WashU weekly Neuroscience publications

Lack of observed tolerance to diazepam nasal spray (Valtoco®) after long-term rescue therapy in patients with epilepsy: Interim results from a phase 3, open-label, repeat-dose safety study
(2021) Epilepsy and Behavior, 120, art. no. 107983, . 

Cascino, G.D.^a , Tarquinio, D.^b , Wheless, J.W.^c , Hogan, R.E.^d , Sperling, M.R.^e , Liow, K.^f , Desai, J.^g , Davis, C.^h , Rabinowicz, A.L.ⁱ , Carrazana, E.ⁱ , DIAZ.001.05 Study Group^j

^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 Hawaii Pacific Neuroscience, Honolulu, HI, United States
^g Children’s Hospital of Los AngelesCA, United States
^h SD Biostatistics, Inc., Oro Valley, AZ, United States
ⁱ Neurelis, Inc., San Diego, CA, United States

Abstract
Objective: Tolerance is a known consideration for maintenance use of benzodiazepines and other antiseizure drugs; however, clinical experience suggests that tolerance may not be anticipated with long-term intermittent use of benzodiazepines as rescue therapy. Diazepam nasal spray (Valtoco®) is a proprietary intranasal formulation approved for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (ie, seizure clusters, acute repetitive seizures) in patients with epilepsy aged ≥6 years. Reported here are exploratory analyses investigating whether there was evidence of development of tolerance in an interim analysis of a long-term, phase 3, open-label safety study of diazepam nasal spray. Methods: Patients and care partners were trained to administer 5, 10, 15, or 20 mg of diazepam nasal spray (age- and weight-based dosing), with a second dose administered 4–12 hours later if needed. A series of analyses were performed to assess evidence of tolerance using 2 equal, adjacent time periods and data for each patient to compare the proportion of events for which second doses of diazepam nasal spray (as a proxy for effectiveness) were administered in period 1 compared with period 2. Results: A total of 175 patients were enrolled at interim cutoff, and 158 were treated with diazepam nasal spray for 3370 seizure-cluster events. For 73.4% of patients, duration of exposure to diazepam nasal spray was ≥12 months. A total of 191 analyses were conducted; the proportion of analyses in which second doses in period 2 were lower than in period 1 was 72.8%. Only 5 analyses showed nominally statistically significant changes (P < 0.05); this is fewer than expected by chance, and these differences were not directionally consistent. There was no safety signal with continued use. Conclusions: These analyses found no statistical evidence of tolerance with the use of diazepam nasal spray over time based on use of a second dose in an initial period of the study compared with a subsequent period for each patient. These results are in agreement with prior studies of benzodiazepine rescue therapy. © 2021 The Author(s)

Author Keywords
Benzodiazepines;  Diazepam nasal spray;  Rescue therapy;  Seizure clusters;  Tolerance

Funding details
Novartis
School of Public Health, University of California BerkeleyUCB
Medtronic
Eisai Incorporated

Qualitative study of musculoskeletal tissues and their radiographic correlates in diabetic neuropathic foot deformity
(2021) Foot, 47, art. no. 101777, . 

Hastings, M.K.^a , Commean, P.K.^b , Chen, L.^c , Zellers, J.A.^a , Sinacore, D.R.^a , Baker, J.C.^d

^a Program in Physical Therapy, Washington University School of Medicine in St. Louis, Campus Box 8502, 4444 Forest Park Blvd., Room 1101, St. Louis, MO 63108, United States
^b Mallinckrodt Institute of Radiology, Division of Radiological Science, Washington University School of Medicine in St. Louis, 510 South Kingshighway Blvd., St. Louis, MO 63110, United States
^c Division of Biostatistics, Washington University School of Medicine in St. Louis, Campus Box 8067, St. Louis, MO 63110, United States
^d Mallinckrodt Institute of Radiology, Musculoskeletal Section, Washington University School of Medicine, Campus Box 8131, St. Louis, MO 63110, United States

