WashU weekly Neuroscience publications: May 2, 2022

Naturalistic driving measures of route selection associate with resting state networks in older adults
(2022) Scientific Reports, 12 (1), art. no. 6486, . 

Wisch, J.K.^a , Roe, C.M.^a , Babulal, G.M.^a d e , Metcalf, N.^a , Johnson, A.M.^f , Murphy, S.^a , Hicks, J.^a , Doherty, J.M.^a , Morris, J.C.^a c , Ances, B.M.^a b c

^a Department of Neurology, Washington University in Saint Louis School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO 63110, United States
^b Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
^d Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
^e Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
^f Center for Clinical Studies, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities. © 2022, The Author(s).

Funding details
P01AG003991, P01AG026276, P30AG0066444
R01AG056466, R01AG067428, R01AG074302
UL1 TR000448
National Institutes of HealthNIHR01AG068183, R01NR012657, R01NR012907, R01NR014449
Foundation for the National Institutes of HealthFNIH
BrightFocus FoundationBFFA2021142S
Foundation for Barnes-Jewish HospitalFBJH
Hope Center for Neurological Disorders

Behavioral outcomes of complete Freund adjuvant-induced inflammatory pain in the rodent hind paw: a systematic review and meta-analysis
(2022) Pain, 163 (5), pp. 809-819. 

Burek, D.J.^a b c , Massaly, N.^a c , Yoon, H.J.^a c , Doering, M.^d , Morón, J.A.^a b c e

^a Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^c Washington University in St. Louis Pain Center, St. Louis, MO, United States
^d Bernard Becker Medical Library, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
ABSTRACT: Many analgesics inadequately address the psychiatric comorbidities of chronic and persistent pain, but there is no standard preclinical model of pain-altered behavior to support the development of new therapies. To explore this conflicting and inconclusive literature, we conducted a focused systematic review and meta-analysis on the effect of complete Freund adjuvant-induced (CFA) rodent hind paw inflammation on multiple classical indicators of exploratory behavior, stress coping, and naturalistic behavior. Our primary objective was to define CFA’s effect on assays including, but not limited to, the elevated plus maze and forced swim test. Our secondary objective was to discover how variables such as species and strain may influence outcomes in such assays. We searched Ovid MEDLINE, Embase, Scopus, and Web of Science in April and October 2020 for studies with adult rodents injected with CFA into the hind paw and subsequently tested for aspects of “anxiety-like” or “depressive-like” behaviors. Forty-four studies evaluated performance in the elevated plus or zero maze, open field test, light-dark box, place escape and avoidance paradigm, forced swim test, tail suspension test, sucrose preference test, wheel running, and burrowing assay. Complete Freund adjuvant modestly but significantly decreased exploratory behavior, significantly increased passive stress coping in the tail suspension test but not the forced swim test, and significantly decreased preference for sucrose and naturally rewarding activity. Subgroup analyses revealed significant differences between species and animal sourcing. Based on the evidence provided here, we conclude future studies should focus on CFA’s effect on natural rewards and naturalistic behaviors. Copyright © 2022 International Association for the Study of Pain.

Centrosome-dependent microtubule modifications set the conditions for axon formation
(2022) Cell Reports, 39 (3), art. no. 110686, . 

Meka, D.P.^a , Kobler, O.^b , Hong, S.^a , Friedrich, C.M.^a , Wuesthoff, S.^a , Henis, M.^a c , Schwanke, B.^a , Krisp, C.^d , Schmuelling, N.^a , Rueter, R.^a , Ruecker, T.^a , Betleja, E.^e , Cheng, T.^e , Mahjoub, M.R.^e , Soba, P.^f g , Schlüter, H.^d , Fornasiero, E.F.^h , Calderon de Anda, F.^a

^a Institute of Developmental Neurophysiology, Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, 20251, Germany
^b Combinatorial Neuroimaging Core Facility, Leibniz Institute for Neurobiology, Magdeburg, 39118, Germany
^c Department of Anatomy and Histology, Faculty of Veterinary Medicine, New Valley University, El-Kharga, 72511, Egypt
^d Institute for Clinical Chemistry and Laboratory Medicine, Mass Spectrometric Proteomics Group, Campus Forschung, University Medical Center Hamburg-Eppendorf, Hamburg, 20246, Germany
^e Department of Medicine (Nephrology Division), Washington University, St. Louis, MO 63110, United States
^f LIMES Institute, Department of Molecular Brain Physiology and Behavior, University of Bonn, Bonn, 53115, Germany
^g Institute of Physiology and Pathophysiology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, 91054, Germany
^h Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, Göttingen, 37073, Germany

