WashU weekly Neuroscience publications

Mitofusin activation enhances mitochondrial motility and promotes neuroregeneration in CMT2A
(2021) Neural Regeneration Research, 16 (11), pp. 2201-2203. 

Dorn, G.

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

Funding details
National Institutes of HealthNIH

Influence of anhedonic symptom severity on reward circuit connectivity in PTSD
(2021) Behavioural Brain Research, 407, art. no. 113258, . 

Pessin, S.^a , Philippi, C.L.^a , Reyna, L.^a , Buggar, N.^a , Bruce, S.E.^a b

^a Department of Psychological Sciences, University of Missouri-St. Louis, 1 University Blvd., St. Louis, MO 63121, United States
^b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Anhedonia, marked by deficits in reward processing, is a prominent symptom of several psychiatric conditions and has been shown to influence functional connectivity between reward-related regions. However, the unique influence of anhedonia severity on reward circuit connectivity in posttraumatic stress disorder (PTSD) remains unclear. To address this, we examined resting-state functional connectivity (rsFC) of the ventral striatum as a function of anhedonia for individuals with PTSD. Resting-state functional MRI scans and behavioral assessments were collected for 71 women diagnosed with PTSD. Seed-based voxelwise rsFC analyses for left and right nucleus accumbens (NAcc) seed regions of interest were performed. Voxelwise regression analyses were conducted to examine the relationship between anhedonia severity and rsFC of left and right NAcc. Results indicated that greater anhedonia severity was associated with reduced rsFC between the left NAcc and a cluster in the left caudate extending to the thalamus. This relationship between anhedonia and rsFC remained significant after controlling for PTSD symptom severity or depression severity. Our findings suggest that reward circuit dysfunction at rest is associated with anhedonia in PTSD. These results further contribute to our understanding of the neural correlates of anhedonia in psychiatric conditions. © 2021 Elsevier B.V.

Author Keywords
Anhedonia;  Functional connectivity;  Nucleus accumbens;  Posttraumatic stress disorder;  Resting-state fMRI;  Reward circuit

Funding details
National Institutes of HealthNIHK23 MH090366, RC1 MH089704
National Institute of Mental HealthNIMH

Examination of a blood-brain barrier targeting β-galactosidase-monoclonal antibody fusion protein in a murine model of GM1-gangliosidosis
(2021) Molecular Genetics and Metabolism Reports, 27, art. no. 100748, . 

Przybilla, M.J.^a , Stewart, C.^b , Carlson, T.W.^c , Ou, L.^a , Koniar, B.L.^d , Sidhu, R.^e , Kell, P.J.^e , Jiang, X.^e , Jarnes, J.R.^f , O’Sullivan, M.G.^c , Whitley, C.B.^a

^a Gene Therapy Center, Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
^b Research Department, Tanabe Research Laboratories U.S.A., Inc, San Diego, CA, United States
^c Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center, Saint Paul, MN, United States
^d Center for Translational Medicine, Academic Health Center, University of Minnesota, Minneapolis, MN, United States
^e Department of Medicine, Washington University School of Medicine, Saint Louis, MO, United States
^f Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, United States

Abstract
GM1-gangliosidosis is a lysosomal disease resulting from a deficiency in the hydrolase β-galactosidase (β-gal) and subsequent accumulation of gangliosides, primarily in neuronal tissue, leading to progressive neurological deterioration and eventually early death. Lysosomal diseases with neurological involvement have limited non-invasive therapies due to the inability of lysosomal enzymes to cross the blood-brain barrier (BBB). A novel fusion enzyme, labeled mTfR-GLB1, was designed to act as a ferry across the BBB by fusing β-gal to the mouse monoclonal antibody against the mouse transferrin receptor and tested in a murine model of GM1-gangliosidosis (β-gal−/−). Twelve hours following a single intravenous dose of mTfR-GLB1 (5.0 mg/kg) into adult β-gal−/− mice showed clearance of enzyme activity in the plasma and an increase in β-gal enzyme activity in the liver and spleen. Long-term efficacy of mTfR-GLB1 was assessed by treating β-gal−/− mice intravenously twice a week with a low (2.5 mg/kg) or high (5.0 mg/kg) dose of mTfR-GLB1 for 17 weeks. Long-term studies showed high dose mice gained weight normally compared to vehicle-treated β-gal−/− mice, which are significantly heavier than heterozygous controls. Behavioral assessment at six months of age using the pole test showed β-gal−/− mice treated with mTfR-GLB1 had improved motor function. Biochemical analysis showed an increase in β-gal enzyme activity in the high dose group from negligible levels to 20% and 11% of heterozygous levels in the liver and spleen, respectively. Together, these data show that mTfR-GLB1 is a catalytically active β-gal fusion enzyme in vivo that is readily taken up into tissues. Despite these indications of bioactivity, behavior tests other than the pole test, including the Barnes maze, inverted screen, and accelerating rotarod, showed limited or no improvement of treated mice compared to β-gal−/− mice receiving vehicle only. Further, administration of mTfR-GLB1 was insufficient to create measurable increases in β-gal enzyme activity in the brain or reduce ganglioside content (biochemically and morphologically). © 2021

Author Keywords
Enzyme replacement therapy;  Fusion enzyme;  GM1-gangliosidosis

Pore-forming transmembrane domains control ion selectivity and selectivity filter conformation in the KirBac1.1 potassium channel
(2021) The Journal of General Physiology, 153 (5), . 

Matamoros, M., Nichols, C.G.

Center for Investigation of Membrane Excitability Diseases, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO

Abstract
Potassium (K+) channels are membrane proteins with the remarkable ability to very selectively conduct K+ ions across the membrane. High-resolution structures have revealed that dehydrated K+ ions permeate through the narrowest region of the pore, formed by the backbone carbonyls of the signature selectivity filter (SF) sequence TxGYG. However, the existence of nonselective channels with similar SF sequences, as well as effects of mutations in other regions on selectivity, suggest that the SF is not the sole determinant of selectivity. We changed the selectivity of the KirBac1.1 channel by introducing mutations at residue I131 in transmembrane helix 2 (TM2). These mutations increase Na+ flux in the absence of K+ and introduce significant proton conductance. Consistent with K+ channel crystal structures, single-molecule FRET experiments show that the SF is conformationally constrained and stable in high-K+ conditions but undergoes transitions to dilated low-FRET states in high-Na+/low-K+ conditions. Relative to wild-type channels, I131M mutants exhibit marked shifts in the K+ and Na+ dependence of SF dynamics to higher K+ and lower Na+ concentrations. These results illuminate the role of I131, and potentially other structural elements outside the SF, in controlling ion selectivity, by suggesting that the physical interaction of these elements with the SF contributes to the relative stability of the constrained K+-induced SF configuration versus nonselective dilated conformations. © 2021 Matamoros and Nichols.

Inner ear drug delivery through a cochlear implant: Pharmacokinetics in a Macaque experimental model
(2021) Hearing Research, 404, art. no. 108228, . 