Abstract
Background: Diabetes mellitus (DM) with peripheral neuropathy (PN) results in foot deformity increasing ulceration, joint dislocation, and amputation risk. This study describes the frequency and severity of foot and ankle musculoskeletal abnormalities and their relationship to radiographic alignment in people with DMPN with (DMPN + MCD) and without (DMPN − MCD) medial column deformity (MCD) compared to age- and body mass index-matched controls without DMPN or MDC. Methods: DMPN + MCD (n = 11), DMPN − MCD (n = 12), and controls (n = 12) were studied. A radiologist scored foot and ankle magnetic resonance images (MRI) for abnormalities in tendons/fascia, ligaments, muscles, joints, and bones. Higher scores represent greater abnormalities. Foot alignment was measured from lateral weightbearing radiographs. Frequency of abnormalities between groups and relationships between abnormalities and foot alignment in the combined group (n = 35) were examined. Results: DMPN + MCD had higher total muscle, joint, and bone scores compared to controls and higher total joint scores than DMPN − MCD. DMPN − MCD had higher total muscle scores than controls. DMPN + MCD higher bone and joint scores were driven by increased frequency of osteophytes, cartilage damage, focal bone marrow edema, new bone formation, and subchondral cysts. Significant correlations included cuboid height and total bone and joint scores (ρ = −0.37 and ρ = −0.40, respectively) and talar declination angle and total joint score (ρ = 0.38). Conclusion: High contrast resolution MRI allowed identification of structural lesions of the foot affecting the cartilage surfaces, bone marrow, and soft tissue supports in patients with DMPN + MCD. As expected, the presence of bone and joint lesions on MRI were strongly associated with DMPN + MCD; surprisingly, although the sample is small, lesions of the soft tissue supports were not associated with MCD. While MRI is not done routinely to investigate MCD, opportunistic use of the information from MRI done for the common clinical indications may allow early identification of the structural lesions associated with MCD and facilitate early, aggressive therapy. Level of evidence: III. © 2021 Elsevier Ltd

Author Keywords
Cuneiform;  Diabetes;  Fatty muscle atrophy;  Spring ligament;  Talus

Funding details
National Institutes of HealthNIHR01DK107809, T32HD007434, F32DK123916, K12 HD055931, UL1TR002345

Generation of a gene-corrected human isogenic iPSC line from an Alzheimer’s disease iPSC line carrying the London mutation in APP (V717I)
(2021) Stem Cell Research, 53, art. no. 102373, . 

Hernández, D.^a , Morgan Schlicht, S.^a , Daniszewski, M.^a , Karch, C.M.^b , Goate, A.M.^c , Pébay, A.^a d , Dominantly Inherited Alzheimer Network (DIAN)^e

^a Department of Anatomy and Physiology, the University of Melbourne, Parkville, VIC 3010, Australia
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States
^d Department of Surgery, Royal Melbourne Hospital, the University of Melbourne, Parkville, VIC 3010, Australia

Abstract
We report the genome-editing of an existing iPSC line carrying the London mutation in APP (V717I) into an iPSC line in which the pathogenic mutation was corrected. The resulting isogenic iPSC line maintained pluripotent stem cell morphology, a normal karyotype, expression of pluripotency markers and the ability to differentiate into the three germ-layers in vitro. © 2021 The Author(s)

Funding details
Japan Agency for Medical Research and DevelopmentAMED
National Institute on AgingNIA
Korea Health Industry Development InstituteKHIDI
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Japan Agency for Medical Research and DevelopmentAMED
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
National Health and Medical Research CouncilNHMRC1154389
Brain Foundation
University of MelbourneUNIMELB

A target-agnostic screen identifies approved drugs to stabilize the endoplasmic reticulum-resident proteome
(2021) Cell Reports, 35 (4), p. 109040. 

