicine, University of Texas Medical Center, San Antonio, TX, United States
^u Center For Psychiatric Medicine, Lawrence, MA, United States
^v Department of Psychiatry, Harvard School of Medicine, Boston, MA, United States
^w Department of Psychiatry, Harvard University School of Medicine, Cambridge, MA, United States
^x Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30–600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence. © 2021, The Author(s).

Author Keywords
GARS;  Genetic risk;  Hyperalgesia;  Hypodopaminergia;  Neuroadaptation;  Opioids;  Pain;  Polymorphisms;  Tolerance

Psychometric analysis of the behavioral assessment screening tool (BAST) in adults with stroke
(2021) Topics in Stroke Rehabilitation, . 

Osborne, C.^a , Wong, A.^b , Vo, W.^a , Juengst, S.^a

^a Department of Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, Dallas, United States
^b Program in Occupational Therapy and Department of Neurology, Washington University School of Medicine, St. Louis, United States

Abstract
Purpose: The purpose of this study was to examine the initial psychometric properties of the Behavioral Assessment Screening Tool (BAST), a self-reported measure of neurobehavioral symptoms, in adults with stroke. Methods: We assessed subscale and item-level reliabilities of the five BAST subscales in 75 community-dwelling adults with stroke. We further assessed the known-groups validity of the BAST to differentiate individuals with and without self-reported lifetime stroke history (n = 47 with stroke and n = 1843 neurologically healthy controls). Results: Cronbach’s alpha coefficients of all subscales were >0.7, demonstrating acceptable to good internal consistency reliabilities, and corrected item-total correlations were all >.30 demonstrating good item-level reliabilities. ROC curves demonstrated strong known-groups validity of the negative affect, executive function, and fatigue subscales for classifying stroke versus healthy controls (AUC = .669-.758, p < .001). Conclusion: The BAST demonstrates good initial psychometric properties as a screening tool to identify neurobehavioral symptoms in community-dwelling adults with stroke. Future work will add stroke-specific items, further assess the validity of the BAST, and employ item response theory or Rasch analyses to identify highly discriminative items for potential smart device-based ecological momentary assessments. © 2021 Taylor & Francis Group, LLC.

Author Keywords
measurement;  neurobehavioral;  psychometrics;  Stroke;  validity

Simple action alters attention towards visual features
(2021) Attention, Perception, and Psychophysics, . 

Wang, Z.^a b , Weidler, B.J.^c , Sun, P.^a , Abrams, R.A.^d

^a Department of Psychology, Tsinghua University, Haidian, Beijing, China
^b Department of Psychology, University of California, Berkeley, CA, United States
^c Department of Psychology, Towson University, Towson, MD, United States
^d Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
Recent studies have revealed an action effect, in which a simple action towards a prime stimulus biases attention in a subsequent visual search in favor of objects that match the prime. However, to date the majority of research on the phenomenon has studied search elements that are exact matches to the prime, and that vary only on the dimension of color, making it unclear how general the phenomenon is. Here, across a series of experiments, we show that action can also prioritize objects that match the shape of the prime. Additionally, action can prioritize attention to objects that match only one of either the color or the shape of the prime, suggesting that action enhances individual visual features present in the acted-on objects. The pattern of results suggests that the effect may be stronger for color matches – prioritization for shape only occurred when attention was not drawn to the color of the prime, whereas prioritization for color occurred regardless. Taken together, the results reveal that a prior action can exert a strong influence on subsequent attention towards features of the acted-on object. © 2021, The Author(s).

Author Keywords
Action;  Attention;  Visual search

Amygdala Activation in Cognitive Task fMRI Varies with Individual Differences in Cognitive Traits
(2021) Cognitive, Affective and Behavioral Neuroscience, . 