Abstract
Microtubule (MT) modifications are critical during axon development, with stable MTs populating the axon. How these modifications are spatially coordinated is unclear. Here, via high-resolution microscopy, we show that early developing neurons have fewer somatic acetylated MTs restricted near the centrosome. At later stages, however, acetylated MTs spread out in soma and concentrate in growing axon. Live imaging in early plated neurons of the MT plus-end protein, EB3, show increased displacement and growth rate near the MTOC, suggesting local differences that might support axon selection. Moreover, F-actin disruption in early developing neurons, which show fewer somatic acetylated MTs, does not induce multiple axons, unlike later stages. Overexpression of centrosomal protein 120 (Cep120), which promotes MT acetylation/stabilization, induces multiple axons, while its knockdown downregulates proteins modulating MT dynamics and stability, hampering axon formation. Collectively, we show how centrosome-dependent MT modifications contribute to axon formation. © 2022 The Author(s)

Author Keywords
acetylated microtubules;  axon formation;  centrosome;  Cep120;  CP: Cell biology;  microtubules;  neuronal polarity

Funding details
SO 1337/2-2, SO 1337/4-1, SO 1337/6-1, SO 1337/7-1
FO 1342/1-3, T0287/35359/2020
EU Joint Programme – Neurodegenerative Disease ResearchJPND01ED1806
Deutsche ForschungsgemeinschaftDFGCA 1495/4-1, CA 1495/7-1, CA1495/1-1, FOR 2419
Bundesministerium für Bildung und ForschungBMBF01 EW2108B, 01EW1410, 01EW1910
Universitätsklinikum Hamburg-EppendorfUKE

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders
(2022) Cell Reports Medicine, 3 (4), art. no. 100607, . 

Gendron, T.F.^a b , Heckman, M.G.^c , White, L.J.^c , Veire, A.M.^a , Pedraza, O.^d , Burch, A.R.^e , Bozoki, A.C.^f , Dickerson, B.C.^g , Domoto-Reilly, K.^h , Foroud, T.ⁱ , Forsberg, L.K.^j , Galasko, D.R.^k , Ghoshal, N.^l m , Graff-Radford, N.R.^e , Grossman, M.ⁿ , Heuer, H.W.^o , Huey, E.D.^p q , Hsiung, G.-Y.R.^r , Irwin, D.J.^s , Kaufer, D.I.^f , Leger, G.C.^k , Litvan, I.^k , Masdeu, J.C.^t , Mendez, M.F.^u v , Onyike, C.U.^w , Pascual, B.^t , Ritter, A.^x , Roberson, E.D.^y , Rojas, J.C.^o , Tartaglia, M.C.^z , Wszolek, Z.K.^e , Rosen, H.^o , Boeve, B.F.^j , Boxer, A.L.^o , Appleby, B.S.^aa , Barmada, S.^aa , Bordelon, Y.^aa , Botha, H.^aa , Brushaber, D.^aa , Clark, D.^aa , Coppola, G.^aa , Darby, R.^aa , Devick, K.^aa , Dickson, D.^aa , Faber, K.^aa , Fagan, A.^aa , Fields, J.A.^aa , Gavrilova, R.^aa , Geschwind, D.^aa , Goldman, J.^aa , Graff-Radford, J.^aa , Grant, I.^aa , Jones, D.T.^aa , Kantarci, K.^aa , Kerwin, D.^aa , Knopman, D.S.^aa , Kornak, J.^aa , Kremers, W.^aa , Lapid, M.^aa , Lago, A.L.^aa , Ljubenkov, P.^aa , Lucente, D.^aa , Mackenzie, I.R.^aa , McGinnis, S.^aa , Mester, C.^aa , Miller, B.L.^aa , Pressman, P.^aa , Rademakers, R.^aa , Ramanan, V.K.^aa , Ramos, E.M.^aa , Rankin, K.P.^aa , Rao, M.^aa , Rascovsky, K.^aa , Savica, R.^aa , Seeley, W.^aa , Staffaroni, A.M.^aa , Syrjanen, J.^aa , Taylor, J.^aa , VandeVrede, L.^aa , Weintraub, S.^aa , Wong, B.^aa , Petrucelli, L.^a b , ALLFTD consortium^ab

