WashU weekly Neuroscience publications | Office of Neuroscience Research

“Advanced cognitive impairment among older nursing home residents” (2021) BMC Geriatrics

Advanced cognitive impairment among older nursing home residents
(2021) BMC Geriatrics, 21 (1), art. no. 382, .

Gracner, T.^a , Stone, P.W.^b , Agarwal, M.^c , Sorbero, M.^d , Mitchell, S.L.^e ^f , Dick, A.W.^g

^a RAND Corporation, 1776 Main Street, Santa Monica, CA 90401, United States
^b Center for Health Policy, Columbia University School of Nursing, 560 W. 168th St, New York, NY 10032, United States
^c Washington University School of Medicine, 660 S Euclid Ave, St.Louis, MO 63110, United States
^d RAND Corporation, 4570 Fifth Ave #600, Pittsburgh, PA 15213, United States
^e Hebrew Senior Life Marcus Institute for Aging Research, Boston, MA, United States
^f Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
^g RAND Corporation, 20 Park Plaza #920, Boston, MA 02116, United States

Abstract
Background: Though work has been done studying nursing home (NH) residents with either advanced Alzheimer’s disease (AD) or Alzheimer’s disease related dementia (ADRD), none have distinguished between them; even though their clinical features affecting survival are different. In this study, we compared mortality risk factors and survival between NH residents with advanced AD and those with advanced ADRD. Methods: This is a retrospective observational study, in which we examined a sample of 34,493 U.S. NH residents aged 65 and over in the Minimum Data Set (2011–2013). Incident assessment of advanced disease was defined as the first MDS assessment with severe cognitive impairment (Cognitive Functional Score equals to 4) and diagnoses of AD or ADRD. Demographics, functional limitations, and comorbidities were evaluated as mortality risk factors using Cox models. Survival was characterized with Kaplan-Maier functions. Results: Of those with advanced cognitive impairment, 35 % had AD and 65 % ADRD. At the incident assessment of advanced disease, those with AD had better health compared to those with ADRD. Mortality risk factors were similar between groups (shortness of breath, difficulties eating, substantial weight-loss, diabetes mellitus, heart failure, chronic obstructive pulmonary disease, and pneumonia; all p < 0.01). However, stroke and difficulty with transfer (for women) were significant mortality risk factors only for those with advanced AD. Urinary tract infection, and hypertension (for women) only were mortality risk factors for those with advanced ADRD. Median survival was significantly shorter for the advanced ADRD group (194 days) compared to the advanced AD group (300 days). Conclusions: There were distinct mortality and survival patterns of NH residents with advanced AD and ADRD. This may help with care planning decisions regarding therapeutic and palliative care. © 2021, The Author(s).

Author Keywords
Advanced cognitive impairment; Alzheimer’s disease; Dementia; End-of-Life; Survival

Funding details
National Institute on AgingNIAK24AG033640
National Institute of Nursing ResearchNINRR01NR013687

Document Type: Article
Publication Stage: Final
Source: Scopus

“KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease” (2021) Nature Communications

KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer’s disease
(2021) Nature Communications, 12 (1), art. no. 3825, .