Henderson, M.J.^a , Trychta, K.A.^b , Yang, S.-M.^a , Bäck, S.^b , Yasgar, A.^a , Wires, E.S.^b , Danchik, C.^a , Yan, X.^b , Yano, H.^b , Shi, L.^b , Wu, K.-J.^c , Wang, A.Q.^a , Tao, D.^a , Zahoránszky-Kőhalmi, G.^a , Hu, X.^a , Xu, X.^a , Maloney, D.^a , Zakharov, A.V.^a , Rai, G.^a , Urano, F.^d , Airavaara, M.^e , Gavrilova, O.^f , Jadhav, A.^a , Wang, Y.^c , Simeonov, A.^a , Harvey, B.K.^b

^a National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, United States
^b National Institute on Drug Abuse, National Institutes of Health, Baltimore, United States
^c Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan
^d Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University in St. Louis, St. Louis, MO 63110, USA
^e Neuroscience Center, HiLIFE & Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
^f National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, United States

Abstract
Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects in cell-based models of exodosis as well as in vivo models of stroke and diabetes. Bromocriptine analogs with reduced dopamine receptor activity retain similar efficacy in stabilizing the ER proteome, indicating a non-canonical mechanism of action. This study describes a strategic approach to identify small-molecule drugs capable of improving ER proteostasis in human disease conditions. Published by Elsevier Inc.

Author Keywords
bromocriptine;  diabetes;  endoplasmic reticulum;  ER calcium;  ER proteome;  ER retention sequence;  ER stress;  exodosis;  SERCaMP;  stroke

Traumatic Brain Injury: Ultrastructural Features in Neuronal Ferroptosis, Glial Cell Activation and Polarization, and Blood-Brain Barrier Breakdown
(2021) Cells, 10 (5), . 

Qin, D.^a , Wang, J.^a , Le, A.^b , Wang, T.J.^c , Chen, X.^a , Wang, J.^a

^a Department of Human Anatomy, College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China
^b Program in the McKelvey School of Engineering, Washington University in St. Louis, MO, Saint Louis 63130, United States
^c Winston Churchill High School, Potomac, United States

Abstract
The secondary injury process after traumatic brain injury (TBI) results in motor dysfunction, cognitive and emotional impairment, and poor outcomes. These injury cascades include excitotoxic injury, mitochondrial dysfunction, oxidative stress, ion imbalance, inflammation, and increased vascular permeability. Electron microscopy is an irreplaceable tool to understand the complex pathogenesis of TBI as the secondary injury is usually accompanied by a series of pathologic changes at the ultra-micro level of the brain cells. These changes include the ultrastructural changes in different parts of the neurons (cell body, axon, and synapses), glial cells, and blood-brain barrier, etc. In view of the current difficulties in the treatment of TBI, identifying the changes in subcellular structures can help us better understand the complex pathologic cascade reactions after TBI and improve clinical diagnosis and treatment. The purpose of this review is to summarize and discuss the ultrastructural changes related to neurons (e.g., condensed mitochondrial membrane in ferroptosis), glial cells, and blood-brain barrier in the existing reports of TBI, to deepen the in-depth study of TBI pathomechanism, hoping to provide a future research direction of pathogenesis and treatment, with the ultimate aim of improving the prognosis of patients with TBI.

Author Keywords
cell structure;  ferroptosis;  inflammation;  mitochondria;  neuron;  TBI;  ultrastructure

Integrating neuroimaging biomarkers into the multicentre, high-dose erythropoietin for asphyxia and encephalopathy (HEAL) trial: Rationale, protocol and harmonisation
(2021) BMJ Open, 11 (4), art. no. 043852, . 