Manrique-Huarte, R.^a , Linera-Alperi, M.A.D.^a , Parilli, D.^a , Rodriguez, J.A.^b , Borro, D.^e , Dueck, W.F.^d , Smyth, D.^d , Salt, A.^c , Manrique, M.^a

^a Otorhinolaringolgy Department, University of Navarra Clinic, Pamplona, Spain
^b Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-Universidad de Navarra, IdiSNA; CIBERCV, Pamplona, Spain
^c Department of Otolaryngology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8115, St. Louis, MO 63110, United States
^d Cochlear Limited, Macquarie University, 1 University AvenueNSW 2109, Australia
^e CEIT and Tecnun (University of Navarra), San Sebastián, Spain

Abstract
Objectives: The method of drug delivery directly into the cochlea with an implantable pump connected to a CI electrode array ensures long-term delivery and effective dose control, and also provides the possibility to use different drugs. The objective is to develop a model of inner ear pharmacokinetics of an implanted cochlea, with the delivery of FITC-Dextran, in the non-human primate model. Design: A preclinical cochlear electrode array (CI Electrode Array HL14DD, manufactured by Cochlear Ltd.) attached to an implantable peristaltic pump filled with FITC-Dextran was implanted unilaterally in a total of 15 Macaca fascicularis (Mf). Three groups were created (5 Mf in each group), according to three different drug delivery times: 2 hours, 24 hours and 7 days. Perilymph (10 samples, 1μL each) was sampled from the apex of the cochlea and measured immediately after extraction with a spectrofluorometer. After scarifying the specimens, x-Rays and histological analysis were performed. Results: Surgery, sampling and histological analysis were performed successfully in all specimens. FITC-Dextran quantification showed different patterns, depending on the delivery group. In the 2 hours injection experiment, an increase in FITC-Dextran concentrations over the sample collection time was seen, reaching maximum concentration peaks (420-964µM) between samples 5 and 7, decreasing in successive samples, without returning to baseline. The 24-hours and 7-days injection experiments showed even behaviour throughout the 10 samples obtained, reaching a plateau with mean concentrations ranging from 2144 to 2564 µM and from 1409 to 2502µM, respectively. Statistically significant differences between the 2 hours and 24 hours groups (p = 0.001) and between the 2 hours and 7 days groups (p = 0.037) were observed, while between the 24 hours and 7 days groups no statistical differences were found. Conclusions: This experimental study shows that a model of drug delivery and pharmacokinetics using an active pump connected to an electrode array is feasible in Mf. An infusion time ranging from 2 to 24 hours is required to reach a maximum concentration peak at the apex. It establishes then an even concentration profile from base to apex that is maintained throughout the infusion time in Mf. Flow mechanisms during injection and during sampling that may explain such findings may involve cochlear aqueduct flow as well as the possible existence of substance exchange from scala tympani to extracellular spaces, such as the modiolar space or the endolymphatic sinus, acting as a substance reservoir to maintain a relatively flat concentration profile from base to apex during sampling. Leveraging the learnings achieved by experimentation in rodent models, we can move to experiment in non-human primate with the aim of achieving a useful model that provides transferrable data to human pharmacokinetics. Thus, it may broaden clinical and therapeutic approaches to inner ear diseases. © 2021

Author Keywords
Cochlear implant;  Dexamethasone;  Drug delivery;  Hearing loss;  Hearing preservation;  Round window approach

Funding details
Universidad de Navarra

Mapping temperature-dependent conformational change in the voltage-sensing domain of an engineered heat-activated K+ channel
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (14), . 

Chen, H.^a b , Deng, J.^c , Cui, Q.^c , Chanda, B.^d e , Henzler-Wildman, K.^b f

^a Graduate Program in Biophysics, University of Wisconsin-Madison, Madison, WI 53706, United States
^b Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, United States
^c Department of Chemistry, Boston University, Boston, MA 02215
^d Graduate Program in Biophysics, University of Wisconsin-Madison, Madison, WI 53706; henzlerwildm@wisc.edu
^e Department of Anesthesiology, Center for Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO 63110
^f Graduate Program in Biophysics, University of Wisconsin-Madison, Madison, WI 53706; bchanda@wustl.edu henzlerwildm@wisc.edu

Abstract
Temperature-dependent regulation of ion channel activity is critical for a variety of physiological processes ranging from immune response to perception of noxious stimuli. Our understanding of the structural mechanisms that underlie temperature sensing remains limited, in part due to the difficulty of combining high-resolution structural analysis with temperature stimulus. Here, we use NMR to compare the temperature-dependent behavior of Shaker potassium channel voltage sensor domain (WT-VSD) to its engineered temperature sensitive (TS-VSD) variant. Further insight into the molecular basis for temperature-dependent behavior is obtained by analyzing the experimental results together with molecular dynamics simulations. Our studies reveal that the overall secondary structure of the engineered TS-VSD is identical to the wild-type channels except for local changes in backbone torsion angles near the site of substitution (V369S and F370S). Remarkably however, these structural differences result in increased hydration of the voltage-sensing arginines and the S4-S5 linker helix in the TS-VSD at higher temperatures, in contrast to the WT-VSD. These findings highlight how subtle differences in the primary structure can result in large-scale changes in solvation and thereby confer increased temperature-dependent activity beyond that predicted by linear summation of solvation energies of individual substituents.

Author Keywords
ion channels;  MD;  thermosensing NMR;  voltage sensor domain

Buprenorphine Patch as a Bridge to Sublingual Treatment of Opioid Use Disorder in Pregnancy
(2021) Obstetrics and Gynecology, 137 (4), pp. 713-716. 

Galati, B.M., Carter, E.B., Perez, M., Russell, S., Nazeer, S., Raghuraman, N., Kelly, J.C.

Departments of Psychiatry and Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Pediatric Neurodevelopmental Delays in Children 0 to 5 Years of Age With Sickle Cell Disease: A Systematic Literature Review
(2021) Journal of Pediatric Hematology/Oncology, 43 (3), pp. 104-111. 

Knight, L.M.J.^a , King, A.A.^b , Strouse, J.J.^a , Tanabe, P.^a

^a Duke University School of Nursing, Durham
^b Washington University School of Medicine, St. Louis, MO

Abstract
INTRODUCTION: Sickle cell disease (SCD) is the most common abnormal genetic blood disease that affects ∼100,000 Americans. Approximately 20% to 37% of children with sickle cell anemia have silent cerebral infarcts by the age of 14 years old. Neurocognitive deficits are identified in infants and preschool children with SCD. The purpose of this systematic literature review is to provide a comprehensive understanding of the prevalence, severity, and the associated risk factors for neurodevelopmental delays (NDDs) in children with SCD 5 years of age and younger. METHODS: Systematic search of 6 databases identified 2467 potentially relevant publications and 8 were identified through a manual search. Only 24 articles met the inclusion criteria. RESULTS: We identified an increased prevalence of NDDs (cognitive, motor, or both). Children experienced deficits with language, attention and behavior, executive functioning, school readiness and/or academic performance, and motor skills (fine and gross motor functioning). Risk factors include silent cerebral infarcts and strokes, SCD genotype (HbSS>HbSC), other biologic, and social factors. CONCLUSION: NDDs are common in children ages 0 to 5 years old with SCD. There is an opportunity to improve adherence to national guideline recommendations and early detection practices by pediatricians, hematologists, and other health care providers. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Automated Quantification of Reduced Sulcal Volume Identifies Early Brain Injury After Aneurysmal Subarachnoid Hemorrhage
(2021) Stroke, 52 (4), pp. 1380-1389. 