Neitzel, J.^a ^b ^c , Franzmeier, N.^a , Rubinski, A.^a , Dichgans, M.^a ^d ^e , Brendel, M.^f , Weiner, M.^g , Aisen, P.^h , Petersen, R.ⁱ , Jack, C.R., Jr.ⁱ , Jagust, W.^j , Trojanowki, J.Q.^k , Toga, A.W.^l , Beckett, L.^m , Green, R.C.ⁿ , Saykin, A.J.^o , Morris, J.^p , Shaw, L.M.^q , Liu, E.^r , Montine, T.^s , Thomas, R.G.^h , Donohue, M.^h , Walter, S.^h , Gessert, D.^h , Sather, T.^h , Jiminez, G.^h , Harvey, D.^m , Bernstein, M.ⁱ , Fox, N.^t , Thompson, P.^u , Schuff, N.^v , DeCArli, C.^m , Borowski, B.ⁱ , Gunter, J.ⁱ , Senjem, M.ⁱ , Vemuri, P.ⁱ , Jones, D.ⁱ , Kantarci, K.ⁱ , Ward, C.ⁱ , Koeppe, R.A.^w , Foster, N.^x , Reiman, E.M.^y , Chen, K.^y , Mathis, C.^z , Landau, S.^j , Cairns, N.J.^p , Householder, E.^p , Reinwald, L.T.^p , Lee, V.^aa , Korecka, M.^aa , Figurski, M.^aa , Crawford, K.^l , Neu, S.^l , Foroud, T.M.^o , Potkin, S.^ab , Shen, L.^o , Kelley, F.^o , Kim, S.^o , Nho, K.^o , Kachaturian, Z.^ac , Frank, R.^ad , Snyder, P.J.^ae , Molchan, S.^af , Kaye, J.^ag , Quinn, J.^ag , Lind, B.^ag , Carter, R.^ag , Dolen, S.^ag , Schneider, L.S.^ah , Pawluczyk, S.^ah , Beccera, M.^ah , Teodoro, L.^ah , Spann, B.M.^ah , Brewer, J.^ai , Vanderswag, H.^ai , Fleisher, A.^y , Heidebrink, J.L.^w , Lord, J.L.^w , Mason, S.S.ⁱ , Albers, C.S.ⁱ , Knopman, D.ⁱ , Johnson, K.ⁱ , Doody, R.S.^aj , Meyer, J.V.^aj , Chowdhury, M.^aj , Rountree, S.^aj , Dang, M.^aj , Stern, Y.^ak , Honig, L.S.^ak , Bell, K.L.^ak , Ances, B.^al , Morris, J.C.^al , Carroll, M.^al , Leon, S.^al , Mintun, M.A.^al , Schneider, S.^al , OliverNG, A.^am , Griffith, R.^am , Clark, D.^am , Geldmacher, D.^am , Brockington, J.^am , Roberson, E.^am , Grossman, H.^an , Mitsis, E.^an , deToledo-Morrell, L.^ao , Shah, R.C.^ao , Duara, R.^ap , Varon, D.^ap , Greig, M.T.^ap , Roberts, P.^ap , Albert, M.^aq , Onyike, C.^aq , D’Agostino, D., II^aq , Kielb, S.^aq , Galvin, J.E.^ar , Pogorelec, D.M.^ar , Cerbone, B.^ar , Michel, C.A.^ar , Rusinek, H.^ar , de Leon, M.J.^ar , Glodzik, L.^ar , De Santi, S.^ar , Doraiswamy, P.M.^as , Petrella, J.R.^as , Wong, T.Z.^as , Arnold, S.E.^q , Karlawish, J.H.^q , Wolk, D.^q , Smith, C.D.^at , Jicha, G.^at , Hardy, P.^at , Sinha, P.^at , Oates, E.^at , Conrad, G.^at , Lopez, O.L.^z , Oakley, M.A.^z , Simpson, D.M.^z , Porsteinsson, A.P.^au , Goldstein, B.S.^au , Martin, K.^au , Makino, K.M.^au , Ismail, M.S.^au , Brand, C.^au , Mulnard, R.A.^av , Thai, G.^av , Mc Adams Ortiz, C.^av , Womack, K.^aw , Mathews, D.^aw , Quiceno, M.^aw , Arrastia, R.D.^aw , King, R.