West, H.V.^a , Burgess, G.C.^a , Dust, J.^a , Kandala, S.^a , Barch, D.M.^a b c

^a Department of Psychiatry, Washington University, 4525 Scott Avenue, St. Louis, MO 63110, United States
^b Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
^c Department of Radiology, Washington University, St. Louis, MO, United States

Abstract
The amygdala has been implicated in processing threat and learning fear. However, the amygdala also responds to motivationally relevant stimuli even in the absence of explicit emotional content. We investigated the relationship among amygdala activation, cognitive and emotional factors, and fMRI task data in participants from the Young Adult Human Connectome Project. We expected to see variation in amygdala activation that corresponded with variation in traits that could affect the salience of task related stimuli (i.e., internalizing symptoms and fearful faces). We found no relationship between amygdala activation during face viewing and emotion related traits. However, amygdala activation under working memory load was negatively correlated with fluid intelligence and reading level. There also was a negative relationship between task performance and activation in the amygdala. The observed relationship suggests that the role of amygdala is not limited to the processing of emotional content of incoming information but is instead related to salience, which can be influenced by individual differences. © 2021, The Psychonomic Society, Inc.

Author Keywords
Amygdala;  Anxiety;  Cognitive control;  Emotion;  Working memory

Visual acuity, refractive error, and regression outcomes in 169 children with high myopia who were implanted with Ophtec-Artisan or Visian phakic IOLs
(2021) Journal of AAPOS, . 

Faron, N.^a , Hoekel, J.^a , Tychsen, L.^a b c

^a John F. Hardesty, MD, Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Department of Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Purpose: To analyze outcomes in a large cohort of spectacle-aversive children with high myopia who were treated by implantation of the Ophtec-Artisan or Visian phakic intraocular lens (pIOL). Methods: Outcome data were collated retrospectively in 78 children (115 eyes) implanted with the Ophtec-Artisan iris-enclaved anterior chamber pIOL and 91 children (154 eyes) implanted with the Visian ICL (intraocular collamer lens) sulcus pIOL. All children had difficulties with spectacle or contact lens wear. Mean age at surgery was 9.9 years; mean follow-up was 3.9 years (range, 0.6-14.1 years). Results: A total of 248 of 269 eyes (92%) were corrected to within ± 0.5 D of their target value. Spherical correction averaged 12.3 ± 1.0 D. Refractive spherical regression was −0.04 D/year at last follow-up. Uncorrected distance visual acuity improved from an average logMAR 1.8 to 0.4; corrected distance visual acuity improved an average 0.3 logMAR. Of the treated children, 68% had a gain in binocular fusion. Neurobehavioral and/or visuomotor comorbidities were present in 87% of children. Five eyes (2%) developed retinal detachment an average 6 years after implantation. Nine eyes (3%) implanted with the Ophtec-Artisan pIOL required repositioning after trauma. Conclusions: Implantation of pIOLs in children is an effective method for correcting high myopia in spectacle noncompliant children. Rates of myopic regression after pIOL surgery are substantially lower than those reported for children treated by excimer laser photorefractive keratectomy (PRK). The prevalence of major complications was relatively low in this high-risk population. © 2021 American Association for Pediatric Ophthalmology and Strabismus

Funding details
Research to Prevent BlindnessRPB

Primary and metastatic glioblastoma of the spine in the pediatric population: a systematic review
(2021) Child’s Nervous System, . 

Yang, R.^a , Isaacs, A.M.^b c , Cadieux, M.^c , Hirmer, T.J.^d , CreveCoeur, T.S.^e , Lapointe, A.P.^a , Opoku-Darko, M.^f , Premji, Z.^g , Riva-Cambrin, J.^c , Gallagher, C.N.^c

^a Cumming School of Medicine, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB, Canada
^b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Clinical Neuroscience, Section of Neurosurgery, University of Calgary, Calgary, AB, Canada
^d Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
^e Department of Neurological Surgery, Columbia University, New York, NY, United States
^f Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
^g Libraries and Cultural Resources, University of Calgary, Calgary, AB, Canada