Yuan, J.Y.^a , Chen, Y.^b , Kumar, A.^b , Zlepper, Z.^b , Jayaraman, K.^a , Aung, W.Y.^b , Clarke, J.V.^a , Allen, M.^d , Athiraman, U.^c , Osbun, J.^a , Zipfel, G.J.^a b , Dhar, R.^b

^a Department of Neurosurgery (J.Y.Y., K.J., J.V.C., J.O., G.J.Z.), Washington University in St. Louis School of Medicine, St Louis, MO
^b Department of Neurology (Y.C., A.K., Z.Z., W.Y.A., M.A., G.J.Z., R.D.), Washington University in St. Louis School of Medicine, St Louis, MO
^c Department of Anesthesiology (U.A.), Washington University in St. Louis School of Medicine, St Louis, MO

Abstract
BACKGROUND AND PURPOSE: Early brain injury may be a more significant contributor to poor outcome after aneurysmal subarachnoid hemorrhage (aSAH) than vasospasm and delayed cerebral ischemia. However, studying this process has been hampered by lack of a means of quantifying the spectrum of injury. Global cerebral edema (GCE) is the most widely accepted manifestation of early brain injury but is currently assessed only through subjective, qualitative or semi-quantitative means. Selective sulcal volume (SSV), the CSF volume above the lateral ventricles, has been proposed as a quantitative biomarker of GCE, but is time-consuming to measure manually. Here we implement an automated algorithm to extract SSV and evaluate the age-dependent relationship of reduced SSV on early outcomes after aSAH. METHODS: We selected all adults with aSAH admitted to a single institution with imaging within 72 hours of ictus. Scans were assessed for qualitative presence of GCE. SSV was automatically segmented from serial CTs using a deep learning-based approach. Early SSV was the lowest SSV from all early scans. Modified Rankin Scale score of 4 to 6 at hospital discharge was classified as a poor outcome. RESULTS: Two hundred forty-four patients with aSAH were included. Sixty-five (27%) had GCE on admission while 24 developed it subsequently within 72 hours. Median SSV on admission was 10.7 mL but frequently decreased, with minimum early SSV being 3.0 mL (interquartile range, 0.3-11.9). Early SSV below 5 mL was highly predictive of qualitative GCE (area under receiver-operating-characteristic curve, 0.90). Reduced early SSV was an independent predictor of poor outcome, with a stronger effect in younger patients. CONCLUSIONS: Automated assessment of SSV provides an objective biomarker of GCE that can be leveraged to quantify early brain injury and dissect its impact on outcomes after aSAH. Such quantitative analysis suggests that GCE may be more impactful to younger patients with SAH.

Author Keywords
brain edema;  cerebrospinal fluid;  deep learning;  intracranial aneurysm;  subarachnoid hemorrhage

Long, noncoding RNA dysregulation in glioblastoma
(2021) Cancers, 13 (7), art. no. 1604, . 

DeSouza, P.A.^a b , Qu, X.^a , Chen, H.^a c , Patel, B.^a , Maher, C.A.^b d e f , Kim, A.H.^a f

^a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^b Department of Internal Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^e McDonnell Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^f Siteman Cancer Center, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Transcription occurs across more than 70% of the human genome and more than half of currently annotated genes produce functional noncoding RNAs. Of these transcripts, the majority-long, noncoding RNAs (lncRNAs)-are greater than 200 nucleotides in length and are necessary for various roles in the cell. It is increasingly appreciated that these lncRNAs are relevant in both health and disease states, with the brain expressing the largest number of lncRNAs compared to other organs. Glioblastoma (GBM) is an aggressive, fatal brain tumor that demonstrates remarkable intratumoral heterogeneity, which has made the development of effective therapies challenging. The cooperation between genetic and epigenetic alterations drives rapid adaptation that allows therapeutic evasion and recurrence. Given the large repertoire of lncRNAs in normal brain tissue and the well-described roles of lncRNAs in molecular and cellular processes, these transcripts are important to consider in the context of GBM heterogeneity and treatment resistance. Herein, we review the general mechanisms and biological roles of lncRNAs, with a focus on GBM, as well as RNA-based therapeutics currently in development. © 2021 by the authors.

Author Keywords
Glioblastoma;  Heterogeneity;  LncRNA;  MiRNA;  Noncoding RNA;  RNAi

Funding details
National Institutes of HealthNIHR01 NS051255, R01 NS094670, R01 NS106612
Foundation for Barnes-Jewish Hospital
Alvin J. Siteman Cancer Center

“I feel you”: Greater linkage between friends’ physiological responses and emotional experience is associated with greater empathic accuracy
(2021) Biological Psychology, 161, art. no. 108079, . 

Zerwas, F.K.^a , Springstein, T.^b , Karnilowicz, H.R.^a , Lam, P.^c , Butler, E.A.^d , John, O.P.^a , Mauss, I.B.^a

^a University of California, Berkeley, United States
^b Washington University in St. Louis, United States
^c Northwestern University, United States
^d University of Arizona, United States

Abstract
How do people come to know others’ feelings? One idea is that affective processes (e.g., physiological responses) play an important role, leading to the prediction that linkage between one’s physiological responses and others’ emotions relates to one’s ability to know how others feel (i.e., empathic accuracy). Participants (N = 96, 48 female friend pairs) completed a stressful speech task and then provided continuous ratings of their own (as “targets”) and their friend’s (as “perceivers”) emotional experience for the video-taped speeches. We measured physiology-physiology linkage (linkage between perceivers’ and targets’ physiology), physiology-experience linkage (linkage between perceivers’ physiology and targets’ experience), and empathic accuracy (linkage between perceivers’ ratings of targets’ experience and targets’ ratings of their experience). Physiology-experience (but not physiology-physiology) linkage was associated with greater empathic accuracy even when controlling for key potential confounds (random linkage, targets’ and perceivers’ emotional reactivity, and relationship closeness). Results suggest that physiological responses play a role in empathic accuracy. © 2021

Author Keywords
Empathic accuracy;  Empathy;  Friends;  Physiological linkage

Funding details
National Science FoundationNSFBCS-1941868
National Institutes of HealthNIHR01AG043592

Unique challenges for glioblastoma immunotherapy-discussions across neuro-oncology and non-neuro-oncology experts in cancer immunology. Meeting Report from the 2019 SNO Immuno-Oncology Think Tank
(2021) Neuro-oncology, 23 (3), pp. 356-375. 

Chuntova, P.^a , Chow, F.^b , Watchmaker, P.B.^a , Galvez, M.^c , Heimberger, A.B.^d , Newell, E.W.^e , Diaz, A.^a , DePinho, R.A.^f , Li, M.O.^g , Wherry, E.J.^h , Mitchell, D.ⁱ , Terabe, M.^j , Wainwright, D.A.^k , Berzofsky, J.A.^j , Herold-Mende, C.^l , Heath, J.R.^m , Lim, M.ⁿ , Margolin, K.A.^o , Chiocca, E.A.^p , Kasahara, N.^a , Ellingson, B.M.^q , Brown, C.E.^r , Chen, Y.^s , Fecci, P.E.^t , Reardon, D.A.^u , Dunn, G.P.^v , Liau, L.M.^w , Costello, J.F.^a , Wick, W.^x , Cloughesy, T.^b , Timmer, W.C.^y , Wen, P.Y.^z , Prins, R.M.^c aa , Platten, M.^ab ac , Okada, H.^a aa

^a Department of Neurological Surgery, UCSF, San Francisco, CA, Mexico
^b Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
^c Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
^d Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX
^e Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
^f Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX
^g Immunology Program, Memorial Sloan Kettering Cancer CenterNY
^h Department of Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
ⁱ Department of Neurosurgery, University of Florida College of Medicine, Gainesville, FL, United States
^j Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
^k Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, Mexico
^l Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
^m Institute for Systems Biology, Seattle, WA, United States
ⁿ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^o Department of Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, California
^p Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA
^q Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
^r Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, California
^s Department of Microbiology, Immunology & Molecular Genetics, UCLA, Los Angeles, CA, Mexico
^t Department of Neurosurgery, Duke University School of Medicine, Durham, NC
^u Department of Medicine/Medical Oncology, Harvard Medical School, Boston, MA
^v Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^w Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, Mexico
^x Department of Neurology, University Hospital Heidelberg, Heidelberg, Germany
^y Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, United States
^z Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
^aa Parker Institute for Cancer Immunotherapy, San Francisco, CA, Mexico
^ab Department of Neurology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
^ac DKTK CCU Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany

Abstract
Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
clinical trial;  conference report;  glioblastoma;  immunosuppression;  immunotherapy

Radiation therapy to the developing brain: advanced technology is ready for robust optimization parameters
(2021) Neuro-oncology, 23 (3), pp. 350-351. 

