WashU weekly Neuroscience publications

Exercise routine change is associated with prenatal depression scores during the COVID-19 pandemic among pregnant women across the United States
(2021) PLoS ONE, 15 (12 December), art. no. e0243188, . 

Gildner, T.E.^a b , Laugier, E.J.^a c , Thayer, Z.M.^a c

^a Department of Anthropology, Dartmouth College, Hanover, NH, United States
^b Department of Anthropology, Washington University, St. Louis, MO, United States
^c Ecology, Evolution, Environment and Society Program, Dartmouth College, Hanover, NH, United States

Abstract
Background The COVID-19 pandemic has negatively affected physical and mental health worldwide. Pregnant women already exhibit an elevated risk for depression compared to the general public, a pattern expected to be exacerbated by the pandemic. Certain lifestyle factors, including moderate exercise, may help support mental health during pregnancy, but it is unclear how the pandemic may impact these associations across different locations. Here, we test whether: (i) reported exercise routine alterations during the pandemic are associated with depression scores; and, (ii) the likelihood of reporting pandemic-related exercise changes varies between women living in metro areas and those in non-metro areas. Methods This cross-sectional study used data from the COVID-19 And Reproductive Effects (CARE) study, an online survey of pregnant women in the United States. Participants were recruited April-June 2020 (n = 1,856). Linear regression analyses assessed whether reported COVID-19-related exercise change was associated with depression score as measured by the Edinburgh Postnatal Depression Survey. Logistic regression analyses tested whether a participant’s Rural-Urban Continuum Code classification of “metro” was linked with higher odds of reporting exercise changes compared to a “non-metro” classification. Results Women who reported exercise changes during the pandemic exhibited significantly higher depression scores compared to those reporting no changes. Moreover, individuals living in metro areas of all sizes were significantly more likely to report exercise changes compared to women living in non-metro areas. Conclusions These results suggest that the ability to maintain an exercise routine during the pandemic may help support maternal mental health. It may therefore be prudent for providers to explicitly ask patients how the pandemic has impacted their exercise routines and consider altered exercise routines a potential risk factor for depression. An effort should also be made to recommend exercises that are tailored to individual space restrictions and physical health. © 2021 Gildner et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Precision functional mapping of the subcortex and cerebellum
(2021) Current Opinion in Behavioral Sciences, 40, pp. 12-18. 

Marek, S.^a , Greene, D.J.^b

^a Department of Psychiatry, Washington University School of Medicine, United States
^b Department of Cognitive Science, University of California San Diego, United States

Abstract
Human functional brain networks can be reliably characterized within individuals using precision functional mapping. This approach entails the collection of large quantities of functional magnetic resonance imaging (fMRI) data from each individual subject. Studies employing precision functional mapping in the cerebral cortex have found that individuals manifest unique representations of functional brain networks around a central tendency described by previous group average approaches. We recently extended precision functional mapping to the subcortex and cerebellum, which has revealed several novel organizational principles within these structures. Here, we detail these principles and provide insights into how precision functional mapping of subcortical structures and the cerebellum may become clinically translatable. © 2021 Elsevier Ltd

Funding details
R01 MH104592, K99 MH121518

Leveraging COVID-19 to sustain regulatory flexibility in the treatment of opioid use disorder
(2021) Journal of Substance Abuse Treatment, 123, art. no. 108263, . 

Stringer, K.L.^a b , Langdon, K.J.^c , McKenzie, M.^d , Brockmann, B.^e , Marotta, P.^b f

^a Social Intervention Group, Columbia University, New York, NY, United States
^b The Lifespan/Brown Criminal Justice Research Training Program on Substance Use, HIV, and Comorbidities, Center for Prisoner Health and Human Rights, Brown University, United States
^c Department of Psychiatry, Rhode Island Hospital, United States
^d The Miriam Hospital/Brown Alpert Medical School, United States
^e Dept. of Health Services, Policy and Practice, Brown University School of Public Health, United States
^f Washington University in St. Louis, United States

Abstract
The U.S. government declared the opioid epidemic as a national public health emergency in 2017, but regulatory frameworks that govern the treatment of opioid use disorder (OUD) through pharmaceutical interventions have remained inflexible. The emergence of the COVID-19 pandemic has effectively removed regulatory restrictions that experts in the field of medications for opioid use disorder (MOUD) have been proposing for decades and has expanded access to care. The regulatory flexibilities implemented to avoid unnecessary COVID-related death must be made permanent to ensure that improved access to evidence-based treatment remains available to vulnerable individuals with OUD who otherwise face formidable barriers to MOUD. We must seize this moment of COVOD-19 regulatory flexibilities to demonstrate the feasibility, acceptability, and safety of delivering treatment for OUD through a low-threshold approach. © 2020 Elsevier Inc.

Author Keywords
Barriers to care;  Buprenorphine;  Medications for opioid use disorder;  Opioid use disorder;  Regulations;  Structural stigma

Funding details
National Institute on Drug AbuseNIDA

Modelling white matter in gyral blades as a continuous vector field
(2021) NeuroImage, 227, art. no. 117693, . 

Cottaar, M.^a , Bastiani, M.^a b , Boddu, N.^a , Glasser, M.F.^c d e , Haber, S.^f g , van Essen, D.C.^c , Sotiropoulos, S.N.^a b , Jbabdi, S.^a

^a Wellcome Centre for Integrative Neuroimaging (WIN), Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, United Kingdom
^b Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, United Kingdom
^c Department of Neuroscience, Washington University Medical School, Saint Louis, MO 63110, United States
^d Department of Radiology, Washington University Medical School, Saint Louis, MO 63110, United States
^e St. Luke’s Hospital, Saint Louis, MO 63017, United States
^f McLean Hospital, Harvard Medical School, Belmont, United States
^g Department of Pharmacology and Physiology, University of Rochester School of Medicine & Dentistry, Rochester, United States

Abstract
Many brain imaging studies aim to measure structural connectivity with diffusion tractography. However, biases in tractography data, particularly near the boundary between white matter and cortical grey matter can limit the accuracy of such studies. When seeding from the white matter, streamlines tend to travel parallel to the convoluted cortical surface, largely avoiding sulcal fundi and terminating preferentially on gyral crowns. When seeding from the cortical grey matter, streamlines generally run near the cortical surface until reaching deep white matter. These so-called “gyral biases” limit the accuracy and effective resolution of cortical structural connectivity profiles estimated by tractography algorithms, and they do not reflect the expected distributions of axonal densities seen in invasive tracer studies or stains of myelinated fibres. We propose an algorithm that concurrently models fibre density and orientation using a divergence-free vector field within gyral blades to encourage an anatomically-justified streamline density distribution along the cortical white/grey-matter boundary while maintaining alignment with the diffusion MRI estimated fibre orientations. Using in vivo data from the Human Connectome Project, we show that this algorithm reduces tractography biases. We compare the structural connectomes to functional connectomes from resting-state fMRI, showing that our model improves cross-modal agreement. Finally, we find that after parcellation the changes in the structural connectome are very minor with slightly improved interhemispheric connections (i.e, more homotopic connectivity) and slightly worse intrahemispheric connections when compared to tracers. © 2020

Author Keywords
connectome;  diffusion MRI;  gyral bias;  tractography

Funding details
215573/Z/19/Z, MR/L009013/1
Wellcome TrustWT203139/Z/16/Z, 217266/Z/19/Z, 1U54MH091657
NIH Blueprint for Neuroscience Research
Engineering and Physical Sciences Research CouncilEPSRCEP/L023067/1/
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience

Rare and de novo coding variants in chromodomain genes in Chiari I malformation
(2021) American Journal of Human Genetics, 108 (1), pp. 100-114. 