Wisnowski, J.L.^a b , Bluml, S.^a , Panigrahy, A.^c , Mathur, A.M.^d e , Berman, J.^f , Chen, P.-S.K.^g , DIx, J.^h , Flynn, T.ⁱ , Fricke, S.^j k , Friedman, S.D.^l , Head, H.W.^m , Ho, C.Y.ⁿ , Kline-Fath, B.^o , Oveson, M.^p , Patterson, R.^q , Pruthi, S.^r , Rollins, N.^s , Ramos, Y.M.^q , Rampton, J.^p , Rusin, J.^t , Shaw, D.W.^l , Smith, M.^t , Tkach, J.^o , Vasanawala, S.^u , Vossough, A.^f , Whitehead, M.T.^j , Xu, D.ⁱ , Yeom, K.^u , Comstock, B.^v , Heagerty, P.J.^w , Juul, S.E.^x , Wu, Y.W.^y , McKinstry, R.C.^z

^a Radiology, Children’s Hospital of Los Angeles, Los Angeles, CA, United States
^b Pediatrics, Children’s Hospital Los Angeles Division of Neonatology, Los Angeles, CA, United States
^c Radiology, Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^d Pediatrics, Division of Neonatal-Perinatal Medicine, SSM Health Cardinal Glennon Children’s Hospital, Saint Louis, MO, United States
^e Pediatrics, Division of Neonatal-Perinatal Medicine, Saint Louis University, Saint Louis, MO, United States
^f Radiology, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^g Radiology, Children’s Hospital of San Antonio, San Antonio, TX, United States
^h Radiology, Methodist Children’s Hospital, San Antonio, TX, United States
ⁱ Radiology, University of California San Francisco, San Francisco, CA, United States
^j Radiology, Children’s National Medical Center, Washington, DC, United States
^k Radiology, Georgetown University Medical Center, Washington, DC, United States
^l Radiology, Seattle Children’s Hospital, Seattle, WA, United States
^m Radiology, Cook Children’s Medical Center, Fort Worth, TX, United States
ⁿ Radiology, Indiana University School of Medicine, Indianapolis, IN, United States
^o Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^p Radiology, Primary Children’s Hospital, Salt Lake City, UT, United States
^q Radiology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, MN, United States
^r Radiology, Vanderbilt University, Nashville, TN, United States
^s Radiology, University of Texas Southwestern Medical School, Dallas, TX, United States
^t Radiology, Nationwide Children’s Hospital, Columbus, OH, United States
^u Radiology, Stanford University, Stanford, CA, United States
^v Biostatistics, University of Washington, Seattle, WA, United States
^w Department of Biostatistics, University of Washington, Seattle, WA, United States
^x Pediatrics, Division of Neonatology, University of Washington, Seattle, WA, United States
^y Neurology, University of California San Francisco, San Francisco, CA, United States
^z Radiology, St. Louis Children’s Hospital and Washington University, Saint Louis, MO, United States

Abstract
Introduction MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms. Methods and analysis Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation – thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans. Ethics and dissemination IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor. Trial registration number NCT02811263; Pre-result. ©

Author Keywords
developmental neurology & neurodisability;  neonatal intensive & critical care;  neonatology;  neurological injury;  neuroradiology;  paediatric radiology

Dorsal anterior cingulate cortex encodes the integrated incentive motivational value of cognitive task performance
(2021) Journal of Neuroscience, 41 (16), pp. 3707-3720. 

Yee, D.M.^a b , Crawford, J.L.^a , Lamichhane, B.^a , Braver, T.S.^a

^a Psychological and Brain Sciences, Washington University, St. Louis, MI 63130, United States
^b Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI 02906, United States

Abstract
Humans can seamlessly combine value signals from diverse motivational incentives, yet it is not well understood how these signals are “bundled” in the brain to modulate cognitive control. The dorsal ACC (dACC) is theorized to integrate motivational value dimensions in the service of goal-directed action, although this hypothesis has yet to receive rigorous confirmation. In the present study, we examined the role of human dACC in motivational incentive integration. Healthy young adult men and women were scanned with fMRI while engaged in an experimental paradigm that quantifies the combined effects of liquid (e.g., juice, neutral, saltwater) and monetary incentives on cognitive task performance. Monetary incentives modulated trial-by-trial dACC activation, whereas block-related effects of liquid incentives on dACC activity were observed. When bundled together, incentive-related dACC modulation predicted fluctuations in both cognitive performance and self-report motivation ratings. Statistical mediation analyses suggest that dACC encoded the incentives in terms of their integrated subjective motivational value, and that this value signal was most proximally associated with task performance. Finally, we confirmed that these incentive integration effects were selectively present in dACC. Together, the results support an account in which dACC integrates motivational signals to compute the expected value of goal-directed cognitive control. © 2021 Society for Neuroscience. All rights reserved.