Perkins, S.^a , Acharya, S.^b

^a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Longitudinal Accumulation of Cerebral Microhemorrhages in Dominantly Inherited Alzheimer Disease
(2021) Neurology, 96 (12), pp. e1632-e1645. 

Joseph-Mathurin, N., Wang, G., Kantarci, K., Jack, C.R., Jr, McDade, E., Hassenstab, J., Blazey, T.M., Gordon, B.A., Su, Y., Chen, G., Massoumzadeh, P., Hornbeck, R.C., Allegri, R.F., Ances, B.M., Berman, S.B., Brickman, A.M., Brooks, W.S., Cash, D.M., Chhatwal, J.P., Chui, H.C., Correia, S., Cruchaga, C., Farlow, M.R., Fox, N.C., Fulham, M., Ghetti, B., Graff-Radford, N.R., Johnson, K.A., Karch, C.M., Laske, C., Lee, A.K.W., Levin, J., Masters, C.L., Noble, J.M., O’Connor, A., Perrin, R.J., Preboske, G.M., Ringman, J.M., Rowe, C.C., Salloway, S., Saykin, A.J., Schofield, P.R., Shimada, H., Shoji, M., Suzuki, K., Villemagne, V.L., Xiong, C., Yakushev, I., Morris, J.C., Bateman, R.J., Benzinger, T.L.S., Dominantly Inherited Alzheimer Network

From the Departments of Radiology (N.J.-M., T.M.B., B.A.G., G.C., P.M., R.C.H., T.L.S.B.), Neurology (E.M., J.H., B.M.A., R.J.P., J.C.M., R.J.B.), Psychological and Brain Sciences (J.H.), Psychiatry (C.C., C.M.K.), and Pathology and Immunology (R.J.P.) and Division of Biostatistics (G.W., C.X.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimers Institute (Y.S.), Phoenix, AZ; Department of Cognitive Neurology and Neuropsychology (R.F.A.), Instituto de Investigaciones Neurológicas Fleni, Buenos Aires, Argentina; Departments of Neurology and Clinical and Translational Science (S.B.B.), University of Pittsburgh School of Medicine, PA; Department of Neurology (A.M.B.), Taub Institute for Research on Alzheimers Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY; Neuroscience Research Australia (W.S.B., P.R.S.); School of Medical Sciences (P.R.S.), University of New South Wales (W.S.B.), Sydney, Australia; Dementia Research Centre and UK Dementia Research Institute (D.M.C., N.C.F., A.O.), UCL Queen Square Institute of Neurology, London, UK

Abstract
OBJECTIVE: To investigate the inherent clinical risks associated with the presence of cerebral microhemorrhages (CMHs) or cerebral microbleeds and characterize individuals at high risk for developing hemorrhagic amyloid-related imaging abnormality (ARIA-H), we longitudinally evaluated families with dominantly inherited Alzheimer disease (DIAD). METHODS: Mutation carriers (n = 310) and noncarriers (n = 201) underwent neuroimaging, including gradient echo MRI sequences to detect CMHs, and neuropsychological and clinical assessments. Cross-sectional and longitudinal analyses evaluated relationships between CMHs and neuroimaging and clinical markers of disease. RESULTS: Three percent of noncarriers and 8% of carriers developed CMHs primarily located in lobar areas. Carriers with CMHs were older, had higher diastolic blood pressure and Hachinski ischemic scores, and more clinical, cognitive, and motor impairments than those without CMHs. APOE ε4 status was not associated with the prevalence or incidence of CMHs. Prevalent or incident CMHs predicted faster change in Clinical Dementia Rating although not composite cognitive measure, cortical thickness, hippocampal volume, or white matter lesions. Critically, the presence of 2 or more CMHs was associated with a significant risk for development of additional CMHs over time (8.95 ± 10.04 per year). CONCLUSION: Our study highlights factors associated with the development of CMHs in individuals with DIAD. CMHs are a part of the underlying disease process in DIAD and are significantly associated with dementia. This highlights that in participants in treatment trials exposed to drugs, which carry the risk of ARIA-H as a complication, it may be challenging to separate natural incidence of CMHs from drug-related CMHs. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Preferentially Expressed Antigen in Melanoma (PRAME) Expression in Malignant, but Not Benign, Peripheral Nerve Sheath Tumors
(2021) Journal of Neuropathology and Experimental Neurology, 80 (4), pp. 384-386. 

Cadwell, C.R.^a , Yuksek, G.E.^a , Hirbe, A.C.^b , Srihari, D.^b , LeBoit, P.^c , Dahiya, S.^d , Pekmezci, M.^a

^a Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, CA, Mexico
^b Division of Medical Oncology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Division of Dermatopathology, Departments of Pathology and Dermatology, University of California San Francisco, San Francisco, CA, Mexico
^d Division of Neuropathology, Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States

Neuroscience of Object Relations in Health and Disorder: A Proposal for an Integrative Model
(2021) Frontiers in Psychology, 12, art. no. 583743, . 

Svrakic, D.M.^a , Zorumski, C.F.^a b

^a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Recent advances in the neuroscience of episodic memory provide a framework to integrate object relations theory, a psychoanalytic model of mind development, with potential neural mechanisms. Object relations are primordial cognitive-affective units of the mind derived from survival- and safety-level experiences with caretakers during phase-sensitive periods of infancy and toddlerhood. Because these are learning experiences, their neural substrate likely involves memory, here affect-enhanced episodic memory. Inaugural object relations are encoded by the hippocampus-amygdala synaptic plasticity, and systems-consolidated by medial prefrontal cortex (mPFC). Self- and object-mental representations, extracted from these early experiences, are at first dichotomized by contradictory affects evoked by frustrating and rewarding interactions (“partial object relations”). Such affective dichotomization appears to be genetically hardwired the amygdala. Intrinsic propensity of mPFC to form schematic frameworks for episodic memories may pilot non-conscious integration of dichotomized mental representations in neonates and infants. With the emergence of working memory in toddlers, an activated self- and object-representation of a particular valence can be juxtaposed with its memorized opposites creating a balanced cognitive-affective frame (conscious “integration of object relations”). Specific events of object relations are forgotten but nevertheless profoundly influence the mental future of the individual, acting (i) as implicit schema-affect templates that regulate attentional priorities, relevance, and preferential assimilation of new information based on past experience, and (ii) as basic units of experience that are, under normal circumstances, integrated as attractors or “focal points” for interactive self-organization of functional brain networks that underlie the mind. A failure to achieve integrated object relations is predictive of poor adult emotional and social outcomes, including personality disorder. Cognitive, cellular-, and systems-neuroscience of episodic memory appear to support key postulates of object relations theory and help elucidate neural mechanisms of psychodynamic psychotherapy. Derived through the dual prism of psychoanalysis and neuroscience, the gained insights may offer new directions to enhance mental health and improve treatment of multiple forms of psychopathology. © Copyright © 2021 Svrakic and Zorumski.

Author Keywords
cognitive neuroscience;  emotion-enhanced episodic memory;  molecular- and systems-neuroscience;  object relations;  systems-consolidation of memory;  trans-disciplinary integration

Odontoblast TRPC5 channels signal cold pain in teeth
(2021) Science Advances, 7 (13), . 