Sadler, B.^a , Wilborn, J.^b , Antunes, L.^c , Kuensting, T.^b , Hale, A.T.^d , Gannon, S.R.^e , McCall, K.^c , Cruchaga, C.^f , Harms, M.^g , Voisin, N.^h , Reymond, A.^h , Cappuccio, G.^i j , Burnetti-Pierri, N.^i j , Tartaglia, M.^k , Niceta, M.^k , Leoni, C.^l , Zampino, G.^l , Ashley-Koch, A.^m , Urbizu, A.^m , Garrett, M.E.^m , Soldano, K.^m , Macaya, A.ⁿ , Conrad, D.^o , Strahle, J.^b , Dobbs, M.B.^c p , Turner, T.N.^s , Shannon, C.N.^d , Brockmeyer, D.^q , Limbrick, D.D.^b , Gurnett, C.A.^a c r , Haller, G.^b r s

^a Department of Pediatrics, Washington University, St. Louis, MO 63110, United States
^b Department of Neurosurgery, Washington University, St. Louis, MO 63110, United States
^c Department of Orthopaedic Surgery, Washington University, St. Louis, MO 63110, United States
^d Division of Genetic Medicine, Vanderbilt University Medical Center & Medical Scientist Training Program, Vanderbilt University School of Medicine, Nashville, TN 37232, United States
^e Division of Pediatric Neurosurgery and Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN 37232, United States
^f Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
^g Department of Neurology, Columbia University, New York, NY 10027, United States
^h Center for Integrative Genomics (CIG), University of Lausanne, Lausanne, 1015, Switzerland
ⁱ Department of Translational Medicine, Section of Pediatrics, Federico II University, Naples, 80138, Italy
^j Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, 80078, Italy
^k Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, 00165, Italy
^l Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione-Policlinico-Universitario-A. Gemelli-IRCCS, Rome, 00168, Italy
^m Duke Molecular Physiology Institute, Department of Medicine, Duke University, Durham, NC 27708, United States
ⁿ Pediatric Neurology Research group, University Hospital Vall d’Hebron, Barcelona, 08035, Spain
^o Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006, United States
^p Shriners Hospital for Children, St. Louis, MO 63110, United States
^q Department of Neurological Surgery, University of Utah, Primary Children’s Hospital, Salt Lake City, UT 84113, United States
^r Department of Neurology, Washington University, St. Louis, MO 63110, United States
^s Department of Genetics, Washington University, St. Louis, MO 63110, United States

Abstract
Chiari I malformation (CM1), the displacement of the cerebellum through the foramen magnum into the spinal canal, is one of the most common pediatric neurological conditions. Individuals with CM1 can present with neurological symptoms, including severe headaches and sensory or motor deficits, often as a consequence of brainstem compression or syringomyelia (SM). We conducted whole-exome sequencing (WES) on 668 CM1 probands and 232 family members and performed gene-burden and de novo enrichment analyses. A significant enrichment of rare and de novo non-synonymous variants in chromodomain (CHD) genes was observed among individuals with CM1 (combined p = 2.4 × 10−10), including 3 de novo loss-of-function variants in CHD8 (LOF enrichment p = 1.9 × 10−10) and a significant burden of rare transmitted variants in CHD3 (p = 1.8 × 10−6). Overall, individuals with CM1 were found to have significantly increased head circumference (p = 2.6 × 10−9), with many harboring CHD rare variants having macrocephaly. Finally, haploinsufficiency for chd8 in zebrafish led to macrocephaly and posterior hindbrain displacement reminiscent of CM1. These results implicate chromodomain genes and excessive brain growth in CM1 pathogenesis. © 2020 American Society of Human Genetics

Author Keywords
Chiari I malformation;  chromodomain genes;  de novo mutations;  gene burden;  macrocephaly;  rare variants;  zebrafish disease model

Small Molecule SARM1 Inhibitors Recapitulate the SARM1−/− Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate
(2021) Cell Reports, 34 (1), art. no. 108588, . 

Hughes, R.O.^a , Bosanac, T.^a , Mao, X.^b , Engber, T.M.^a , DiAntonio, A.^c d , Milbrandt, J.^b d , Devraj, R.^a , Krauss, R.^a

^a Disarm Therapeutics, a wholly owned subsidiary of Eli Lilly & Co, Cambridge, MA 02142, United States
^b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Axonal degeneration is prevalent in neurodegenerative disorders of the central and peripheral nervous systems. Hughes et al. developed potent small molecule inhibitors of SARM1, a central driver of axonal degeneration, that protect axons and allow recovery of already-injured axons that otherwise would degenerate. SARM1 inhibition may treat axonal degeneration. © 2020 The Author(s)

Axonal degeneration is responsible for disease progression and accumulation of disability in many neurodegenerative conditions. The axonal degenerative process can generate a metastable pool of damaged axons that remain structurally and functionally viable but fated to degenerate in the absence of external intervention. SARM1, an NADase that depletes axonal energy stores upon activation, is the central driver of an evolutionarily conserved program of axonal degeneration. We identify a potent and selective small molecule isoquinoline inhibitor of SARM1 NADase that recapitulates the SARM1−/− phenotype and protects axons from degeneration induced by axotomy or mitochondrial dysfunction. SARM1 inhibition post-mitochondrial injury with rotenone allows recovery and rescues axons that already entered the metastable state. We conclude that SARM1 inhibition with small molecules has the potential to treat axonopathies of the central and peripheral nervous systems by preventing axonal degeneration and by allowing functional recovery of a metastable pool of damaged, but viable, axons. © 2020 The Author(s)

Author Keywords
ALS;  axonal degeneration;  axonopathy;  CIPN;  multiple sclerosis;  neurodegeneration;  neuropathy;  SARM1;  Wallerian;  WldS

Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy
(2021) Journal of Psychiatry & Neuroscience: JPN, 46 (1), pp. E88-E96. 

Lissemore, J.I., Mulsant, B.H., Rajji, T.K., Karp, J.F., Reynolds, C.F., Lenze, E.J., Downar, J., Chen, R., Daskalakis, Z.J., Blumberger, D.M.

From the Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Lissemore, Rajji, Daskalakis, Blumberger); the Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Lissemore, Mulsant, Rajji, Downar, Daskalakis, Blumberger); the Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ont., Canada (Mulsant, Rajji, Daskalakis, Blumberger); the Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA (Karp, Reynolds); the Healthy Mind Lab, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA (Lenze); the MRI-Guided rTMS Clinic and Krembil Research Institute, University Health Network, Toronto, Ont., Canada (Downar); and the Division of Neurology, Department of Medicine, University of Toronto and Krembil Research Institute Toronto, Ont., Canada (Chen)

Abstract
BACKGROUND: Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown. METHODS: Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment. RESULTS: Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology. LIMITATIONS: The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex. CONCLUSION: These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities. © 2021 Joule Inc. or its licensors

Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders
(2021) Journal of Psychiatry & Neuroscience: JPN, 46 (1), pp. E97-E110. 