^a Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, United States
^b Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, United States
^c Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL 32224, United States
^d Department of Psychiatry & Psychology, Mayo Clinic, Jacksonville, FL 32224, United States
^e Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, United States
^f Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
^g Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States
^h Department of Neurology, University of Washington, Seattle, WA 98104, United States
ⁱ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, United States
^j Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
^k Parkinson and Other Movement Disorder Center, Department of Neuroscience, University of California, San Diego, La Jolla, CA 92037, United States
^l Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^m Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁿ Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, United States
^o Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA 94158, United States
^p Department of Psychiatry, Taub Institute, Columbia University, New York, NY 10032, United States
^q Department of Neurology, Taub Institute, Columbia University, New York, NY 10032, United States
^r Centre for Brain Health, Department of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
^s Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States
^t Nantz National Alzheimer Center, Stanley H. Appel Department of Neurology, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX 77030, United States
^u Department of Neurology, University of California at Los Angeles, Los Angeles, CA 90095, United States
^v Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA 90095, United States
^w Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD 21287, United States
^x Neurological Institute, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV 89106, United States
^y Center for Neurodegeneration and Experimental Therapeutics, Alzheimer’s Disease Center, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
^z Krembil Brain Institute, Tanz Centre for Research in Neurodegenerative Diseases, Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada

Abstract
Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations. © 2022 The Author(s)

Author Keywords
behavioral variant frontotemporal dementia;  biomarker;  corticobasal syndrome;  neurofilament light;  plasma;  presymptomatic;  primary progressive aphasia;  progressive supranuclear palsy;  Richardson’s syndrome

Funding details
BHV3241-301, BHV4157-206
U24AG021886
NLY01-PD-1
01.001, VGL101
National Institutes of HealthNIHR01AG038791, R01AG073482, U24AG057437
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDSU19AG063911, U54NS092089
Mayo Clinic
Alzheimer’s AssociationAA
Bristol-Myers SquibbBMS
Alzheimer’s Drug Discovery FoundationADDF
Association for Frontotemporal DegenerationAFTDP01NS084974, P01NS099114, R35NS097273
Eli Lilly and Company
GlaxoSmithKlineGSK
Novartis
Roche
Biogen
National Center for Advancing Translational SciencesNCATSU01AG045390
AbbVie
University of California, San DiegoUCSD
Janssen Pharmaceuticals
Lawson Health Research Institute
Applied Genetic Technologies CorporationAGTCK23AG059888
Sol Goldman Charitable Trust
Rainwater Charitable FoundationRCF
Eisai

High-speed multi-parametric photoacoustic microscopy of cerebral hemodynamic and metabolic responses to acute hemodilution
(2022) Optics Letters, 47 (8), pp. 1988-1991. 

Wang, Y.^a b c , Zhong, F.^a d , Sun, N.^a d , Xu, Z.^a c , Li, J.^e , Liu, Q.^c , Li, Z.^b c , Zuo, Z.^e , Hu, S.^a d

^a Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, United States
^b National Engineering Laboratory for Fiber Optic Sensing Technology, Wuhan University of Technology, Wuhan, 430070, China
^c School of Information Engineering, Wuhan University of Technology, Wuhan, 430070, China
^d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^e Department of Anesthesiology, University of Virginia, Charlottesville, VA 22908, United States

Abstract
The ability of hemodilution to improve vascular circulatory impairment has been demonstrated. However, the effects of acute hemodilution on cerebral hemodynamics and oxygen metabolism have not been assessed at the microscopic level, due to technical limitations. To fill this void, we have developed a new, to the best of our knowledge, photoacoustic microscopy system, which enables high-speed imaging of blood hemoglobin concentration, oxygenation, flow, and oxygen metabolism in vivo. The system performance was examined in both phantoms and the awake mouse brain. This new technique enabled wide-field (4.5×3 mm2) multi-parametric imaging of the mouse cortex at 1 frame/min. Narrowing the field of view to 1.5×1.5 mm2 allowed dynamic imaging of the cerebral hemodynamic and metabolic responses to acute hypervolemic hemodilution at 6 frames/min. Quantitative analysis of the hemodilutioninduced cerebrovascular responses over time showed rapid increases in the vessel diameter (within 50-210 s) and blood flow (50-210 s), as well as decreases in the hemoglobin concentration (10-480 s) and metabolic rate of oxygen (20-480 s) after the acute hemodilution, followed by a gradual recovery to the baseline levels in 1440 s. Providing comprehensive insights into dynamic changes of the cerebrovascular structure and function in vivo, this technique opens new opportunities for mechanistic studies of acute brain diseases or responses to various stimuli. © 2022 Optica Publishing Group.

Failed Targeted Muscle Reinnervation: Findings at Revision Surgery and Concepts for Success
(2022) Plastic and Reconstructive Surgery – Global Open, 10 (4), p. E4229. 