Abstract
Pediatric glioblastoma multiforme (GBM) involving the spine is an aggressive tumor with a poor quality of life for patients. Despite this, there is only a limited number of reports describing the outcomes of pediatric spinal GBMs, both as primary spinal GBMs and metastases from an intracranial tumor. Here, we performed an individual patient meta-analysis to characterize factors affecting prognosis of pediatric spinal GBM. MEDLINE, Embase, and the Cochrane databases were searched for published studies on GBMs involving the spine in pediatric patients (age ≤ 21 years old). Factors associated with the survival were assessed with multi-factor ANOVAs, Cox hazard regression, and Kaplan-Meier analyses. We extracted data on 61 patients with spinal GBM from 40 studies that met inclusion criteria. Median survival was significantly longer in the primary spinal GBM compared that those with metastatic GBM (11 vs 3 months, p < 0.001). However, median survival of metastatic GBM patients was 10 months following diagnosis of their primary brain tumor, which was not different from that of primary spinal GBM patients (p = 0.457). Among primary spinal GBM patients, chemotherapy (hazard ratio (HR) = 0.255 [0.106–0.615], p = 0.013) and extent of resection (HR = 0.582 [0.374–0.905], p = 0.016) conferred a significant survival benefit. Younger age (less than 14 years) was associated with longer survival in patients treated with chemotherapy than those who did not undergo chemotherapy (β = − 1.12, 95% CI [− 2.20, − 0.03], p < 0.05). In conclusion, survival after presentation of metastases from intracranial GBM is poor in the pediatric population. In patients with metastatic GBM, chemotherapy may have provided the most benefit in young patients, and its efficacy might have an association with extent of surgical resection. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

Author Keywords
Glioblastoma multiforme;  Grade IV glioma;  Spinal metastasis

Correction to: De novo variants in SNAP25 cause an early-onset developmental and epileptic encephalopathy (Genetics in Medicine, (2020), 10.1038/s41436-020-01020-w)
(2021) Genetics in Medicine, . 

löckner, C.^a , Sticht, H.^b , Zacher, P.^c , Popp, B.^a , Babcock, H.E.^d , Bakker, D.P.^e , Barwick, K.^f , Bonfert, M.V.^g , Bönnemann, C.G.^h , Brilstra, E.H.ⁱ , Chung, W.K.^j , Clarke, A.J.^k , Devine, P.^l , Donkervoort, S.^h , Fraser, J.L.^m , Friedman, J.^n o , Gates, A.^p , Ghoumid, J.^q , Hobson, E.^r , Horvath, G.^s , Keller-Ramey, J.^t , Keren, B.^u , Kurian, M.A.^f , Lee, V.^v , Leppig, K.A.^p , Lundgren, J.^w , McDonald, M.T.^x , McLaughlin, H.M.^y , McTague, A.^f , Mefford, H.C.^z , Mignot, C.^aa , Mikati, M.A.^ab , Nava, C.^ac , Raymond, F.L.^ad ae , Sampson, J.R.^k , Sanchis-Juan, A.^ad af , Shashi, V.^x , Shieh, J.T.C.^ag ah , Shinawi, M.^ai , Slavotinek, A.^ag , Stödberg, T.^aj , Stong, N.^ak , Sullivan, J.A.^x , Taylor, A.C.^al , Toler, T.L.^ai , van den Boogaard, M.-J.ⁱ , van der Crabben, S.N.^am , van Gassen, K.L.I.ⁱ , van Jaarsveld, R.H.ⁱ , Van Ziffle, J.^l , Wadley, A.F.^an , Wagner, M.^ao , Wigby, K.^ap , Wortmann, S.B.^aq ar , Zarate, Y.A.^as , Møller, R.S.^at au , Lemke, J.R.^a , Platzer, K.^a , Care4Rare Canada Consortium^av