Lenze, E.J., Nicol, G.E., Barbour, D.L., Kannampallil, T., Wong, A.W.K., Piccirillo, J., Drysdale, A.T., Sylvester, C.M., Haddad, R., Miller, J.P., Low, C.A., Lenze, S.N., Freedland, K.E., Rodebaugh, T.L.

From the Washington University School of Medicine, St. Louis, Missouri (Lenze, Nicol, Kannampallil Wong, Piccirillo, Drysdale, Sylvester, Haddad, Miller, Lenze, Freedland); the Washington University McKelvey School of Engineering, St. Louis, MO (Barbour); the University of Pittsburgh, Pittsburgh, PA (Low); and the Washington University School of Arts & Sciences, St. Louis, MO (Rodebaugh)

Abstract
The goal of precision medicine (individually tailored treatments) is not being achieved for neurobehavioural conditions such as psychiatric disorders. Traditional randomized clinical trial methods are insufficient for advancing precision medicine because of the dynamic complexity of these conditions. We present a pragmatic solution: the precision clinical trial framework, encompassing methods for individually tailored treatments. This framework includes the following: (1) treatment-targeted enrichment, which involves measuring patients’ response after a brief bout of an intervention, and then randomizing patients to a full course of treatment, using the acute response to predict long-term outcomes; (2) adaptive treatments, which involve adjusting treatment parameters during the trial to individually optimize the treatment; and (3) precise measurement, which involves measuring predictor and outcome variables with high accuracy and reliability using techniques such as ecological momentary assessment. This review summarizes precision clinical trials and provides a research agenda, including new biomarkers such as precision neuroimaging, transcranial magnetic stimulation-electroencephalogram digital phenotyping and advances in statistical and machine-learning models. Validation of these approaches – and then widespread incorporation of the precision clinical trial framework – could help achieve the vision of precision medicine for neurobehavioural conditions. © 2021 Joule Inc. or its licensors

Practicing Retrieval Facilitates Learning
(2021) Annual Review of Psychology, 72, pp. 609-633. 

McDermott, K.B.

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

Abstract
How do we go about learning new information? This article reviews the importance of practicing retrieval of newly experienced information if one wants to be able to retrieve it again in the future. Specifically, practicing retrieval shortly after learning can slow the forgetting process. This benefit can be seen across various material types, and it seems prevalent in all ages and learner abilities and on all types of test. It can also be used to enhance student learning in a classroom setting. I review theoretical understanding of this phenomenon (sometimes referred to as the testing effect or as retrieval-based learning) and consider directions for future research. © 2021 Annual Reviews Inc.. All rights reserved.

Author Keywords
learning;  memory;  retrieval practice;  retrieval-based learning;  testing effect

TLR3 controls constitutive IFN-β antiviral immunity in human fibroblasts and cortical neurons
(2021) Journal of Clinical Investigation, 131 (1), art. no. e134529, . 

Gao, D.^a b c , Ciancanelli, M.J.^a d , Zhang, P.^a , Harschnitz, O.^e f , Bondet, V.^g , Hasek, M.^a , Chen, J.^a , Mu, X.^h , Itan, Y.^i j , Cobat, A.^k l , Sancho-Shimizu, V.^k l m , Bigio, B.^a , Lorenzo, L.^k l , Ciceri, G.^e f , McAlpine, J.^e f , Anguiano, E.ⁿ , Jouanguy, E.^a k l , Chaussabel, D.^n o p , Meyts, I.^q r s , Diamond, M.S.^t , Abel, L.^a k l , Hur, S.^h , Smith, G.A.^u , Notarangelo, L.^v , Duffy, D.^g , Studer, L.^e f , Casanova, J.-L.^{a k l w x} , Zhang, S.-Y.^a k l

^a St.Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, United States
^b Department of General Surgery, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
^c Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
^d Turnstone Biologics, New York, NY, United States
^e The Center for Stem Cell Biology, Sloan-Kettering Institute for Cancer Research, New York, NY, United States
^f Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, United States
^g Translational Immunology Laboratory, Pasteur Institute, Paris, France
^h Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, United States
ⁱ The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^j Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^k Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Paris, France
^l Paris Descartes University, Imagine Institute, Paris, France
^m Department of Paediatric Infectious Diseases, Division of Medicine, Imperial College London, Norfolk Place, United Kingdom
ⁿ Baylor Institute for Immunology Research, ANRS Center for Human Vaccines, INSERM U899, Dallas, TX, United States
^o Benaroya Research Institute, Seattle, WA, United States
^p Sidra Medicine, Doha, Qatar
^q Laboratory of Inborn Errors of Immunity, Department of Immunology and Microbiology, KU Leuven, Leuven, Belgium
^r Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
^s Precision Immunology Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^t Departments of Medicine Molecular Microbiology Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
^u Department of Microbiology-Immunology, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
^v Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, United States
^w Pediatric Immunology-Hematology Unit, Necker Hospital for Sick Children, Paris, France
^x Howard Hughes Medical Institute, New York, NY, United States

Abstract
Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/β induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-β protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-β secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-β immunity. © 2021, American Society for Clinical Investigation.

Funding details
KU LeuvenC16/18/007
Institut National de la Santé et de la Recherche MédicaleInserm
Rockefeller University
St. Giles Foundation
Université Paris Descartes
National Institutes of HealthNIHUL1TR001866, R01NS072381, R21AI151663, R01AI088364
Agence Nationale de la RechercheANRANR-10-IAHU-01
ANR-14-CE14-0008-01, ANR-10-LABX-62-IBEID, ANR-18-CE15-0020-02
G0C8517N
National Center for Advancing Translational SciencesNCATS
National Natural Science Foundation of ChinaNSFC319708550
Charles H. Revson Foundation

Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins
(2021) Journal of Clinical Investigation, 131 (1), art. no. e139807, . 

Mo, J.^a , Anastasaki, C.^b , Chen, Z.^a , Shipman, T.^a , Papke, J.^b , Yin, K.^a , Gutmann, D.H.^b , Le, L.Q.^a c d

^a Department of Dermatology, UT Southwestern Medical Center, Dallas, TX, United States
^b Department of Neurology, Washington University, School of Medicine in St. Louis, St. Louis, MO, United States
^c Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States
^d Hamon Center for Regenerative Science and Medicine, UT Southwestern Medical Center, Dallas, TX, United States

Abstract
Neurofibromatosis type 1 (NF1) is a common tumor predisposition syndrome caused by NF1 gene mutation, in which affected patients develop Schwann cell lineage peripheral nerve sheath tumors (neurofibromas). To investigate human neurofibroma pathogenesis, we differentiated a series of isogenic, patient-specific NF1-mutant human induced pluripotent stem cells (hiPSCs) into Schwannian lineage cells (SLCs). We found that, although WT and heterozygous NF1-mutant hiPSCs-SLCs did not form tumors following mouse sciatic nerve implantation, NF1-null SLCs formed bona fide neurofibromas with high levels of SOX10 expression. To confirm that SOX10+ SLCs contained the cells of origin for neurofibromas, both Nf1 alleles were inactivated in mouse Sox10+ cells, leading to classic nodular cutaneous and plexiform neurofibroma formation that completely recapitulated their human counterparts. Moreover, we discovered that NF1 loss impaired Schwann cell differentiation by inducing a persistent stem-like state to expand the pool of progenitors required to initiate tumor formation, indicating that, in addition to regulating MAPK-mediated cell growth, NF1 loss also altered Schwann cell differentiation to promote neurofibroma development. Taken together, we established a complementary humanized neurofibroma explant and, to our knowledge, first-in-kind genetically engineered nodular cutaneous neurofibroma mouse models that delineate neurofibroma pathogenesis amenable to future therapeutic target discovery and evaluation. © 2021, American Society for Clinical Investigation.