Felder, J.M., Pripotnev, S., Ducic, I., Skladman, R., Ha, A.Y., Pet, M.A.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Although it was initially described for improved myoelectric control, targeted muscle reinnervation (TMR) has quickly gained popularity as a technique for neuroma control. With this rapid increase in utilization has come broadening indications and variability in the described technique. As a result, it becomes difficult to interpret published outcomes. Furthermore, there is no literature discussing the management of failed cases which are undoubtedly occurring. Methods: This is a retrospective case series of two patients who underwent revision surgery for failed TMR. The authors also review the current literature on TMR and outline technical and conceptual pitfalls and pearls based on our local experience. Results: Excessive donor nerve redundancy, kinking, donor-recipient nerve size mismatch, superficial placement of the nerve coaptation, inappropriate target selection, and incomplete target muscle denervation were identified as technical pitfalls of TMR surgery. Techniques to avoid these pitfalls were described. Conclusions: Although TMR has been a major development in amputee care for both pain management and improved myoelectric control, it is important to acknowledge that it is not a foolproof surgery and does not provide a guaranteed result. Failed cases of TMR represent opportunities to learn about factors contributing to unfavorable outcomes and refine our techniques empirically. © 2022 Lippincott Williams and Wilkins. All rights reserved.

A Multivariate Functional Connectivity Approach to Mapping Brain Networks and Imputing Neural Activity in Mice
(2022) Cerebral Cortex (New York, N.Y. : 1991), 32 (8), pp. 1593-1607. 

Brier, L.M.^a , Zhang, X.^b , Bice, A.R.^a , Gaines, S.H.^a , Landsness, E.C.^c , Lee, J.-M.^c , Anastasio, M.A.^b , Culver, J.P.^a d e f

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Department of Bioengineering, University of Illinois, Urbana-ChampaignIL 61801, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, USA
^d Department of Biomedical Engineering, Washington University School of Engineering, St. Louis, MO 63105, USA
^e Department of Electrical and Systems Engineering, Washington University School of Engineering, St. Louis, MO 63112, USA
^f Department of Physics, Washington University School of Arts and Science, St. Louis, MO 63130, USA

Abstract
Temporal correlation analysis of spontaneous brain activity (e.g., Pearson “functional connectivity,” FC) has provided insights into the functional organization of the human brain. However, bivariate analysis techniques such as this are often susceptible to confounding physiological processes (e.g., sleep, Mayer-waves, breathing, motion), which makes it difficult to accurately map connectivity in health and disease as these physiological processes affect FC. In contrast, a multivariate approach to imputing individual neural networks from spontaneous neuroimaging data could be influential to our conceptual understanding of FC and provide performance advantages. Therefore, we analyzed neural calcium imaging data from Thy1-GCaMP6f mice while either awake, asleep, anesthetized, during low and high bouts of motion, or before and after photothrombotic stroke. A linear support vector regression approach was used to determine the optimal weights for integrating the signals from the remaining pixels to accurately predict neural activity in a region of interest (ROI). The resultant weight maps for each ROI were interpreted as multivariate functional connectivity (MFC), resembled anatomical connectivity, and demonstrated a sparser set of strong focused positive connections than traditional FC. While global variations in data have large effects on standard correlation FC analysis, the MFC mapping methods were mostly impervious. Lastly, MFC analysis provided a more powerful connectivity deficit detection following stroke compared to traditional FC. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
calcium neuroimaging;  multivariate functional connectivity;  Pearson functional connectivity;  support vector regression

Functional Connectivity of the Developing Mouse Cortex
(2022) Cerebral Cortex (New York, N.Y. : 1991), 32 (8), pp. 1755-1768. 

Rahn, R.M.^a b c , Brier, L.M.^a , Bice, A.R.^a , Reisman, M.D.^d , Dougherty, J.D.^b c , Culver, J.P.^a d e

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA
^d Department of Physics, Washington University in St. Louis, St. Louis, MO 63110, USA
^e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, USA

Abstract
Cross-sectional studies have established a variety of structural, synaptic, and cell physiological changes corresponding to critical periods in cortical development. However, the emergence of functional connectivity (FC) in development has not been fully characterized, and hemodynamic-based measures are vulnerable to any neurovascular coupling changes occurring in parallel. We therefore used optical fluorescence imaging to trace longitudinal calcium FC in the awake, resting-state mouse cortex at 5 developmental timepoints beginning at postnatal day 15 (P15) and ending in early adulthood at P60. Calcium FC displayed coherent functional maps as early as P15, and FC significantly varied in connections between many regions across development, with the developmental trajectory’s shape specific to the functional region. Evaluating 325 seed-seed connections, we found that there was a significant increase in FC between P15 and P22 over the majority of the cortex as well as bilateral connectivity and node degree differences in frontal, motor, and retrosplenial cortices after P22. A rebalancing of inter- and intrahemispheric FC and local-distal FC dominance was also observed during development. This longitudinal developmental calcium FC study therefore provides a resource dataset to the field and identifies periods of dynamic change which cross-sectional studies may target for examination of disease states. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
calcium imaging;  development;  mouse model;  resting state

Frequency of the Dopamine Receptor D3 (rs6280) vs. Opioid Receptor µ1 (rs1799971) Polymorphic Risk Alleles in Patients with Opioid Use Disorder: A Preponderance of Dopaminergic Mechanisms?
(2022) Biomedicines, 10 (4), art. no. 870, . 