Author Keywords
Cognitive control;  DACC;  Incentive integration;  Motivation;  Reward;  Value

Funding details
National Institutes of HealthNIHR21-AG058206, R21-AG067295, R24-AG054355
McDonnell Center for Systems NeuroscienceF31-DA042574, T32-AG000030, T32-NS073547

Evolution of genetic networks for human creativity
(2021) Molecular Psychiatry, . 

Zwir, I.^a b , Del-Val, C.^b , Hintsanen, M.^c , Cloninger, K.M.^d , Romero-Zaliz, R.^b , Mesa, A.^b , Arnedo, J.^b , Salas, R.^e , Poblete, G.F.^e f , Raitoharju, E.^g , Raitakari, O.^h , Keltikangas-Järvinen, L.ⁱ , de Erausquin, G.A.^j , Tattersall, I.^k , Lehtimäki, T.^g , Cloninger, C.R.^a d

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Computer Science and Artificial Intelligence, University of Granada, Andalusian Research Institute in Data Science and Computational Intelligence, Granada, Spain
^c Unit of Psychology, Faculty of Education, University of Oulu, Oulu, Finland
^d Anthropedia Foundation, St. Louis, MO, United States
^e The Menninger Clinic, Baylor College of Medicine, and DeBakey VA Medical Center, Houston, TX, United States
^f The Menninger Clinic, Houston, TX, United States
^g Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^h Center for Population Health Research, University of Turku and Turku University Hospital; Research Center of Applied and Preventive Cardiovascular Medicine, University of Turku; Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
ⁱ Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
^j Department of Psychiatry, University of Texas San Antonio, Long School of Medicine, The Glenn Briggs Institute of Alzheimer’s and Neurodegenerative Disorders, San Antonio, TX, United States
^k American Museum of Natural History, New York, NY, United States

Abstract
The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and chimpanzees in their numbers of genes for both self-control and self-awareness. 95% of the 267 genes we found only in modern humans were not protein-coding, including many long-non-coding RNAs in the self-awareness network. These genes may have arisen by positive selection for the characteristics of human well-being and behavioral modernity, including creativity, prosocial behavior, and healthy longevity. The genes that cluster in association with those found only in modern humans are over-expressed in brain regions involved in human self-awareness and creativity, including late-myelinating and phylogenetically recent regions of neocortex for autobiographical memory in frontal, parietal, and temporal regions, as well as related components of cortico-thalamo-ponto-cerebellar-cortical and cortico-striato-cortical loops. We conclude that modern humans have more than 200 unique non-protein-coding genes regulating co-expression of many more protein-coding genes in coordinated networks that underlie their capacities for self-awareness, creativity, prosocial behavior, and healthy longevity, which are not found in chimpanzees or Neanderthals. © 2021, The Author(s).

Funding details
Ministerio de Ciencia y TecnologíaMICYTRTI2018-098983-B-100, DPI2015 -69585-R
Paavo Nurmen Säätiö
Juho Vainion Säätiö
Horizon 2020755320, 848146
Suomen KulttuurirahastoSKR
Sydäntutkimussäätiö
Emil Aaltosen Säätiö
Suomen Akatemia41071, 286284, 126925, 117787, 308676, 134309, 121584, 129378, 322098, 124282
Signe ja Ane Gyllenbergin Säätiö
Tampereen Tuberkuloosisäätiö
Turun Yliopistollinen KeskussairaalaAUCSX51001
Yrjö Jahnssonin Säätiö

The american society of pain and neuroscience (Aspn) practical guidelines to study design and scientific manuscript preparation in neuromodulation
(2021) Journal of Pain Research, 14, pp. 1027-1041. 