Funding details
U54 CA 196519, R01 CA166593
National Cancer InstituteNCIR50CA233164
U.S. Department of DefenseDODW81XWH1910687
National Institutes of HealthNIHR35 NS097211

The Brain-Gut-Microbiotal Axis: A framework for understanding functional GI illness and their therapeutic interventions
(2021) European Journal of Internal Medicine, . 

Tait, C.^a , Sayuk, G.S.^a b c

^a Department of Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Psychiatry at Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Gastroenterology Section, St. Louis Veterans Affairs Medical Center, St. Louis, MO, United States

Abstract
Functional gastrointestinal disorders (FGIDs), characterized by chronic abdominal complaints without a structural or biochemical cause, are common diseases that are frequently encountered by specialists in internal medicine. Collectively, irritable bowel syndrome (IBS) and functional dyspepsia are estimated to affect up to 22% of the population, and are often associated with additional somatic and pain complaints, all without an obvious structural source [1,2]. An appreciation of the current understanding of the mechanistic basis for these disorders is key to developing treatment goals and optimization of patient management strategies. In recent years, the brain-gut axis increasingly has been recognized as a central factor in the experience of functional abdominal pain disorders, including the most recent Rome IV guidelines which identify FGIDs as disorders of gut-brain interaction [3]. The brain-gut axis (BGA), simply defined, is a complex network of bidirectional communication between the central and enteric nervous systems. This axis broadly includes all the systems involved with communication between the GI tract and central nervous system (CNS), with principle inputs into this network occurring between the CNS, enteric nervous system (ENS), and autonomic nervous systems (ANS), but also includes interfaces with numerous other factors, including endocrine hormones and immune effector cells as well as interactions with the gut microbiota. Perturbances to this system have been found to play a critical role in the development of visceral hypersensitivity, bowel dysregulation, and mood. This review will summarize the principle processes involved in the neurologic and biologic function of the brain-gut axis, our current understanding of its role in functional GI disorders, and potential targets for therapeutic intervention. © 2021

Author Keywords
Brain gut axis;  enteric nervous system;  functional gastrointestinal disorders;  microbiota

Reduced gray-white matter contrast localizes the motor cortex on double inversion recovery (DIR) 3T MRI
(2021) Neuroradiology, . 

Joshi, H.^a , Hoch, M.J.^b , Braileanu, M.^c , Gore, A.^d , Willie, J.T.^e , Hu, R.^a

^a Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA, United States
^b Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Radiology, Division of Neuroradiology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States
^d Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
^e Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Purpose: Reduced gray-white matter contrast along the central sulcus has been described on T1- and T2-weighted magnetic resonance imaging (MRI). The purpose of this study was to assess the gray-white matter contrast of the motor cortex on double inversion recovery (DIR), a sequence with superior gray-white matter differentiation. Methods: The gray-white matter signal on DIR was retrospectively compared to T1-weighted magnetization-prepared rapid gradient echo (T1-MPRAGE) using normal (n = 25) and abnormal (n = 25) functional MRI (fMRI) exams. Quantitative gray-white matter contrast ratios (CR) of the precentral and adjacent gyri were obtained on normal exams. Two neuroradiologists qualitatively rated reduced gray-white matter contrast of the hemispheres of both normal and abnormal exams. Hand motor functional mapping was used as a reference. Results: In normal hemispheres (n = 50), the mean CR was significantly lower on DIR (0.44) vs T1-MPRAGE (0.63, p < 0.001). Reduced gray-white matter contrast was categorized as “definitely present” more frequently on DIR than T1-MPRAGE by reviewers in both normal (n = 50; reviewer 1 DIR 88% and MPRAGE 68%, p = 0.02; reviewer 2 DIR 86% and T1-MPRAGE 64%; p=0.01) and abnormal hemispheres (n = 50; reviewer 1 DIR 80% and T1-MPRAGE 38%, p < 0.001; reviewer 2 DIR 74% and T1-MPRAGE 46%, p = 0.005). Conclusion: Reduced gray-white matter contrast of the motor cortex is more pronounced on DIR compared to T1-MPRAGE on quantitative and qualitative assessments of normal MRI exams. In abnormal cases, reviewers more definitively identified the motor cortex on DIR. In cases with distorted brain anatomy, DIR may be a useful adjunct sequence to localize the motor cortex. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

Author Keywords
3D T1-weighted magnetization-prepared rapid gradient echo (T1-MPRAGE);  Double inversion recovery (DIR);  fMRI;  Gray-white matter junction;  Motor cortex

Head tremor and pain in cervical dystonia
(2021) Journal of Neurology, . 

Vu, J.P.^a , Lee, H.Y.^a , Chen, Q.^a , Cisneros, E.^a , Barbano, R.L.^b , Goetz, C.G.^c , Jankovic, J.^d , Jinnah, H.A.^e , Perlmutter, J.S.^f g , Berman, B.D.^h , Appelbaum, M.I.ⁱ , Stebbins, G.T.^c , Comella, C.L.^c , Peterson, D.A.^a j

^a Institute for Neural Computation, University of California, La Jolla, San Diego, CA, United States
^b Department of Neurology, University of Rochester, Rochester, NY, United States
^c Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^d Department of Neurology, Parkinson’s Disease Center and Movement Disorders Clinic, Baylor College of Medicine, Houston, TX, United States
^e Departments of Neurology and Human Genetics, Emory University, Atlanta, GA, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
ⁱ Department of Psychology, University of California, La Jolla, San Diego, CA, United States
^j Computational Neurobiology Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, La Jolla, San Diego, CA 92037, United States

Abstract
Background: Although head tremor (HT) and pain are prevalent in cervical dystonia (CD), their joint relationship to phenotypic features of focal dystonia remains unclear. Objectives: We examined how severity of HT and pain are associated with age of CD onset and duration, and whether HT subtypes (“jerky” or “regular”) exhibit distinct relationships between severity of HT and pain. Methods: The severity of HT and pain were assessed with the Toronto Western Spasmodic Torticollis Rating Scale in retrospective review of 188 CD patients recruited through the Dystonia Coalition. Results: HT severity was associated with longer CD duration (p < 0.0005), whereas pain severity was associated with younger age at onset (p = 0.043). HT severity and pain severity were not correlated for jerky HT (p = 0.996), but positively correlated for regular HT (p = 0.01). Conclusions: The distinct associations of HT and pain with age at onset, disease duration, and HT subtype further characterize the heterogeneity of CD’s clinical presentation and suggest similarly heterogeneous underlying mechanisms. © 2021, Springer-Verlag GmbH, DE part of Springer Nature.

Author Keywords
Cervical dystonia;  Dystonic tremor;  Head tremor;  Pain

Funding details
National Center for Advancing Translational SciencesNCATSU54 TR001456
Office of the Assistant Secretary for HealthOASHW81XWH-17-1-0393
National Institute of Neurological Disorders and StrokeNINDSU54 NS116025, U54 NS065701

A Brief Digital Cognitive Assessment for Detection of Cognitive Impairment in Cuban Older Adults
(2021) Journal of Alzheimer’s Disease, 79 (1), pp. 85-94. 