^a Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
^b Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
^c The Saxon Epilepsy Center Kleinwachau, Radeberg, Germany
^d Rare Disease Institute, Children’s National Hospital, Washington, DC, United States
^e Department of Child Neurology, Amsterdam University Medical Centers, Amsterdam, Netherlands
^f Institute of Child Health, University Collge London, London, United Kingdom
^g Department of Pediatric Neurology and Developmental Medicine and LMU Center for Children with Medical Complexity, Dr. von Hauner Children’s Hospital, LMU – University Hospital, LudwigMaximilians-Universität, Munich, Germany
^h Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
ⁱ Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
^j Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, United States
^k Division of Cancer & Genetics, School of Medicine, Cardiff University, Wales, United Kingdom
^l Department of Pathology, University of California San Francisco, San Francisco, CA, United States
^m Rare Disease Institute, Division of Genetics and Metabolism, Children’s National Hospital, Washington, DC, United States
ⁿ Departments of Neurosciences and Pediatrics, University of California San Diego and Division of Neurology, Rady Children’s Hospital, San Diego, CA, United States
^o Rady Children’s Institute for Genomic Medicine, San Diego, CA, United States
^p Department of Genetic Services, Kaiser Permanente Washington, Seattle, WA, United States
^q Service de Génétique Clinique, Hôpital Jeanne de Flandre, CHU Lille, Lille, France
^r Yorkshire Clinical Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom
^s Department of Pediatrics, Division of Biochemical Diseases, University of British Columbia, Vancouver, Canada
^t GeneDx, Gaithersburg, MD, United States
^u APHP, Département de Génétique, Groupe Hospitalier Pitié Salpêtrière, Paris, France
^v Department of Neurology, University of California San Francisco, San Francisco, CA, United States
^w Institute of Clinical Sciences, Skane University Hospital, Lund, Sweden
^x Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
^y Invitae Corporation, San Francisco, CA, United States
^z Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, United States
^aa Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et Hôpital Trousseau, APHP, Sorbonne Université, Paris, France
^ab Division of Pediatric Neurology, Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
^ac Sorbonne University, Paris Brain Institute, Inserm U1127, CNRS UMR 7225, AP-HP, Pitié Salpêtrière Hospital, Department of Genetics, Paris, France
^ad NIHR BioResource, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom
^ae Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
^af Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, United Kingdom
^ag Division of Medical Genetics, University of California, San Francisco, San Francisco, CA, United States
^ah Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, United States
^ai Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
^aj Department of Women’s and Children’s Health Karolinska Institutet, Stockholm, Sweden
^ak Institute for Genomic Medicine, Columbia University, New York, NY, United States
^al Section of Genetics, Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
^am Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
^an University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
^ao Institute of Neurogenomics, Helmholtz Zentrum Munich, Neuherberg, Germany
^ap Department of Pediatrics, Division of Genetics, University of California, San Diego and Rady Children’s Hospital-San Diego, San Diego, CA, United States
^aq Amalia Children’s Hospital, Radboud University Nijmegen, Nijmegen, Netherlands
^ar University Childrens Hospital, Paracelsus Medical University, Salzburg, Austria
^as Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^at Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
^au Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark

Abstract
Unfortunately, in the first sentence in the abstract, a spelling mistake was introduced during the production process after our proofreading. The wording was changed from “aims” to “aimsed.” Heather M. McLaughlin was not listed among the authors. The original article has been corrected. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

ALS Untangled #60: light therapy
(2021) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, . 

Bedlack, R.^a , Barkhaus, P.^b , Barnes, B.^c , Bereman, M.^d , Bertorini, T.^e , Carter, G.^f , Crayle, J.^g , Kihuwa-Mani, S.^h , Bowser, R.ⁱ , Kittrell, P.^j , McDermott, C.^k , Pattee, G.^l , Salmon, K.^m , Wicks, P.ⁿ

^a Department of Neurology, Duke University, Durham, NC, United States
^b Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States
^c Department of Neurology, Augusta University Medical Center, Augusta, GA, United States
^d Department of Chemistry, North Carolina State University, Raleigh, NC, United States
^e Department of Neurology, Methodist University Hospital, Memphis, TN, United States
^f Department of Neurology, St Lukes Rehabilitation Hospital, Chesterfield, MO, United States
^g Department of Neurology, Washington University in St Louis School of Medicine, St Louis, MO, United States
^h University of North Carolina at Greensboro, Lloyd International Honors College, Greensboro, NC, United States
ⁱ Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
^j Department of Neurology, University of Texas Health Science Center, Houston, TX, United States
^k Department of Neuroscience, University of Sheffield, Sheffield, United Kingdom
^l Department of Neurology, Nebraska Medicine, Omaha, NE, United States
^m Department of Neurology, McGill Centre for Research in Neuroscience, Montreal, QC, Canada
ⁿ Independent Consultant, United Kingdom

Abstract
ALSUntangled reviews alternative and off-label treatments for people with ALS. Here we review light therapy. We show that it has theoretically plausible mechanisms, three flawed pre-clinical data, studies, and one incompletely documented case report supporting its use. We explain why further studies are needed to determine whether any specific light therapy protocol can help people with ALS. © 2021 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.

Author Keywords
alternative therapy;  energy;  epidemiology;  ethics;  Light;  therapy