Bernal, L.^a b , Sotelo-Hitschfeld, P.^a c , König, C.^a , Sinica, V.^a d , Wyatt, A.^e , Winter, Z.^a , Hein, A.^f , Touska, F.^a d , Reinhardt, S.^g , Tragl, A.^a , Kusuda, R.^a , Wartenberg, P.^e , Sclaroff, A.^h , Pfeifer, J.D.ⁱ , Ectors, F.^j , Dahl, A.^g , Freichel, M.^k , Vlachova, V.^d , Brauchi, S.^c l , Roza, C.^b , Boehm, U.^e , Clapham, D.E.^m , Lennerz, J.K.ⁿ , Zimmermann, K.^o

^a Department of Anesthesiology, Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany
^b Departamento de Biología de Sistemas, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain
^c Institute of Physiology, Faculty of Medicine and Center for Interdisciplinary Studies on the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile
^d Department of Cellular Neurophysiology, Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic
^e Experimental Pharmacology, Center for Molecular Signaling (PZMS), Saarland University School of Medicine, Homburg, Germany
^f HHMI, Cardiovascular Division, Boston Children’s Hospital, Department of Neurobiology, Harvard Medical School, MA, Boston, United States
^g Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden, Dresden, Germany
^h Department of Otolaryngology, Washington University School of Medicine, St Louis, MO, USA
ⁱ Department of Pathology, Washington University School of Medicine, St Louis, MO, USA
^j FARAH Mammalian Transgenics Platform, Liège University, Liège, Belgium
^k Institute of Pharmacology, University of Heidelberg, Heidelberg, Germany
^l Millennium Nucleus of Ion Channel-associated Diseases (MiNICAD)Santiago, Chile
^m HHMI, Cardiovascular Division, Boston Children’s Hospital, Department of Neurobiology, Harvard Medical School, MA, Boston, United States
ⁿ Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital/Harvard Medical School, MA, Boston, United States
^o Department of Anesthesiology, Erlangen University Hospital, Friedrich Alexander University of Erlangen-Nuremberg (FAU), Erlangen, Germany

Abstract
Teeth are composed of many tissues, covered by an inflexible and obdurate enamel. Unlike most other tissues, teeth become extremely cold sensitive when inflamed. The mechanisms of this cold sensation are not understood. Here, we clarify the molecular and cellular components of the dental cold sensing system and show that sensory transduction of cold stimuli in teeth requires odontoblasts. TRPC5 is a cold sensor in healthy teeth and, with TRPA1, is sufficient for cold sensing. The odontoblast appears as the direct site of TRPC5 cold transduction and provides a mechanism for prolonged cold sensing via TRPC5’s relative sensitivity to intracellular calcium and lack of desensitization. Our data provide concrete functional evidence that equipping odontoblasts with the cold-sensor TRPC5 expands traditional odontoblast functions and renders it a previously unknown integral cellular component of the dental cold sensing system. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

A novel precision approach to overcome the “addiction pandemic” by incorporating genetic addiction risk severity (Gars) and dopamine homeostasis restoration
(2021) Journal of Personalized Medicine, 11 (3), art. no. 212, . 

Blum, K.^{a b c d e f g} , Kazmi, S.^a , Modestino, E.J.^h , Downs, B.W.^f , Bagchi, D.^f i , Baron, D.^a , McLaughlin, T.^c , Green, R.^c j , Jalali, R.^c g , Thanos, P.K.^k , Elman, I.^l , Badgaiyan, R.D.^m n , Bowirrat, A.^o , Gold, M.S.^p

^a College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, United States
^b Institute of Psychology, ELTE Eötvös Loránd University, Budapest, 1117, Hungary
^c Division of Nutrigenomics, The Kenneth Blum Behavioral Neurogenetic Institute, Austin, TX 78712, United States
^d Department of Psychiatry, University of Vermont, Burlington, VT 05405, United States
^e Department of Psychiatry, Wright University Boonshoff School of Medicine, Dayton, OH 45435, United States
^f Division of Precision Nutrition, Victory Nutrition International, Lederach, PA 19450, United States
^g Center for Genomic Testing, Geneus Health LLC, San Antonio, TX 78249, United States
^h Department of Psychology, Curry College, Milton, MA 02186, United States
ⁱ Department of Pharmaceutical Sciences, College of Pharmacy & Health Sciences, Texas Southern University, Houston, TX 77004, United States
^j Precision Translational Medicine (Division of Ivitalize), San Antonio, TX 78249, United States
^k Department of Psychology & Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, University at Buffalo, Buffalo, NY 14260, United States
^l Department of Psychiatry, Harvard University, School of Medicine, Cambridge, MA 02142, United States
^m Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital and Long School of Medicine, University of Texas Health Science Center, San Antonio, TX 78249, United States
ⁿ Department of Psychiatry, MT. Sinai School of Medicine, New York, NY 10003, United States
^o Department of Molecular Biology and Adelson School of Medicine, Ariel University, Ariel, 40700, Israel
^p Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Dopamine homeostasis;  Enkephalinase-Inhibition;  Genetic Addiction Risk System (GARS);  Hypodopaminergia;  Pro-dopamine regulation;  Reward Deficiency Syndrome (RDS)

Funding details
Howard University

Itle: An open-source device for measuring food intake and operant behavior in rodent home-cages
(2021) eLife, 10, art. no. e66173, . 

Matikainen-Ankney, B.A.^a , Earnest, T.^a , Ali, M.^b c , Casey, E.^a , Wang, J.G.^d , Sutton, A.K.^b , Legaria, A.A.^d , Barclay, K.M.^d , Murdaugh, L.B.^e , Norris, M.R.^d f , Chang, Y.-H.^d , Nguyen, K.P.^b , Lin, E.^a , Reichenbach, A.^h , Clarke, R.E.^h , Stark, R.^h , Conway, S.M.^f g , Carvalho, F.ⁱ , Al-Hasani, R.^f g , McCall, J.G.^f g , Creed, M.C.^a d g , Cazares, V.^j , Buczynski, M.W.^e , Krashes, M.J.^b , Andrews, Z.B.^h , Kravitz, A.V.^a d g

^a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^b National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
^c Department of Bioengineering, University of Maryland, College Park, MD, United States
^d Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Neuroscience, Virginia Polytechnic and State University, Blacksburg, VA, United States
^f Center for Clinical Pharmacology, University of Health Sciences and Pharmacy, St. Louis, MO, United States
^g Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Physiology, Monash University, Clayton, Australia
ⁱ Open Ephys Production Site, Lisbon, Portugal
^j Department of Psychology, Williams College, Williamstown, MA, United States

Abstract
Feeding is critical for survival and disruption in the mechanisms that govern food intake underlie disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: The Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of feeding behavior with minimal experimenter intervention. It has a programmable output for synchronizing behavior with optogenetic stimulation or neural recordings. Finally, FED3 design files are open-source and freely available, allowing researchers to modify FED3 to suit their needs. © 2021, eLife Sciences Publications Ltd. All rights reserved.

A Bioinformatics Analysis of Gene Expression Changes in Human Alzheimer’s Disease and Mouse Models
(2021) Proceedings of the 2021 International Conference on Bioinformatics and Intelligent Computing, BIC 2021, art. no. 3448755, pp. 29-37. 

Xu, K.^a , Zhou, Y.^b

^a Suzhou Foreign Language School, China
^b Washington University in St. Louis, United States

Abstract
Alzheimers disease (AD), the most common form of dementia, affects more than 50 million people worldwide, with no current treatment to halt the disease. The exact molecular mechanisms modulating disease progression remains elusive, even though numerous studies using mouse AD models have been done. In addition, as mouse models do not fully recapitulate human pathology, it is unclear to what extent results acquired from mouse models can be applied to treat humans. In this study, we conducted comprehensive bioinformatics analyses on transcriptomic profiles from mice bearing Abeta or tau pathology and human AD to identify differentially expressed genes (DEGs) and biological pathways shared among them. We identified the disease-associated microglia (DAM) signature and inflammatory pathways in both amyloid and tau mouse models compared to controls. Although GFAP was the only DEG shared by human AD and mouse AD models, pathways such as inflammatory response were identified in both human and mouse. Common pathways found in this study may modulate disease progression and provide new therapeutic targets. © 2021 ACM.