^aw , Weiner, M.^aw , Cook, K.M.^aw , DeVous, M.^aw , Levey, A.I.^ax , Lah, J.J.^ax , Cellar, J.S.^ax , Burns, J.M.^ay , Anderson, H.S.^ay , Swerdlow, R.H.^ay , Apostolova, L.^az , Tingus, K.^az , Woo, E.^az , Silverman, D.H.S.^az , Lu, P.H.^az , Bartzokis, G.^az , Radford, N.R.G.^ba , ParfittH, F.^ba , Kendall, T.^ba , Johnson, H.^ba , Farlow, M.R.^o , Hake, A.M.^o , Matthews, B.R.^o , Herring, S.^o , Hunt, C.^o , van Dyck, C.H.^bb , Carson, R.E.^bb , MacAvoy, M.G.^bb , Chertkow, H.^bc , Bergman, H.^bc , Hosein, C.^bc , Black, S.^bd , Stefanovic, B.^bd , Caldwell, C.^bd , Hsiung, G.Y.R.^be , Feldman, H.^be , Mudge, B.^be , Past, M.A.^be , Kertesz, A.^bf , Rogers, J.^bf , Trost, D.^bf , Bernick, C.^bg , Munic, D.^bg , Kerwin, D.^bh , Mesulam, M.M.^bh , Lipowski, K.^bh , Wu, C.K.^bh , Johnson, N.^bh , Sadowsky, C.^bi , Martinez, W.^bi , Villena, T.^bi , Turner, R.S.^bj , Johnson, K.^bj , Reynolds, B.^bj , Sperling, R.A.^bk , Johnson, K.A.^bk , Marshall, G.^bk , Frey, M.^bk , Yesavage, J.^bl , Taylor, J.L.^bl , Lane, B.^bl , Rosen, A.^bl , Tinklenberg, J.^bl , Sabbagh, M.N.^bm , Belden, C.M.^bm , Jacobson, S.A.^bm , Sirrel, S.A.^bm , Kowall, N.^bn , Killiany, R.^bn , Budson, A.E.^bn , Norbash, A.^bn , Johnson, P.L.^bn , Obisesan, T.O.^bo , Wolday, S.^bo , Allard, J.^bo , Lerner, A.^bp , Ogrocki, P.^bp , Hudson, L.^bp , Fletcher, E.^bq , Carmichael, O.^bq , Olichney, J.^bq , DeCarli, C.^bq , Kittur, S.^br , Borrie, M.^bs , Lee, T.Y.^bs , Bartha, R.^bs , Johnson, S.^bt , Asthana, S.^bt , Carlsson, C.M.^bt , Potkin, S.G.^bu , Preda, A.^bu , Nguyen, D.^bu , Tariot, P.^y , Reeder, S.^y , Bates, V.^bv , Capote, H.^bv , Rainka, M.^bv , Scharre, D.W.^bw , Kataki, M.^bw , Adeli, A.^bw , Zimmerman, E.A.^bx , Celmins, D.^bx , Brown, A.D.^bx , Pearlson, G.D.^by , Blank, K.^by , Anderson, K.^by , Santulli, R.B.^bz , Kitzmiller, T.J.^bz , Schwartz, E.S.^bz , SinkS, K.M.^ca , Williamson, J.D.^ca , Garg, P.^ca , Watkins, F.^ca , Ott, B.R.^cb , Querfurth, H.^cb , Tremont, G.^cb , Salloway, S.^cc , Malloy, P.^cc , Correia, S.^cc , Rosen, H.J.^g , Miller, B.L.^g , Mintzer, J.^cd , Spicer, K.^cd , Bachman, D.^cd , Finger, E.^ce , Pasternak, S.^ce , Rachinsky, I.^ce , Drost, D.^ce , Pomara, N.^cf , Hernando, R.^cf , Sarrael, A.^cf , Schultz, S.K.^cg , Ponto, L.L.B.^cg , Shim, H.^cg , Smith, K.E.^cg , Relkin, N.^ch , Chaing, G.^ch , Raudin, L.^ch , Smith, A.^ci , Fargher, K.^ci , Raj, B.A.^ci , Malik, R.^a , Ewers, M.^a ^d , Alzheimer’s Disease Neuroimaging Initiative (ADNI)^cj