Eshraghi, Y.^a b c , Chakravarthy, K.^d e , Strand, N.H.^f , Shirvalkar, P.^g , Schuster, N.M.^d , Abdallah, R.T.^h , Vallejo, R.^i j , Sayed, D.^k , Kim, D.^k , Kim, C.^l , Meacham, K.^m , Deer, T.^n o

^a Department of Anesthesia, Interventional Pain Management, Ochsner Health System, New Orleans, LA, United States
^b University of Queensland Ochsner Clinical School, Academics Department, Ochsner Health System, New Orleans, LA, United States
^c Louisiana State University School of Medicine, New Orleans, LA, United States
^d Division of Pain Medicine, Department of Anesthesiology, University of California San Diego, San Diego, CA, United States
^e VA San Diego Health Care, San Diego, CA, United States
^f Division of Pain Medicine, Department of Anesthesiology, Mayo Clinic, Phoenix, AZ, United States
^g Department of Anesthesiology (Pain Management), Department of Neurology, UCSF School of Medicine, San Francisco, CA, United States
^h Center for Interventional Pain and Spine, Wilmington, DE, United States
ⁱ National Spine and Pain Center, Bloomington, IL, United States
^j Psychology Department, Illinois Wesleyan University, Bloomington, IL, United States
^k University of Kansas Medical Center, Kansas City, KS, United States
^l Departments of Physical Medicine and Rehabilitation and Anesthesiology, Case Western Reserve University/MetroHealth, Cleveland, OH, United States
^m Division of Pain Management, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
ⁿ The Spine and Nerve Center of the Virginias, Charleston, WV, United States
^o West Virginia University, School of Medicine, Charleston, WV, United States

Abstract
Background: Healthcare clinical and even policy decisions are progressively made based on research-based evidence. The process by which the appropriate trials are developed and well-written manuscripts by means of evidence-based medicine recommendations has resulted in unprecedented necessity in evidence-based medicine in neuromodulation. Methods: The essential considerations in the planning of neuromodulation research are discussed in the light of available scientific literature as well as the authors’ scientific expertise regarding research study design and scientific manuscript preparation. Conclusion: This article should enable the reader to understand how to appropriately design a clinical research study and prepare scientific manuscripts. The high-quality and welldesigned studies, when performed and reported effectively, support evidence-based medicine and foster improved patient outcomes. © 2021 Eshraghi et al.

Author Keywords
Clinical evidence review;  Neuromodulation;  Neurostimulation;  Research;  Study design

Funding details
National Institutes of HealthNIH
Migraine Research FoundationMRF

Hemodynamic and oxygen-metabolic responses of the awake mouse brain to hypercapnia revealed by multi-parametric photoacoustic microscopy
(2021) Journal of Cerebral Blood Flow and Metabolism, . 

Cao, R.^a , Tran, A.^b , Li, J.^c , Xu, Z.^a , Sun, N.^a d , Zuo, Z.^c , Hu, S.^a d