Gondré-Lewis, M.C.^a , Elman, I.^b , Alim, T.^c , Chapman, E.^c , Settles-Reaves, B.^a , Galvao, C.^a , Gold, M.S.^d , Baron, D.^e , Kazmi, S.^f , Gardner, E.^g , Gupta, A.^h , Dennen, C.ⁱ , Blum, K.^{e i j k l m}

^a Neuropsychopharmacology Laboratory, Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, United States
^b Department of Psychiatry, Cambridge Health Alliance/Harvard Medical School, Cambridge, MA 02139, United States
^c Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC 20059, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Graduate College, Western University Health Sciences, Pomona, CA 91766, United States
^f College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, United States
^g Neuropsychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, United States
^h Future Biologics, Lawrenceville, GA 30043, United States
ⁱ The Kenneth Blum Behavioral & Neurogenetic Institute, Austin, TX 78701, United States
^j Department of Clinical Psychology and Addiction, Institute of Psychology, Faculty of Education and Psychology, ELTE Eötvös Loránd University, Egyetem tér 1-3, Budapest, 1053, Hungary
^k Department of Psychiatry, School of Medicine, University of Vermont, Burlington, VT 05405, United States
^l Centre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology, Nonakuri, Purba Medinipur, West Bengal721172, India
^m Department of Psychiatry, Wright State University Boonshoft School of Medicine and Dayton VA Medical Centre, Dayton, OH 45324, United States

Abstract
While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwith-standing published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic alterations across dopaminergic reward systems lead to uncontrollable self-administration of opioids and other drugs. For instance, diminished availability via knockout of dopamine D3 receptor (DRD3) increases vulnerability to opioids. Building upon this concept via the use of a sophisticated polymorphic risk analysis in a human cohort of chronic opioid users, we found evidence for a higher frequency of polymorphic DRD3 risk allele (rs6280) than opioid receptor µ1 (rs1799971). In conclusion, while opioidergic mechanisms are involved in OUD, dopamine-related receptors may have primary influ-ence on opioid-seeking behavior in African Americans. These findings suggest OUD-targeted novel and improved neuropharmacological therapies may require focus on DRD3-mediated regulation of dopaminergic homeostasis. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
African American;  brain reward cascade;  dopaminergic mechanisms;  DRD3;  epigenetics;  GARS;  genetic variations;  mesolimbic circuitry;  opioid epidemic;  opioids;  OPRM1

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA021262
National Institute on AgingNIA
National Heart, Lung, and Blood InstituteNHLBI
National Cancer InstituteNCI
National Institute of Nursing ResearchNINR
National Institute of Allergy and Infectious DiseasesNIAID
Fogarty International CenterFIC
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
National Institute of Dental and Craniofacial ResearchNIDCR
Office of AIDS ResearchOAR
National Institute on Minority Health and Health DisparitiesNIMHD007597, MD012318
District of Columbia Developmental Center for AIDS ResearchDC D-CFARP30AI117970
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Howard University

Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials
(2022) Frontiers in Immunology, 13, art. no. 852563, . 

Ziemssen, T.^a , Arnold, D.L.^b c , Alvarez, E.^d , Cross, A.H.^e , Willi, R.^f , Li, B.^g , Kukkaro, P.^f , Kropshofer, H.^f , Ramanathan, K.^f , Merschhemke, M.^f , Kieseier, B.^f , Su, W.^g , Häring, D.A.^f , Hauser, S.L.^h , Kappos, L.^i j , Kuhle, J.^i j

^a Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl-Gustav Carus, Dresden, Germany
^b Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
^c NeuroRx Research, Montreal, QC, Canada
^d Department of Neurology, Rocky Mountain MS Center at the University of Colorado, Aurora, CO, United States
^e Department of Neurology, Washington University School of Medicine, Saint LouisMO, United States
^f Novartis Pharma AG, Basel, Switzerland
^g Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
^h UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, United States
ⁱ Neurologic Clinic and Policlinic and MS Center, Department of Head, Spine and Neuromedicine, University Hospital Basel, Basel, Switzerland
^j Research Center for Clinical Neuroimmunology and Neuroscience (RC2NB), Departments of Biomedicine and Clinical Research, University Hospital and University of Basel, Basel, Switzerland