Rodríguez-Salgado, A.M.^a b , Llibre-Guerra, J.J.^a b c , Tsoy, E.^d , Peñalver-Guia, A.I.^a , Bringas, G.^a , Erlhoff, S.J.^d , Kramer, J.H.^b d , Allen, I.E.^e , Valcour, V.^b d , Miller, B.L.^b d , Llibre-Rodríguez, J.J.^f , Possin, K.L.^b d

^a Department of Neurology, National Institute of Neurology and Neurosurgery, La Havana, Cuba
^b Global Brain Health Institute, University of California San Francisco, San Francisco, CA, United States
^c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^d Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, United States
^e Department of Epidemiology Biostatistics, University of California, San Francisco, CA, United States
^f Alzheimer Research Center, Havana School of Medicine, La Havana, Cuba

Abstract
Background: Rapid technological advances offer a possibility to develop cost-effective digital cognitive assessment tools. However, it is unclear whether these measures are suitable for application in populations from Low and middle-income countries (LMIC). Objective: To examine the accuracy and validity of the Brain Health Assessment (BHA) in detecting cognitive impairment in a Cuban population. Methods: In this cross-sectional study, 146 participants (cognitively healthy = 53, mild cognitive impairment (MCI) = 46, dementia = 47) were recruited at primary care and tertiary clinics. The main outcomes included: accuracy of the BHA and the Montreal Cognitive Assessment (MoCA) in discriminating between controls and cognitively impaired groups (MCI and dementia) and correlations between the BHA subtests of memory, executive functions, and visuospatial skills and criterion-standard paper-and-pencil tests in the same domains. Results: The BHA had an AUC of 0.95 (95% CI: 0.91-0.98) in discriminating between controls and cognitively impaired groups (MCI and dementia, combined) with 0.91 sensitivity at 0.85 specificity. In discriminating between control and MCI groups only, the BHA tests had an AUC of 0.94 (95% CI: 0.90-0.99) with 0.71 sensitivity at 0.85 specificity. Performance was superior to the MoCA across all diagnostic groups. Concurrent and discriminant validity analyses showed moderate to strong correlations between the BHA tests and standard paper-and-pencil measures in the same domain and weak correlations with standard measures in unrelated domains. Conclusion: The BHA has excellent performance characteristics in detecting cognitive impairment including dementia and MCI in a Hispanic population in Cuba and outperformed the MoCA. These results support potential application of digital cognitive assessment for older adults in LMIC. © 2021-IOS Press. All rights reserved.

Author Keywords
Mild cognitive impairment;  primary care;  tablet-based cognitive screening

A voxel-wise assessment of growth differences in infants developing autism spectrum disorder
(2021) NeuroImage: Clinical, 29, art. no. 102551, . 

Cárdenas-de-la-Parra, A.^a , Lewis, J.D.^a , Fonov, V.S.^a , Botteron, K.N.^b , McKinstry, R.C.^b , Gerig, G.^c , Pruett, J.R., Jr.^d , Dager, S.R.^e , Elison, J.T.^f , Styner, M.A.^g , Evans, A.C.^a , Piven, J.^g , Collins, D.L.^a , for the IBIS Network^h

^a Montreal Neurological Institute, McGill University, Montreal, QC H3A 0G4, Canada
^b Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO 63110, United States
^c Tandon School of Engineering, New York University, New York, New York, 10003, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Radiology, University of Washington, Seattle, WA 98105, United States
^f Institute of Child Development, University of Minnesota, Minneapolis, MN 55455, United States
^g Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, United States

Abstract
Autism Spectrum Disorder (ASD) is a phenotypically and etiologically heterogeneous developmental disorder typically diagnosed around 4 years of age. The development of biomarkers to help in earlier, presymptomatic diagnosis could facilitate earlier identification and therefore earlier intervention and may lead to better outcomes, as well as providing information to help better understand the underlying mechanisms of ASD. In this study, magnetic resonance imaging (MRI) scans of infants at high familial risk, from the Infant Brain Imaging Study (IBIS), at 6, 12 and 24 months of age were included in a morphological analysis, fitting a mixed-effects model to Tensor Based Morphometry (TBM) results to obtain voxel-wise growth trajectories. Subjects were grouped by familial risk and clinical diagnosis at 2 years of age. Several regions, including the posterior cingulate gyrus, the cingulum, the fusiform gyrus, and the precentral gyrus, showed a significant effect for the interaction of group and age associated with ASD, either as an increased or a decreased growth rate of the cerebrum. In general, our results showed increased growth rate within white matter with decreased growth rate found mostly in grey matter. Overall, the regions showing increased growth rate were larger and more numerous than those with decreased growth rate. These results detail, at the voxel level, differences in brain growth trajectories in ASD during the first years of life, previously reported in terms of overall brain volume and surface area. © 2021 The Authors

Author Keywords
Autism spectrum disorder;  Longitudinal neuroimaging;  Neurodevelopmental disorders;  Tensor based morphometry

Funding details
National Institutes of HealthNIH
National Institute of Child Health and Human DevelopmentNICHDHD 055741
Simons Foundation Autism Research InitiativeSFARI140209
Autism SpeaksAS
Azrieli FoundationBC_Azrieli_MIRI_3388
Simons FoundationSF

Gait features of dystonia in cerebral palsy
(2021) Developmental Medicine and Child Neurology, . 

Aravamuthan, B.R., Ueda, K., Miao, H., Gilbert, L., Smith, S.E., Pearson, T.S.

Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States

Abstract
Aim: To determine the features cited by motor phenotyping experts when identifying dystonia in people with cerebral palsy (CP). Method: Dystonia identification in CP, particularly when comorbid with spasticity, can be difficult. The dystonia diagnostic criterion standard remains subjective visual identification by expert consensus. For this qualitative study, we conducted an inductive thematic analysis of consensus-building discussions between three pediatric movement disorder physicians as they identified the presence or absence of dystonia in gait videos of 40 participants with spastic CP and periventricular leukomalacia. Results: Unanimous consensus about the presence or absence of dystonia was achieved for 34 out of 40 videos. Two main themes were present during consensus-building discussions as videos were evaluated for dystonia: (1) unilateral leg or foot adduction that was variable over time, and (2) difficulty in identifying dystonia. Codes contributing to the first theme were more likely to be cited by a discussant when they felt dystonia was present (as opposed to absent) in a video (χ2 test, p=0.004). Discussion: These results describe the gait features cited by experts during consensus-building discussion as they identify dystonia in ambulatory people with CP. Qualitative thematic analysis of these discussions could help codify the subjective process of dystonia diagnosis. © 2021 Mac Keith Press

Funding details
National Institute of Neurological Disorders and StrokeNINDS5K12NS098482‐02
National Institute of Neurological Disorders and StrokeNINDS

Flortaucipir (tau) PET in LGI1 antibody encephalitis
(2021) Annals of Clinical and Translational Neurology, . 