Author Keywords
Alzheimer’s disease;  Bioinformatics analysis;  gene expression

Metformin restores hippocampal neurogenesis and learning and memory via regulating gut microbiota in the obese mouse model
(2021) Brain, Behavior, and Immunity, . 

Ma, X.^a , Xiao, W.^b , Li, H.^c , Pang, P.^c d , Xue, F.^e , Wan, L.^b , Pei, L.^c f g , Yan, H.^b c

^a Department of Endocrinology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
^b Department of Biomedical Engineering, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan, 430074, China
^c Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, 430030, China
^d Department of Pathology, the First Affiliated Hospital of Soochow University, Suzhou, 215000, China
^e Department of Laboratory, Xi’an No.3 Hospital, Xi’an, 710018, China
^f Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
^g Departments of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Numerous studies have shown that over-nutritional obesity may lead to pre-diabetes, type 2 diabetes and cognitive decline. As the degree of metabolic disorders increases, the cognitive decline is getting worse. However, the cellular events that cause this cognitive dysfunction is yet to be clarified. We used a high-fat diet (HFD) consumption-induced obesity mouse model to test the effects of metformin on the hippocampal neurogenesis and learning and memory abilities of obese mice. 5-Bromo-2′-deoxyuridine (BrdU) labelling and retrovirus labeling were applied to detect hippocampal newborn neurons. Behavioral experiments were used to detect learning and memory abilities of mice. 16S rRNA gene sequencing was performed to detect the composition of gut microbiota. The positron emission tomography (PET) was conducted to detect the energy metabolism activity of different mouse brain regions. Our results reveal that metformin restores the impairment of neurogenesis in the dentate gyrus and finally prevents the cognitive decline of the obese mice. Moreover, the therapeutic effects of metformin are achieved by regulating the composition of gut microbiota of mice, which may inhibit microglia activation and neuroinflammation in the brain of obese mice. This study suggests that metformin may be taken as a promising candidate for the intervention of cognitive decline related to imbalance of gut microbiota caused by obesity. © 2021 Elsevier Inc.

Author Keywords
Gut microbiota;  Hippocampal neurogenesis;  Learning and memory;  Metformin;  Obesity

Funding details
National Natural Science Foundation of ChinaNSFC81870932, 81901304 HY
China Postdoctoral Science Foundation2019 T120663
Huazhong University of Science and TechnologyHUST
Shanxi Provincial Key Research and Development Project2018SF-090 FX

Reliability and Validity of the Polish Version of the Alzheimer’s Disease Knowledge Scale
(2021) Dementia and Geriatric Cognitive Disorders, art. no. 000514872, . 

Leszko, M.^a , Carpenter, B.D.^b

^a Department of Psychology, University of Szczecin, Szczecin, Poland
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
Introduction: In the context of increasing numbers of older adults and an increased prevalence of neurodegenerative diseases, the early diagnosis of dementia has become an important issue. Poland’s population is aging, and the growing number of individuals with Alzheimer’s disease (AD) may pose challenges for families and the health-care system. While creating effective psychoeducational interventions aiming at increasing caregivers’ knowledge may be beneficial, Poland lacks a standardized measurement for assessing knowledge about AD or a related form of dementia. Methods: The aim of our study was to translate and evaluate the Alzheimer’s Disease Knowledge Scale (ADKS) among Polish individuals. Results: The Polish ADKS was developed through a translation-back translation method. Psychometric evaluation was done with a sample of 942 individuals (caregivers, health-care professionals, and general population) who completed the questionnaire. Discussion: The results indicate that the scale produces acceptable psychometric properties and can be used to evaluate the effectiveness of educational interventions among caregivers, health-care professionals, and the general population. © 2021

Affective temperaments, panic disorder and their bipolar connections
(2021) Medicina (Lithuania), 57 (3), art. no. 289, . 

Belteczki, Z.^a , Rihmer, Z.^b c , Rozsa, S.^d , Ujvari, J.^a , Pompili, M.^e , Gonda, X.^b c , Dome, P.^b c

^a First Department of Psychiatry, University Hospital of Szabolcs-Szatmár-Bereg County, Nagykallo, 4320, Hungary
^b Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, 1085, Hungary
^c Nyiro Gyula National Institute of Psychiatry and Addictions, Budapest, 1135, Hungary
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza University of Rome, Rome, 00189, Italy

Abstract
Background and Objectives: The role of affective temperament in the genesis and outcome of major mood disorders is well studied, but there are only a few reports on the relationship between panic disorder (PD) and affective temperaments. Accordingly, we aimed to study the distribution of affective temperaments (depressive (DE); cyclothymic (CT); irritable (IRR); hyperthymic (HT) and anxious (ANX)) among outpatients with PD. Materials and Methods: Affective temperaments of 118 PD outpatients (80 females and 38 males) with or without agoraphobia but without any other psychiatric disorder at the time of inclusion were evaluated using the Temperament Evaluation of the Memphis, Pisa, Paris, and San Diego Autoquestionnaire (TEMPS-A) and compared with the affective temperament scores of control subjects. All patients were followed up for at least 1.5 years in order to detect the onset of any major affective disorders, substance use disorders and suicide attempts. Results: Among females, the dominant ANX and DE temperaments were four and three times as common as in a large normative Hungarian sample (for both cases p < 0.01). Among male PD patients, only the dominant DE temperament was slightly overrepresented in a non-significant manner. Females with PD obtained significantly higher scores on ANX, DE and CT subscales of the TEMPS-A, whereas males with PD showed significantly higher scores on ANX, DE and HT temperament subscales compared with the members of a large normative Hungarian sample and also with a gender-and age-matched control group. During the follow-up, newly developed unipolar major depression and bipolar spectrum (bipolar I or II and cyclothymic) disorders appeared in 64% and 22% of subjects, respectively. Conclusions: Our preliminary findings suggest that a specific, ANX-DE-CT affective temperament profile is characteristic primarily for female patients, and an ANX-DE-HT affective temperament profile is characteristic for male patients with PD, respectively. These findings are in line with expectations because PD is an anxiety disorder par excellence on the one hand, whereas, on the other hand, it is quite frequently comorbid with mood (including bipolar) disorders. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Affective temperaments;  Agoraphobia;  Bipolar disorder;  Comorbidity;  Panic disorder;  TEMPS

Cytokine Profiling in Plasma from Patients with Brain Tumors Versus Healthy Individuals using 2 Different Multiplex Immunoassay Platforms
(2021) Biomarker Insights, 16, . 

Bender, D.E.^a , Schaettler, M.O.^b , Sheehan, K.C.F.^a c , Johanns, T.M.^d e , Dunn, G.P.^a b e

^a Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, United States
^e The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital, Washington University School of Medicine, St. Louis, MO, United States

Abstract
We compared the performance of two 96-well multiplex immunoassay platforms in assessing plasma cytokine concentrations in patients with glioblastoma (GBM; n = 27), individuals with melanoma, breast or lung cancer metastases to the brain (n = 17), and healthy volunteers (n = 11). Assays included a bead-based fluorescence MILLIPLEX® assay/Luminex (LMX) platform and 4 planar electrochemiluminescence kits from Meso Scale Discovery (MSD). The LMX kit evaluated 21 cytokines and the 3 MSD kits evaluated 20 cytokines in total, with 19 overlapping human cytokines between platforms (GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, IL-17A, IL-21, IL-23, MIP-1α, MIP-1β, MIP-3α, TNFα). The MSD platform had lower LLoQs (lower limits of quantification) than LMX for 17/19 cytokines, and higher LLoQs for IFN-γ and IL-21. The ULoQs were higher in LMX versus MSD assays for 17/19 shared analytes, but lower than MSD for IL-17A and IL-21. With LMX, all 19 shared analytes were quantifiable in each of 55 samples. Although MSD recombinant protein standard curves indicated lower LLoQs than LMX for most cytokines, MSD detected 7/19 (37%) native analytes in &lt;75% of samples, including 0% detection for IL-21 and 8% for IL-23. The LMX platform categorized identical samples at greater concentrations than the MSD system for most analytes (MIP-1β the sole exception), sometimes by orders of magnitude. This mismatched quantification paradigm was supported by Bland-Altman analysis. LMX identified significantly elevated levels of 10 of 19 circulating cytokines in GBM: GM-CSF, IFN-γ, IL-1β, IL-5, IL-10, IL-17A, IL-21, IL-23, MIP-1α, and MIP-3α, consistent with prior findings and confirming the utility of applying appropriate multiplex immunoassay technologies toward developing a cytokine signature profile for GBM. © The Author(s) 2021.