Abstract
Objective: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS). Background: Previous post-hoc studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment. Design/Methods: In this study, we report protocol-planned analyses from the pooled ASCLEPIOS I/II trials (N=1882). Per protocol, patients were stratified by median baseline sNfL levels (9.3 pg/ml) into high (>median) and low (≤median) categories to prognosticate: annualized rate of new/enlarging T2 (neT2) lesions in year 1 and 2, annualized relapse rate, annual percentage change in whole brain (WB) and regional brain volume [thalamus, white matter (WM), cortical gray matter (cGM)], and disability outcomes. Similar analyses were performed for the recently diagnosed (within 3 years), treatment-naive patients (no prior disease-modifying therapy) subgroup. Results: High versus low sNfL at baseline was prognostic of increased on-study T2 lesion formation at year 1 (relative increase: ofatumumab +158%; teriflunomide +69%, both p<0.001), which persisted in year 2 (+65%, p=0.124; +46%, p=0.003); of higher annual percentage change of WB volume (ofatumumab, −0.32% vs. −0.24%, p=0.044, and teriflunomide, −0.43% vs. −0.29%, p=0.002), thalamic volume (−0.56% vs. −0.31%, p=0.047 and −0.94% vs. −0.49%, p<0.001), and WM volume (−0.30% vs. −0.19%, p=0.083 and −0.38% vs. −0.18%, p=0.003) but not of cGM volume (−0.39% vs. −0.32%, p=0.337 and −0.49% vs. −0.46%, p=0.563). A single sNfL assessment at baseline was not prognostic for on-study relapses or disability worsening. Results were similar in the subgroup of recently diagnosed, treatment-naive patients. Conclusion: This study confirms that baseline sNfL levels are prognostic of future on-study lesion formation and whole brain and regional atrophy in all RMS patients, including recently diagnosed, treatment-naive patients. Copyright © 2022 Ziemssen, Arnold, Alvarez, Cross, Willi, Li, Kukkaro, Kropshofer, Ramanathan, Merschhemke, Kieseier, Su, Häring, Hauser, Kappos and Kuhle.

Author Keywords
brain atrophy;  lesion formation;  MS disease activity;  prognostic biomarker;  serum neurofilament light chain

Funding details
Pfizer
Genzyme
Novartis
Roche
Sanofi
EMD Serono
Biogen
Actelion Pharmaceuticals
Teva Pharmaceutical Industries
Allergan
Universität Basel
European Committee for Treatment and Research in Multiple SclerosisECTRIMS
Novartis Pharma
Merck KGaA
Universitätsspital BaselUHB
European CommissionEC
Bayer HealthCareBHC
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF320030_160221
Shire
Schweizerische Multiple Sklerose Gesellschaft

Cerebral amyloid angiopathy is associated with glymphatic transport reduction and time-delayed solute drainage along the neck arteries
(2022) Nature Aging, 2 (3), pp. 214-223. 

Chen, X.^a , Liu, X.^b , Koundal, S.^b , Elkin, R.^c , Zhu, X.^d , Monte, B.^b , Xu, F.^d , Dai, F.^e , Pedram, M.^b , Lee, H.^b , Kipnis, J.^f , Tannenbaum, A.^a g , Van Nostrand, W.E.^d , Benveniste, H.^b h

^a Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, United States
^b Department of Anesthesiology, Yale School of Medicine, New Haven, CT, United States
^c Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY, United States
^d George and Anne Ryan Institute for Neuroscience and the Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, United States
^e Yale Center for Analytical Sciences, Yale School of Public Health, New Haven, CT, United States
^f Center for Brain Immunology and Glia, Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
^g Department of Computer Science, Stony Brook University, Stony Brook, NY, United States
^h Department of Biomedical Engineering, Yale School of Medicine New Haven, New Haven, CT, United States