Day, G.S.^a , Gordon, B.A.^b c , McCullough, A.^b c , Bucelli, R.C.^b d , Perrin, R.J.^b d e , Benzinger, T.L.S.^b c , Ances, B.M.^b c d

^a Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^b Washington University School of Medicine, Saint Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Saint Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine in Saint Louis Jacksonville, Saint Louis, MO, United States
^e Department of Pathology and Immunology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States

Abstract
The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with [18F]flortaucipir PET neuroimaging associated with persistent cognitive impairment and hippocampal atrophy in four recovering LGI1 patients (3 men; median age, 67 [37–88] years). Imaging findings in cases were compared with those observed in age- and gender-similar cognitively normal individuals (n = 124) and individuals with early-symptomatic Alzheimer disease (n = 11). Elevated [18F]flortaucipir retention was observed in the two LGI1 patients with hippocampal atrophy and persistent cognitive impairment, including one with autopsy-confirmed Alzheimer disease. Tau neuropathology may associate with cognitive complaints and hippocampal atrophy in recovering LGI1 patients. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Funding details
National Institutes of HealthNIHR01AG057680, K01AG053474, P01AG003991, K23AG064029, P50AG005681, P01AG026276, R01AG052550
National Institutes of HealthNIHR01AG057680, K01AG053474, P01AG003991, K23AG064029, P50AG005681, P01AG026276, R01AG052550
National Institutes of HealthNIHK23AG064029

Association between APOE Alleles and Change of Neuropsychological Tests in the Long Life Family Study
(2021) Journal of Alzheimer’s Disease, 79 (1), pp. 117-125. 

Du, M.^a , Andersen, S.L.^b , Schupf, N.^c d , Feitosa, M.F.^e , Barker, M.S.^c , Perls, T.T.^b , Sebastiani, P.^f

^a Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^b Geriatrics Section, Department of Medicine, Boston University School of Medicine, Boston, MA, United States
^c Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, NY, United States
^d Department of Epidemiology, Columbia University Mailman School of Public Health, Sergievsky Center, New York, NY, United States
^e Division of Statistical Genomics, Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^f Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, United States

Abstract
Background: The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. Objective: To test whether APOE genotype is associated with change of cognitive function in older adults. Methods: We used Bayesian hierarchical models to test the association between APOE alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ϵ2 or ϵ4 alleles. Results: Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the APOE ϵ4 allele on Logical Memory. Participants carrying at least one copy of the ϵ4 allele had lower scores in both immediate (-0.31 points, 95% CI:-0.57,-0.05) and delayed (-0.37 points, 95% CI:-0.64,-0.10) recall comparing to non-ϵ4 allele carriers. We did not detect any significant longitudinal effect of the ϵ4 allele. There was no cross-sectional or longitudinal effect of the ϵ2 allele. Conclusion: The APOE ϵ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the APOE ϵ2 allele was not significantly associated with any of the cognitive test scores. © 2021-IOS Press. All rights reserved.

Author Keywords
APOE;  cognition;  longevity;  longitudinal studies

Distinct GluN1 and GluN2 Structural Determinants for Subunit-Selective Positive Allosteric Modulation of N-Methyl- d -aspartate Receptors
(2021) ACS Chemical Neuroscience, . 

Strong, K.L.^a b , Epplin, M.P.^b , Ogden, K.K.^a , Burger, P.B.^b , Kaiser, T.M.^b , Wilding, T.J.^d , Kusumoto, H.^a , Camp, C.R.^a , Shaulsky, G.^a , Bhattacharya, S.^e , Perszyk, R.E.^a , Menaldino, D.S.^b , McDaniel, M.J.^a , Zhang, J.^a , Le, P.^a , Banke, T.G.^a , Hansen, K.B.^a c , Huettner, J.E.^d , Liotta, D.C.^b , Traynelis, S.F.^a

^a Department of Pharmacology, Emory University, 1510 Clifton Road, Atlanta, GA 30322, United States
^b Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, United States
^c Center for Biomolecular Structure and Dynamics, Center for Structural and Functional Neuroscience, Division for Biological Sciences, University of Montana, 32 Campus Drive, Missoula, MT 59812, United States
^d Department of Cell Biology and Physiology, Washington University, St Louis, MO 63110, United States
^e Department of Drug Discovery and Development, Auburn University, Auburn, AL 36849, United States

Abstract
N-Methyl-d-aspartate receptors (NMDARs) are ionotropic ligand-gated glutamate receptors that mediate fast excitatory synaptic transmission in the central nervous system (CNS). Several neurological disorders may involve NMDAR hypofunction, which has driven therapeutic interest in positive allosteric modulators (PAMs) of NMDAR function. Here we describe modest changes to the tetrahydroisoquinoline scaffold of GluN2C/GluN2D-selective PAMs that expands activity to include GluN2A- and GluN2B-containing recombinant and synaptic NMDARs. These new analogues are distinct from GluN2C/GluN2D-selective compounds like (+)-(3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)methanone (CIQ) by virtue of their subunit selectivity, molecular determinants of action, and allosteric regulation of agonist potency. The (S)-enantiomers of two analogues (EU1180-55, EU1180-154) showed activity at NMDARs containing all subunits (GluN2A, GluN2B, GluN2C, GluN2D), whereas the (R)-enantiomers were primarily active at GluN2C- and GluN2D-containing NMDARs. Determination of the actions of enantiomers on triheteromeric receptors confirms their unique pharmacology, with greater activity of (S) enantiomers at GluN2A/GluN2D and GluN2B/GluN2D subunit combinations than (R) enantiomers. Evaluation of the (S)-EU1180-55 and EU1180-154 response of chimeric kainate/NMDA receptors revealed structural determinants of action within the pore-forming region and associated linkers. Scanning mutagenesis identified structural determinants within the GluN1 pre-M1 and M1 regions that alter the activity of (S)-EU1180-55 but not (R)-EU1180-55. By contrast, mutations in pre-M1 and M1 regions of GluN2D perturb the actions of only the (R)-EU1180-55 but not the (S) enantiomer. Molecular modeling supports the idea that the (S) and (R) enantiomers interact distinctly with GluN1 and GluN2 pre-M1 regions, suggesting that two distinct sites exist for these NMDAR PAMs, each of which has different functional effects. © 2020 American Chemical Society.

Author Keywords
Electrophysiology;  EPSC;  molecular dynamics;  positive allosteric modulator

Funding details
National Institute of Neurological Disorders and StrokeNINDSNS111619, NS097536, NS30888, NS NS065371, GM103546
Janssen Pharmaceuticals

Phase 1b Study to Evaluate Safety, Tolerability, and Maximum Tolerated Dose of PF-05230907 for Intracerebral Hemorrhage
(2021) Stroke, pp. 294-298. 