Author Keywords
brain metastases;  Chemokine;  cytokine;  detection limit;  dynamic range;  electrochemiluminescence;  fluorescence;  glioblastoma multiforme;  glioma;  in vitro assay;  lower limit of quantification;  multiplex immunoassay;  performance;  precision

Funding details
Merck

U.S. Trends in Adolescent Substance Use and Conduct Problems and Their Relation to Trends in Unstructured In-Person Socializing With Peers
(2021) Journal of Adolescent Health, . 

Borodovsky, J.T.^a , Krueger, R.F.^b , Agrawal, A.^c , Elbanna, B.^c , de Looze, M.^d , Grucza, R.A.^e

^a Center for Technology and Behavioral Health, Dartmouth Geisel School of Medicine, Lebanon, NH, United States
^b Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Interdisciplinary Social Science, Utrecht University, Utrecht, Netherlands
^e Departments of Family and Community Medicine and Health and Clinical Outcomes Research, Saint Louis University, Saint Louis, MO, United States

Abstract
Purpose: This study examined whether national trends in unstructured in-person socializing with peers (i.e., socializing without goals or supervision) among adolescents could help explain recent declines in adolescent risk behaviors (e.g., substance use, fighting, theft). Methods: The sample contained of 44,842 U.S. 12th-grade students (aged 17–18 years) from the Monitoring the Future survey (years 1999–2017). Analyses examined (1) prevalence trends, (2) latent factor structure of risk behaviors and unstructured in-person socializing, and (3) whether trends in the unstructured in-person socializing factor accounted for the relationship between time (i.e., survey year) and the risk behavior factor. Results: Adolescent risk behaviors and unstructured in-person socializing declined by approximately 30% in the U.S., and both formed coherent latent factors. After adjusting for sociodemographics, declines in unstructured in-person socializing accounted for approximately 86% of declines in risk behaviors. Conclusions: The prevalence of risk behaviors and unstructured in-person socializing behaviors declined among U.S. 12th graders from 1999 to 2017. It is unknown whether such effects are directly causal and/or influenced by unmeasured variables. However, the results provide evidence that national declines in unstructured in-person socializing are a likely component of the explanation for national declines in adolescent risk behaviors. © 2021 Society for Adolescent Health and Medicine

Author Keywords
Adolescent;  Delinquency;  Epidemiology;  Multivariate modeling;  Risk behavior;  Substance abuse;  Unstructured socializing

Funding details
National Institute on Drug AbuseNIDAK02DA032573, R01 DA042195, R21DA044744
National Institute on Alcohol Abuse and AlcoholismNIAAAF32AA027941, R21AA025689
National Institute on AgingNIAR01AG053217, U19AG051426
John Templeton FoundationJTF

Disease-modifying therapy prescription patterns in people with multiple sclerosis by age
(2021) Therapeutic Advances in Neurological Disorders, 14, . 

Zhang, Y.^a , Salter, A.^b , Jin, S.^c , Culpepper, W.J., II^d , Cutter, G.R.^e , Wallin, M.^d , Stuve, O.^f

^a Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^c VA Maryland Health Care System, Baltimore, MD, United States
^d VA Multiple Sclerosis Center of Excellence-East, Baltimore, MD, United States
^e Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States
^f Neurology Section, VA North Texas Health Care System, Medical Service Dallas, VA Medical Center, 4500 South Lancaster Rd, Dallas, TX 75216, United States

Abstract
Background: Disease-modifying therapies (DMTs) for multiple sclerosis (MS) are approved for their ability to reduce disease activity, namely clinical relapses and signal changes on magnetic resonance imaging (MRI). Disease activity appears age dependent. Thus, the greatest benefit would be expected in younger people with MS (PwMS) whereas benefits in the elderly are uncertain. Methods: Real-world data were obtained from PwMS from the North American Research Committee on Multiple Sclerosis (NARCOMS) registry and the US Department of Veterans Affairs Multiple Sclerosis Surveillance Registry (MSSR). Results: 6948 PwMS were surveyed from NARCOMS, and the MSSR had 1719 participants. In younger adult PwMS 40-years old or less, 183 (61.4%) in NARCOMS and 179 (70.5%) in the MSSR were prescribed DMTs. Among PwMS over age 60, 1575 (40.1%) in NARCOMS and 239 (36.3%) in the MSSR were prescribed DMTs. More PwMS in the age group of 31–40 (p = 0.035) and 41–50 (p = 0.001) in the MSSR were using DMTs compared with PwMS of the same age groups in NARCOMS. Conclusion: These findings suggest that DMTs are under-utilized in the younger population and continue to be commonly prescribed in the elderly. Broader access may explain the higher prescription rate of DMTs in US veterans. © The Author(s), 2021.

Author Keywords
age;  clinical practice;  disease-modifying therapies;  multiple sclerosis

How COVID-19 Affects the Brain
(2021) JAMA Psychiatry, pp. E1-E2. 

Boldrini, M.^a b , Canoll, P.D.^c , Klein, R.S.^d e f

^a Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, New York, United States
^b Department of Psychiatry, New York State Psychiatric Institute, Columbia University, Irving Medical Center, 1051 Riverside Dr, Unit 42, New York, NY 10032, United States
^c Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
^d Department of Medicine, Washington University, School of Medicine in St Louis, St Louis, MO, United States
^e Department of Neuroscience, Washington University, School of Medicine in St Louis, St Louis, MO, United States
^f Department of Pathology and Immunology, Washington University, School of Medicine in St Louis, St Louis, MO, United States

Practicality of Prophylactic Aflibercept to Reduce Diabetic Retinopathy Progression
(2021) JAMA Ophthalmology, . 

Apte, R.S., Hwang, C.K.

Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine in St Louis, St Louis, MO, United States

Encoding sound in the cochlea: from receptor potential to afferent discharge
(2021) Journal of Physiology, . 

Rutherford, M.A.^a , von Gersdorff, H.^b , Goutman, J.D.^c

^a Department of Otolaryngology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Vollum Institute, Oregon Hearing Research Center, Oregon Health and Sciences University, Portland, OR 97239, United States
^c INGEBI (CONICET), (1428) C. A. Buenos Aires, Argentina

Abstract
Ribbon-class synapses in the ear achieve analog to digital transformation of a continuously graded membrane potential to all-or-none spikes. In mammals, several auditory nerve fibres (ANFs) carry information from each inner hair cell (IHC) to the brain in parallel. Heterogeneity of transmission among synapses contributes to the diversity of ANF sound-response properties. In addition to the place code for sound frequency and the rate code for sound level, there is also a temporal code. In series with cochlear amplification and frequency tuning, neural representation of temporal cues over a broad range of sound levels enables auditory comprehension in noisy multi-speaker settings. The IHC membrane time constant introduces a low-pass filter that attenuates fluctuations of the receptor potential above 1–2 kHz. The ANF spike generator adds a high-pass filter via its depolarization-rate threshold that rejects slow changes in the postsynaptic potential and its phasic response property that ensures one spike per depolarization. Synaptic transmission involves several stochastic subcellular processes between IHC depolarization and ANF spike generation, introducing delay and jitter that limits the speed and precision of spike timing. ANFs spike at a preferred phase of periodic sounds in a process called phase-locking that is limited to frequencies below a few kilohertz by both the IHC receptor potential and the jitter in synaptic transmission. During phase-locking to periodic sounds of increasing intensity, faster and facilitated activation of synaptic transmission and spike generation may be offset by presynaptic depletion of synaptic vesicles, resulting in relatively small changes in response phase. Here we review encoding of spike-timing at cochlear ribbon synapses. © 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society

Author Keywords
first-spike latency;  phase-locking;  receptor potential;  ribbon synapse;  synaptic delay;  temporal code

Funding details
National Institutes of HealthNIHRO1 DC014712
National Institute on Deafness and Other Communication DisordersNIDCDDC012938, RO1 DC004274
Agencia Nacional de Promoción Científica y TecnológicaANPCyTPICT 2016 2155

Upregulation of the pathogenic transcription factor SPI1/PU.1 in tuberous sclerosis complex and focal cortical dysplasia by oxidative stress
(2021) Brain Pathology, . 