Abstract
Cerebral amyloid angiopathy (CAA) is a common disease in older adults that contributes to dementia1–3. In CAA, amyloid beta (Aβ) is deposited along either capillaries (type 1) or vessel walls (type 2)4, with the underlying pathophysiology incompletely understood5. Here, we developed imaging and analysis tools based on regularized optimal mass transport (rOMT) theory6,7 to characterize cerebrospinal fluid (CSF) flow dynamics and glymphatic transport in a transgenic CAA type 1 rat model. We discovered that, in CAA, CSF moves more rapidly along the periarterial spaces that serve as influx routes to the glymphatic system. The observation of high-speed CSF flow currents in CAA was unexpected given the build-up of microvascular Aβ. However, velocity flux vector analysis revealed that CSF currents in CAA are partly diverted away from the brain, resulting in overall decreased glymphatic transport. Imaging at the neck showed that drainage to the deep cervical lymph nodes occurs along the carotid arteries and is time delayed in CAA, implying that upstream connections to the meningeal lymphatics were altered. Based on our findings we propose that, in CAA, both glymphatic transport and lymphatic drainage are compromised and that both systems represent therapeutic targets for treatment of CAA-related cognitive decline and dementia. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAAG053991
Air Force Office of Scientific ResearchAFOSRFA955-20-1-0029
Yale University

Rat Brain Global Ischemia–Induced Diffusion Changes Revisited: Biophysical Modeling of the Water and NAA MR “Diffusion Signal”
(2022) Magnetic Resonance in Medicine, . 

Spees, W.M.^a , Sukstanskii, A.L.^a , Bretthorst, G.L.^a , Neil, J.J.^a b c , Ackerman, J.J.H.^a d e f

^a Biomedical MR Laboratory, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Chemistry, Washington University, St. Louis, MO, United States
^e Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Alvin J Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: To assess changes in intracellular diffusion as a mechanism for the reduction in water ADC that accompanies brain injury. Using NAA as a marker of neuronal cytoplasmic diffusion, NAA diffusion was measured before and after global ischemia (immediately postmortem) in the female Sprague–Dawley rat. Methods: Diffusion-weighted PRESS spectra, with diffusion encoding in a single direction, were acquired from large voxels of rat brain gray matter in vivo and postischemia employing either pairs of pulsed half-sine–shaped gradients (in vivo and postischemia, bmax = 19 ms/μm2) or sinusoidal oscillating gradients (in vivo only) with frequencies of 99.2–250 Hz. A 2D randomly oriented cylinder (neurite) model gave estimates of longitudinal and transverse diffusivities (DL and DT, respectively). In this model, DL represents the “free” diffusivity of NAA, whereas DT reflects highly restricted diffusion. Using oscillating gradients, the frequency dependence of DT [DT(ω)] gave estimates of the cylinder (axon/dendrite) radius. Results: A 10% decrease in DL,NAA followed global ischemia, dropping from 0.391 ± 0.012 μm2/ms to 0.350 ± 0.009 μm2/ms. Modeling DT,NAA(ω) provided an estimate of the neurite radius of 1.0 ± 0.6 μm. Conclusion: Whereas the increase in apparent intraneuronal viscosity suggested by changes in DL,NAA may contribute to the overall reduction in water ADC associated with brain injury, it is not sufficient to be the sole explanation. Estimates of neurite radius based on DT(ω) were consistent with literature values. © 2022 International Society for Magnetic Resonance in Medicine.

Author Keywords
intraneuronal viscosity;  metabolite diffusion;  N-acetyl aspartate;  stroke

Lack of clinically relevant differences in safety and pharmacokinetics after second-dose administration of intranasal diazepam within 4 h for acute treatment of seizure clusters: A population analysis
(2022) Epilepsia, . 

Cascino, G.D.^a , Tarquinio, D.^b , Wheless, J.W.^c , Hogan, R.E.^d , Sperling, M.R.^e , Desai, J.^f , Vazquez, B.^g , Samara, E.^h , Misra, S.N.ⁱ , Carrazana, E.^i j , Rabinowicz, A.L.ⁱ , for the DIAZ.001.05 Study Group^k

^a Mayo Clinic, Rochester, MN, United States
^b Center for Rare Neurological Diseases, Atlanta, GA, United States
^c Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Memphis, TN, United States
^d Washington University in St Louis, St Louis, MO, United States
^e Thomas Jefferson University, Philadelphia, PA, United States
^f Children’s Hospital of Los AngelesCA, United States
^g Comprehensive Epilepsy Center, New York University, New York, NY, United States
^h PharmaPolaris International, Washington, District of Columbia, United States
ⁱ Neurelis, San Diego, CA, United States
^j John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, United States