Silva Blas, Y.^a , Diringer, M.N.^b , Lo, B.^c , Masjuan, J.^d , Pérez De La Ossa, N.^e , Cardinal, M.^f , Yong, F.^f , Zhu, T.^f , Li, G.^g , Arkin, S.^f

^a Hospital Universitari Dr Josep Trueta, Girona, Spain
^b Washington University in St Louis, St Louis, MO, United States
^c Montreal Neurological Institute, Quebec, Canada
^d Hospital Universitario Ramón y Cajal, Madrid, Spain
^e Hospital Universitari Germans Trias i Pujol, Barcelona, Spain
^f Pfizer Inc, Cambridge, MA, United States
^g Pfizer Inc, Collegeville, PA, United States

Abstract
Background and Purpose: This study aimed to determine the maximum tolerated dose and to evaluate the overall safety and tolerability of single doses of PF-05230907 in subjects with acute intracerebral hemorrhage. Methods: Individuals presenting with intracerebral hemorrhage were enrolled in a phase 1, multicenter, open-label clinical trial. A Bayesian modified continual reassessment method design based on treatment-emergent thromboembolic or ischemic events was adopted. Sequential dosing, an external data monitoring committee, and prespecified stopping rules were incorporated as safeguards. Results: Twenty-one subjects received PF-05230907. The mean (±SD) age in years and intracerebral hemorrhage volume in mL at baseline were 62 (±9) and 18 (±11), respectively. Two treatment-emergent thromboembolic or ischemic events occurred (deep vein thrombosis and cerebral ischemia), in the 30 μg/kg dose group. There were no other clear drug-related toxicities at dose levels ranging from 5 to 30 μg/kg. At the time of study termination, the maximum tolerated dose was estimated to be 24 μg/kg, with a mean fitted dose-toxicity estimate of 11.9% (95% CI, 1.2%-27.4%). Conclusions: Single doses of PF-05230907 appeared to be tolerated across a range of doses in the intracerebral hemorrhage population, with thrombotic events observed only at the highest dose level tested. Recruitment within the recommended therapeutic window of opportunity remains a challenge. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02687191. © 2021 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
cerebral hemorrhage;  maximum tolerated dose;  mortality;  patients;  thrombosis

Collateral damage: Impact of SARS-CoV-2 pandemic in people living with HIV
(2021) Journal of NeuroVirology, . 

Cooley, S.A.^a , Nelson, B.^a , Doyle, J.^a , Rosenow, A.^a , Ances, B.M.^a b c

^a Department of Neurology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
^b Department of Radiology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
^c Hope Center for Neurological Disorders, Washington University in Saint Louis, Saint Louis, MO 63110, United States

Abstract
People living with HIV (PLWH) may be at higher risk for adverse outcomes indirectly associated with the severe acute respiratory syndrome coronavirus (SARS-CoV-2). When comparing responses to questionnaires administered when social distancing and quarantine guidelines were first implemented, we found that PLWH were more likely to have restricted access to medical care, increased financial stress, increased symptoms of anxiety and depression, and increased substance use compared to demographically-similar people without HIV. © 2021, Journal of NeuroVirology, Inc.

Author Keywords
COVID-19;  Depression;  HIV;  Substance use

Funding details
National Institute of Nursing ResearchNINRR01NR015738
National Institute of Mental HealthNIMHR01MH118031

Comparative responsiveness of the health utilities index and the RAND-12 for multiple sclerosis
(2021) Multiple Sclerosis Journal, . 

Marrie, R.A.^a f g , Leung, S.^b , Cutter, G.R.^c , Fox, R.J.^d , Salter, A.^e

^a Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
^b Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
^c Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
^d Mellen Center for Multiple Sclerosis, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
^e Department of Biostatistics, Washington University in St. Louis, St. LouisMO, United States
^f Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
^g Health Sciences Centre, Winnipeg, MB, Canada

Abstract
Background: Outcome measures need to be valid and have good test–retest reliability and responsiveness. We compared the responsiveness of the RAND-12 and the Health Utilities Index—mark III (HUI3) in persons with multiple sclerosis (MS). Methods: In Spring 2018 and 2019, North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants completed the HUI3, the RAND-12, and reported disability (Patient Determined Disease Steps (PDDS)) and employment status (full-time, part-time, and no). We used changes in PDDS and employment status as anchors. We assessed responsiveness using effect size, standardized response mean, and the responsiveness index. We used relative efficiency (RE) to compare the responsiveness of the health-related quality of life (HRQOL) scores, adjusting for sociodemographic factors. Results: We included 4769 participants in the analysis. They had a mean (standard deviation (SD)) age of 60.9 (10.1) years, and 3826 participants (80.2%) were women. RE was highest for the HUI3 for changes in in disability status (HUI3: 1.0, Physical Component Score-12 (PCS-12): 0.80, and Mental Component Score-12 (MCS-12): 0.41) and for changes in employment status (HUI3: 1.0, PCS-12: 0.70, and MCS-12: 0.17). Conclusion: The HUI3 was more responsive to changes in disability and employment status than the PCS-12 or MCS-12. Given the HUI3’s other strong psychometric properties, it may be the preferred generic measure of HRQOL in MS. © The Author(s), 2021.

Author Keywords
Multiple sclerosis;  quality of life;  responsiveness

Funding details
Novartis
Multiple Sclerosis Society of CanadaMSSOC
Arthritis Society
Canadian Institutes of Health ResearchCIHR
U.S. Department of DefenseDOD
National Multiple Sclerosis Society

Corpus callosotomy performed with laser interstitial thermal therapy
(2021) Journal of Neurosurgery, 134 (1), pp. 314-322. Cited 1 time.

Roland, J.L.^a , Akbari, S.H.A.^b , Salehi, A.^b , Smyth, M.D.^b

^a Department of Neurological Surgery, University of California, San Francisco, CA, United States
^b Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
OBJECTIVE Corpus callosotomy is a palliative procedure that is effective at reducing seizure burden in patients with medically refractory epilepsy. The procedure is traditionally performed via open craniotomy with interhemispheric microdissection to divide the corpus callosum. Concerns for morbidity associated with craniotomy can be a deterrent to patients, families, and referring physicians for surgical treatment of epilepsy. Laser interstitial thermal therapy (LITT) is a less invasive procedure that has been widely adopted in neurosurgery for the treatment of tumors. In this study, the authors investigated LITT as a less invasive approach for corpus callosotomy. METHODS The authors retrospectively reviewed all patients treated for medically refractory epilepsy by corpus callosotomy, either partial or completion, with LITT. Chart records were analyzed to summarize procedural metrics, length of stay, adverse events, seizure outcomes, and time to follow-up. In select cases, resting-state functional MRI was performed to qualitatively support effective functional disconnection of the cerebral hemispheres. RESULTS Ten patients underwent 11 LITT procedures. Five patients received an anterior two-thirds LITT callosotomy as their first procedure. One patient returned after LITT partial callosotomy for completion of callosotomy by LITT. The median hospital stay was 2 days (IQR 1.5–3 days), and the mean follow-up time was 1.0 year (range 1 month to 2.86 years). Functional outcomes are similar to those of open callosotomy, with the greatest effect in patients with a significant component of drop attacks in their seizure semiology. One patient achieved an Engel class II outcome after anterior two-thirds callosotomy resulting in only rare seizures at the 18-month follow-up. Four others were in Engel class III and 5 were Engel class IV. Hemorrhage occurred in 1 patient at the time of removal of the laser fiber, which was placed through the bone flap of a prior open partial callosotomy. CONCLUSIONS LITT appears to be a safe and effective means for performing corpus callosotomy. Additional data are needed to confirm equipoise between open craniotomy and LITT for corpus callosotomy. © AANS 2021, except where prohibited by US copyright law

Author Keywords
Corpus callosotomy;  Epilepsy;  Laser interstitial thermal therapy;  MR-guided LITT

Direct Neuronal Reprogramming of Common Marmoset Fibroblasts by ASCL1, microRNA-9/9*, and microRNA-124 Overexpression
(2020) Cells, 10 (1), . 