Zimmer, T.S.^a , Korotkov, A.^a , Zwakenberg, S.^b , Jansen, F.E.^c , Zwartkruis, F.J.T.^b , Rensing, N.R.^d , Wong, M.^d , Mühlebner, A.^a e , van Vliet, E.A.^a f , Aronica, E.^a g , Mills, J.D.^a h i

^a Department of (Neuro)Pathology, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
^b Center for Molecular Medicine, Molecular Cancer Research, University Medical Center Utrecht, Utrecht, Netherlands
^c Department of Pediatric Neurology, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands
^d Department of Neurology, Washington University, Saint Louis, MO, United States
^e Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
^f Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, Netherlands
^g Stichting Epilepsie Instellingen Nederland (SEIN), Heemstede, Netherlands
^h Department of Clinical and Experimental Epilepsy, UCL, London, United Kingdom
ⁱ Chalfont Centre for Epilepsy, Chalfont St Peter, United Kingdom

Abstract
Tuberous sclerosis complex (TSC) is a congenital disorder characterized by cortical malformations and concomitant epilepsy caused by loss-of-function mutations in the mTOR suppressors TSC1 or TSC2. While the underlying molecular changes caused by mTOR activation in TSC have previously been investigated, the drivers of these transcriptional change have not been fully elucidated. A better understanding of the perturbed transcriptional regulation could lead to the identification of novel pathways for therapeutic intervention not only in TSC, but other genetic epilepsies in which mTOR activation plays a key role, such as focal cortical dysplasia 2b (FCD). Here, we analyzed RNA sequencing data from cortical tubers and a tsc2−/− zebrafish. We identified differential expression of the transcription factors (TFs) SPI1/PU.1, IRF8, GBX2, and IKZF1 of which SPI1/PU.1 and IRF8 targets were enriched among the differentially expressed genes. Furthermore, for SPI1/PU.1 these findings were conserved in TSC zebrafish model. Next, we confirmed overexpression of SPI1/PU.1 on the RNA and protein level in a separate cohort of surgically resected TSC tubers and FCD tissue, in fetal TSC tissue, and a Tsc1GFAP−/− mouse model of TSC. Subsequently, we validated the expression of SPI1/PU.1 in dysmorphic cells with mTOR activation in TSC tubers. In fetal TSC, we detected SPI1/PU.1 expression prenatally and elevated RNA Spi1 expression in Tsc1GFAP−/− mice before the development of seizures. Finally, in vitro, we identified that in astrocytes and neurons SPI1 transcription was driven by H2O2-induced oxidative stress, independent of mTOR. We identified SPI1/PU.1 as a novel TF involved in the pro-inflammatory gene expression of malformed cells in TSC and FCD 2b. This transcriptional program is activated in response to oxidative stress and already present prenatally. Importantly, SPI1/PU.1 protein appears to be strictly limited to malformed cells, as we did not find SPI1/PU.1 protein expression in mice nor in our in vitro models. © 2021 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology

Author Keywords
brain inflammation;  epilepsy;  focal cortical dysplasia;  mTOR;  oxidative stress;  tuberous sclerosis complex

Funding details
10‐02
952455
National Institutes of HealthNIHR01 NS056872
Seventh Framework ProgrammeFP7602391
Seventh Framework ProgrammeFP7
Epilepsiefonds16‐05, 20‐11
Horizon 2020642881, 722053

Amygdala Functional Connectivity and Negative Reactive Temperament at Age 4 Months
(2021) Journal of the American Academy of Child and Adolescent Psychiatry, . 

Filippi, C.A.^a b , Ravi, S.^a , Bracy, M.^a , Winkler, A.^b , Sylvester, C.M.^c , Pine, D.S.^b , Fox, N.A.^a

^a University of Maryland, College Park, United States
^b National Institute of Mental Health (NIMH), Bethesda, MD, United States
^c Washington University, St. Louis, MO, United States

Abstract
Objective: Infant amygdala connectivity correlates with maternal reports of infant temperament characterized by novelty-evoked distress and avoidance. However, no studies have examined how human infant amygdala connectivity relates to direct observations of novelty-evoked distress. This study examined the link between amygdala connectivity and infant novelty-evoked distress using direct observation of temperament. Method: Novelty-evoked distress was assessed at 4 months of age (N = 90) using a standardized reactivity assessment and parent report. Within 3 weeks of assessment, resting-state functional magnetic resonance imaging was collected in a subset of infants (n = 34). Using a whole-brain voxelwise approach, amygdala connectivity associated with positive and negative affect during the reactivity assessment was examined. Regions where the association of amygdala connectivity with negative affect was higher than with positive affect were then examined. Associations between amygdala connectivity and parent report of temperament were also examined. Results: Greater amygdala-cingulate and amygdala–superior frontal gyrus connectivity was associated with lower positive affect during the reactivity assessment. Further, the association between amygdala-cingulate connectivity was greater for negative affect compared with positive affect. There were no significant associations between latency to approach novelty (as measured by parent report) and amygdala connectivity. Validation analyses conducted using a large independent longitudinal sample (N = 323) demonstrated that negative reactivity was associated with increased child-reported anxiety symptoms in adolescence. Conclusion: These results provide novel insight into the developmental pathophysiology of novelty-evoked distress. This is consistent with research linking an altered cognitive control mechanism to temperamental risk for anxiety. © 2021

Author Keywords
amygdala;  functional connectivity;  infant MRI;  negative reactivity;  temperament

Funding details
National Institute of Mental HealthNIMHK23MH109983, R01MH122389, U01MH093349, ZIA-MH-002782
Brain and Behavior Research FoundationBBRF
James S. McDonnell FoundationJSMF

TicTimer Web: Software for measuring tic suppression remotely
(2021) F1000Research, 9, art. no. 1264, . 

Black, J.K.^a , Black, K.J.^b c d e , Koller, J.M.^b c

^a Department of Mechanical Engineering, Brigham Young University, Provo, UT 84602, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Woods and Himle developed a standardized tic suppression paradigm (TSP) for the experimental setting, to quantify the effects of intentional tic suppression in Tourette syndrome. We previously provided a computer program to facilitate recording tic occurrence and to automate reward delivery during the several experimental conditions of the TSP. The present article describes a web-based program that performs the same functions. Implementing this program on the web allows research sessions to be performed remotely, in tandem with a video calling program. Relevant data for each session, such as the timing of tics and dispensed rewards, are stored in plain text files for later analysis. Expected applications include research on Tourette syndrome and related disorders. © 2021 Black JK et al.

Author Keywords
Reinforcement (psychology);  Reward;  Software;  Tic disorders;  Tourette syndrome