Abstract
Objective: Current diazepam nasal spray labeling requires waiting 4 h before administering a second dose. The objective of the current analyses was to examine safety and pharmacokinetic profiles of second doses of diazepam nasal spray given 0−4 h after the first dose. Methods: Two datasets were analyzed. The first, a long-term, repeat-dose safety study of diazepam nasal spray, compared rates of treatment-emergent adverse events (TEAEs), serious TEAEs, and treatment-related TEAEs for patients receiving ≥1 second dose ≤4 h versus all second doses >4 h after the first. The second was a population pharmacokinetic analysis using data from three phase 1 studies to model drug exposure when a second dose of diazepam nasal spray was administered across multiple time points (1 min−4 h) following the first dose. Results: In the repeat-dose safety study, a second dose of diazepam nasal spray was administered ≤24 h after the first to treat 485 seizure clusters in 79 patients. Rates of TEAEs were similar between patients receiving ≥1 second dose in ≤4 h (89.5%, n = 38) compared with >4–24 h only (80.5%, n = 41). The most common treatment-related TEAEs were associated with nasal discomfort, which was mild or moderate and transient. There were no reports of respiratory or cardiac depression. The pharmacokinetic simulations of second doses predicted comparable elevations of plasma diazepam concentrations with administrations across a range of intervals after the first dose (1 min−4 h). Significance: These data indicate that the safety and pharmacokinetic profiles of a second dose of diazepam nasal spray administered within 4 h of the first dose are consistent with those associated with current labeling. This is potentially important for patients with seizure clusters who have a recurrent seizure within 4 h of first treatment and might benefit from immediate retreatment to reduce the risk of progression to status epilepticus. © 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Author Keywords
acute repetitive seizure;  benzodiazepine;  nasal spray;  seizure emergency

Funding details
School of Public Health, University of California BerkeleyUCB

Protracted course progressive supranuclear palsy
(2022) European Journal of Neurology, . 

Couto, B.^a , Martinez-Valbuena, I.^b , Lee, S.^b , Alfradique-Dunham, I.^c , Perrin, R.J.^d , Perlmutter, J.S.^e , Cruchaga, C.^f , Kim, A.^b , Visanji, N.^a b , Sato, C.^b , Rogaeva, E.^b , Lang, A.E.^a , Kovacs, G.G.^a b g h

^a Edmond J. Safra Program in Parkinson’s Disease, Rossy Program for PSP Research and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada
^b Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada
^c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^d Department of Pathology and Immunology, Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^e Department of Neurology, Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University in St Louis, St Louis, MO, United States
^f Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^g Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, ON, Canada
^h Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada

Abstract
Background and purpose: Progressive supranuclear palsy (PSP) encompasses a broader range of disease courses than previously appreciated. The most frequent clinical presentations of PSP are Richardson syndrome (RS) and PSP with a predominant Parkinsonism phenotype (PSP-P). Time to reach gait dependence and cognitive impairment have been proposed as prognostic disease milestones. Genetic polymorphisms in TRIM11 and SLC2A13 genes have been associated with longer disease duration (DD). Methods: Methods used include retrospective chart review, genetic single nucleotide polymorphism analyses (in three cases), and neuropathology. Results: We identified four cases with long (>10–15 years) or very long (>15 years) DD. Stage 1 PSP tau pathology was present in two cases (one PSP-P and one undifferentiated phenotype), whereas pallidonigroluysian atrophy (PSP-RS) and Stage 4/6 (PSP-P) PSP pathology were found in the other two cases. Three cases were homozygous for the rs564309-C allele of the TRIM11 gene and the H1 MAPT haplotype. Two were heterozygous for rs2242367 (G/A) in SLC2A13, whereas the third was homozygous for the G-allele. Conclusions: We propose a protracted course subtype of PSP (PC-PSP) based on clinical or neuropathological criteria in two cases with anatomically restricted PSP pathology, and very long DD and slower clinical progression in the other two cases. The presence of the rs564309-C allele may influence the protracted disease course. Crystallizing the concept of PC-PSP is important to further understand the pathobiology of tauopathies in line with current hypotheses of protein misfolding, seeding activity, and propagation. © 2022 European Academy of Neurology.

Author Keywords
microglia;  pallidonigroluysian atrophy;  Parkinsonian disorders;  prognosis;  progressive supranuclear palsy;  Richardson syndrome;  tau protein

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAAG64937, ES029524, NS075321, NS075527, NS092865, NS097437, NS097799, NS103957, NS107281, NS109487, R01AG065214, R61 AT010753, RO1NS118146, U10NS077384, U19 NS110456, U24 NS107198, U54NS116025
National Institute of Neurological Disorders and StrokeNINDS
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Huntington’s Disease Society of AmericaHDSA
CHDI FoundationCHDI
National Center for Advancing Translational SciencesNCATS
American Parkinson Disease AssociationAPDA
Foundation for Barnes-Jewish HospitalFBJH
Edmond J. Safra Philanthropic Foundation
Parkinson CanadaPPG 2020‐0000000025