Nemoto, A.^a , Kobayashi, R.^a b , Yoshimatsu, S.^a b c , Sato, Y.^b d , Kondo, T.^a b , Yoo, A.S.^e , Shiozawa, S.^a f , Okano, H.^a b

^a Department of Physiology, School of Medicine, Keio University, Shinjuku-kuTokyo 160-8582, Japan
^b Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain ScienceSaitama 351-0198, Japan
^c Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain ScienceSaitama 351-0198, Japan
^d Graduate School of Science and Technology, Keio UniversityKanagawa 223-8522, Japan
^e Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
^f Institute of Animal Experimentation, School of Medicine, Kurume UniversityFukuoka 830-0011, Japan

Abstract
The common marmoset (Callithrix jacchus) has attracted considerable attention, especially in the biomedical science and neuroscience research fields, because of its potential to recapitulate the complex and multidimensional phenotypes of human diseases, and several neurodegenerative transgenic models have been reported. However, there remain several issues as (i) it takes years to generate late-onset disease models, and (ii) the onset age and severity of phenotypes can vary among individuals due to differences in genetic background. In the present study, we established an efficient and rapid direct neuronal induction method (induced neurons; iNs) from embryonic and adult marmoset fibroblasts to investigate cellular-level phenotypes in the marmoset brain in vitro. We overexpressed reprogramming effectors, i.e., microRNA-9/9*, microRNA-124, and Achaete-Scute family bHLH transcription factor 1, in fibroblasts with a small molecule cocktail that facilitates neuronal induction. The resultant iNs from embryonic and adult marmoset fibroblasts showed neuronal characteristics within two weeks, including neuron-specific gene expression and spontaneous neuronal activity. As directly reprogrammed neurons have been shown to model neurodegenerative disorders, the neuronal reprogramming of marmoset fibroblasts may offer new tools for investigating neurological phenotypes associated with disease progression in non-human primate neurological disease models.

Author Keywords
ASCL1;  common marmoset;  direct reprogramming;  induced neuron (iN);  microRNA-124;  microRNA-9/9*

The Sleep Nullifying Apparatus: A Highly Efficient Method of Sleep Depriving Drosophila
(2020) Journal of Visualized Experiments: JoVE, (166), . 

Melnattur, K.^a , Morgan, E.^a , Duong, V.^a , Kalra, A.^a , Shaw, P.J.^b

^a Department of Neuroscience, Washington University School of Medicine
^b Department of Neuroscience, Washington University School of Medicine;

Abstract
Sleep homeostasis, the increase in sleep observed following sleep loss, is one of the defining criteria used to identify sleep throughout the animal kingdom. As a consequence, sleep deprivation and sleep restriction are powerful tools that are commonly used to provide insight into sleep function. Nonetheless, sleep deprivation experiments are inherently problematic in that the deprivation stimulus itself may be the cause of observed changes in physiology and behavior. Accordingly, successful sleep deprivation techniques should keep animals awake and, ideally, result in a robust sleep rebound without also inducing a large number of unintended consequences. Here, we describe a sleep deprivation technique for Drosophila melanogaster. The Sleep Nullifying Apparatus (SNAP) administers a stimulus every 10s to induce negative geotaxis. Although the stimulus is predictable, the SNAP effectively prevents >95% of nighttime sleep even in flies with high sleep drive. Importantly, the subsequent homeostatic response is very similar to that achieved using hand-deprivation. The timing and spacing of the stimuli can be modified to minimize sleep loss and thus examine non-specific effects of the stimulus on physiology and behavior. The SNAP can also be used for sleep restriction and to assess arousal thresholds. The SNAP is a powerful sleep disruption technique that can be used to better understand sleep function.

Effects of subthalamic nucleus deep brain stimulation and levodopa on balance in people with parkinson’s disease: A cross sectional study
(2020) Brain Sciences, 10 (10), art. no. 693, pp. 1-8. 

May, D.S.^a , van Dillen, L.R.^a b , Earhart, G.M.^a c d , Rawson, K.S.^a , Perlmutter, J.S.^{a c d e f} , Duncan, R.P.^a c

^a Program in Physical Therapy, Washington University in St. Louis, St. Louis, MO 63108-2212, United States
^b Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States
^f Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Subthalamic nucleus deep brain stimulation (STN-DBS) and levodopa are common treatment strategies for Parkinson’s disease (PD). However, the specific effects of these treatment strategies on balance and its components remain unclear. This cross-sectional study of people with PD and STN-DBS compared balance in the treated state (ON-medication/ON-stimulation) and untreated state (OFF-medication/OFF-stimulation) using the Balance Evaluation Systems Test (BESTest). Total BESTest scores from the treated and untreated states were compared to assess overall balance. Scores for the six sections of the BESTest were further compared to assess differences in specific components of balance between treatment conditions. Twenty-nine participants were included (Male: 21, Female: 8, Mean Age ± SD: 65.0 ± 6.9). Total BESTest scores showed improved balance in the treated state compared to the untreated state (Treated: 67.56 ± 10.92; Untreated: 59.23 ± 16.51, p < 0.001). Four sections (Stability Limits/Verticality, Anticipatory Postural Reactions, Sensory Orientation, Stability in Gait) of the BESTest significantly improved in the treated state relative to the untreated state, after correcting for multiple comparisons (p < 0.05). These results demonstrate that STN-DBS and levodopa improve overall balance and provide a first step toward understanding the effects of these treatment strategies on specific components of balance. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Balance;  Deep brain stimulation;  Levodopa;  Parkinson’s disease;  Posture

Funding details
American Parkinson Disease AssociationAPDA
UL1 TR00048
American Parkinson Disease AssociationAPDA
K23 HD100569, K12 HD055931
Foundation for Barnes-Jewish Hospital

Treatable, motor-sensory, axonal neuropathies with C5b-9 complement on endoneurial microvessels
(2020) Muscle and Nerve, . 

Trikamji, B.^a , Pestronk, A.^a b

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

Abstract
Introduction: Identification and treatment of immune-mediated polyneuropathies may lead to improved strength and function. We studied the clinical and laboratory features, and treatment response, in patients with motor-sensory axonal polyneuropathies who were found to have C5b-9 complement staining on endoneurial microvessels. Methods: Retrospective review of 16 consecutive adults with motor-sensory axonal polyneuropathies who were then found to have C5b-9 staining of endoneurial microvessels on nerve biopsy, and subsequently treated with intravenous corticosteroids (1 g methylprednisolone for 5 consecutive days, and then weekly). Strength measurements were done using quantitative handheld dynamometry. Nerve biopsy analysis included frozen and fixed tissue. Results: Patients (mean onset age, 59 ± 4 years; range, 34-83 years; 12 of 16 were males; 9 of 16 had diabetes) had progressive (median duration, 2 years), asymmetric, distal weakness, in the lower extremities (16 of 16) and/or upper extremities (7 of 16), and panmodal sensory loss. Electrodiagnostic studies showed axon loss. Nerve pathology showed abnormal C5b-9 staining on endoneurial microvessels. Axon loss was present in all nerves, often varied among fascicles. Inflammation was uncommon. Distal strength usually improved (mean improvement of 34 ± 6% of normal strength; P =.0003) with corticosteroid treatment. Discussion: Motor-sensory axonal polyneuropathies having noninflammatory, humoral immune pathology with C5b-9 staining of endoneurial microvessels (HIEM) frequently manifest progressive asymmetric, distal, lower extremity with or without upper extremity weakness that improves rapidly during corticosteroid treatment. HIEM may represent a new class of noninflammatory-vasculopathic, treatable axonal motor-sensory neuropathies. © 2020 Wiley Periodicals LLC

Author Keywords
C5b-9, endoneurial microvasculopathy, humoral immune, immune neuropathy, polyneuropathy