^a Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, United States
^b Department of Biology, University of Virginia, Charlottesville, VA, United States
^c Department of Anesthesiology, University of Virginia, Charlottesville, VA, United States
^d Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
A widely used cerebrovascular stimulus and common pathophysiologic condition, hypercapnia is of great interest in brain research. However, it remains controversial how hypercapnia affects brain hemodynamics and energy metabolism. By using multi-parametric photoacoustic microscopy, the multifaceted responses of the awake mouse brain to different levels of hypercapnia are investigated. Our results show significant and vessel type-dependent increases of the vessel diameter and blood flow in response to the hypercapnic challenges, along with a decrease in oxygen extraction fraction due to elevated venous blood oxygenation. Interestingly, the increased blood flow and decreased oxygen extraction are not commensurate with each other, which leads to reduced cerebral oxygen metabolism. Further, time-lapse imaging over 2-hour chronic hypercapnic challenges reveals that the structural, functional, and metabolic changes induced by severe hypercapnia (10% CO2) are not only more pronounced but more enduring than those induced by mild hypercapnia (5% CO2), indicating that the extent of brain’s compensatory response to chronic hypercapnia is inversely related to the severity of the challenge. Offering quantitative, dynamic, and CO2 level-dependent insights into the hemodynamic and metabolic responses of the brain to hypercapnia, these findings might provide useful guidance to the application of hypercapnia in brain research. © The Author(s) 2021.

Author Keywords
hemodynamics;  hypercapnia;  oxygen metabolism;  Photoacoustic microscopy;  vascular response

Funding details
National Science FoundationNSF20,23,988
National Institutes of HealthNIHNS099261, NS099118
American Heart AssociationAHA15SDG25960005

Subjective Identity Concealability and the Consequences of Fearing Identity-Based Judgment
(2021) Personality and Social Psychology Bulletin, . 

Le Forestier, J.M.^a , Page-Gould, E.^a , Lai, C.K.^b , Chasteen, A.L.^a

^a University of TorontoON, Canada
^b Washington University in St. LouisMO, United States

Abstract
In intergroup contexts, people may fear being judged negatively because of an identity they hold. For some, the prospect of concealment offers an opportunity to attenuate this fear. Therefore, believing an identity is concealable may minimize people’s fears of identity-based judgment. Here, we explore the construct of subjective identity concealability: the belief that an identity one holds is concealable from others. Across four pre-registered studies and a set of internal meta-analyses, we develop and validate a scale to measure individual differences in subjective identity concealability and provide evidence that it is associated with lower levels of the psychological costs of fearing judgment in intergroup contexts. Open materials, data, and code for all studies, pre-registrations for Studies 1–4, and online supplementary materials can be found at the following link: https://osf.io/pzcf9/. © 2021 by the Society for Personality and Social Psychology, Inc.

Author Keywords
concealable identities;  intergroup anxiety;  lay beliefs;  social identity threat;  stigma

Funding details
Social Sciences and Humanities Research Council of CanadaSSHRC
Social Sciences and Humanities Research Council of CanadaSSHRC
Canada Research Chairs
Ontario Ministry of Research, Innovation and ScienceMRIS

Quantitative signal properties from standardized MRIs correlate with multiple sclerosis disability
(2021) Annals of Clinical and Translational Neurology, 8 (5), pp. 1096-1109. 

Brier, M.R.^a , Snyder, A.Z.^b , Tanenbaum, A.^a , Rudick, R.A.^c , Fisher, E.^c , Jones, S.^d , Shimony, J.S.^b , Cross, A.H.^a , Benzinger, T.L.S.^b , Naismith, R.T.^a

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Malinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Biogen, Cambridge, MA, United States
^d Imaging Institute, Cleveland Clinic, Cleveland, OH, United States

Abstract
Objective: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice. Methods: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures. Results: Intensity distribution metrics distinguished MS patients from control participants based on normalized non-lesional signal differences. This analysis revealed non-lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non-lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra-lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS-related disability. Interpretation: These results support the notion that non-lesional abnormalities correlate more strongly with MS-related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non-lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS-related disability. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association

Funding details
Biogen
National Institutes of HealthNIH1S10RR022984‐01A1, 1S10OD018091‐01
National Institutes of HealthNIHP30NS098577, 2R25NS090978‐06
Novartis
Biogen
Janssen Pharmaceuticals
Alzheimer’s AssociationAA
National Institutes of HealthNIH
Foundation for Barnes-Jewish Hospital
Avid Radiopharmaceuticals
Genentech
Roche
EMD Serono