^a Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
^b Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
^c Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands
^d German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^e Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^f Department of Nuclear Medicine, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Munich, Germany
^g UC San Francisco, San Francisco, CA, United States
^h UC San Diego, San Diego, CA, United States
ⁱ Mayo Clinic, Rochester, NY, United States
^j UC Berkeley, Berkeley, CA, United States
^k University of Pennsylvania, Pennsylvania, CA, United States
^l USC, Los Angeles, CA, United States
^m UC Davis, Davis, CA, United States
ⁿ Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^o Indiana University, Bloomington, IN, United States
^p Washington University St. Louis, St. Louis, MO, United States
^q University of Pennsylvania, Philadelphia, PA, United States
^r Janssen Alzheimer Immunotherapy, South San Francisco, CA, United States
^s University of Washington, Seattle, WA, United States
^t University of London, London, United Kingdom
^u USC School of Medicine, Los Angeles, CA, United States
^v UCSF MRI, San Francisco, CA, United States
^w University of Michigan, Ann Arbor, MI, United States
^x University of Utah, Salt Lake City, UT, United States
^y Banner Alzheimer’s Institute, Phoenix, AZ, United States
^z University of Pittsburgh, Pittsburgh, PA, United States
^aa UPenn School of Medicine, Philadelphia, PA, United States
^ab UC Irvine, Newport Beach, CA, United States
^ac Khachaturian, Radebaugh & Associates Inc and Alzheimer’s Association’s Ronald and Nancy Reagan’s Research Institute, Chicago, IL, United States
^ad General Electric, Boston, MA, United States
^ae Brown University, Providence, RI, United States
^af National Institute on Aging/National Institutes of Health, Bethesda, MD, United States
^ag Oregon Health and Science University, Portland, OR, United States
^ah University of Southern California, Los Angeles, CA, United States
^ai University of California San Diego, San Diego, CA, United States
^aj Baylor College of Medicine, Houston, TX, United States
^ak Columbia University Medical Center, New York, NY, United States
^al Washington University, St. Louis, MO, United States
^am University of Alabama Birmingham, Birmingham, MO, United States
^an Mount Sinai School of Medicine, New York, NY, United States
^ao Rush University Medical Center, Chicago, IL, United States
^ap Wien Center, Vienna, Austria
^aq Johns Hopkins University, Baltimore, MD, United States
^ar New York University, New York, NY, United States
^as Duke University Medical Center, Durham, NC, United States
^at University of Kentucky, Lexington, NC, United States
^au University of Rochester Medical Center, Rochester, NY, United States
^av University of California, Irvine, CA, United States
^aw University of Texas Southwestern Medical School, Dallas, TX, United States
^ax Emory University, Atlanta, GA, United States
^ay University of Kansas, Medical Center, Lawrence, KS, United States
^az University of California, Los Angeles, CA, United States
^ba Mayo Clinic, Jacksonville, FL, United States
^bb Yale University School of Medicine, New Haven, CT, United States
^bc McGill University, Montreal Jewish General Hospital, Montreal, WI, United States
^bd Sunnybrook Health Sciences, Toronto, ON, Canada
^be U.B.C. Clinic for AD & Related Disorders, British Columbia, BC, Canada
^bf Cognitive Neurology St. Joseph’s, Toronto, ON, Canada
^bg Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
^bh Northwestern University, Evanston, IL, United States
^bi Premiere Research Inst Palm Beach Neurology, West Palm Beach, FL, United States
^bj Georgetown University Medical Center, Washington, DC, United States
^bk Brigham and Women’s Hospital, Boston, MA, United States
^bl Stanford University, Santa Clara County, CA, United States
^bm Banner Sun Health Research Institute, Sun City, AZ, United States
^bn Boston University, Boston, MA, United States
^bo Howard University, Washington, DC, United States
^bp Case Western Reserve University, Cleveland, OH, United States
^bq University of California, Davis Sacramento, CA, United States
^br Neurological Care of CNY, New York, NY, United States
^bs Parkwood Hospital, Parkwood, CA, United States
^bt University of Wisconsin, Madison, WI, United States
^bu University of California, Irvine BIC, Irvine, CA, United States
^bv Dent Neurologic Institute, Amherst, MA, United States
^bw Ohio State University, Columbus, OH, United States
^bx Albany Medical College, Albany, NY, United States
^by Hartford Hospital, Olin Neuropsychiatry Research Center, Hartford, CT, United States
^bz Dartmouth Hitchcock Medical Center, Albany, NY, United States
^ca Wake Forest University Health Sciences, Winston-Salem, NC, United States
^cb Rhode Island Hospital, Providence, RI, United States
^cc Butler Hospital, Providence, RI, United States
^cd Medical University South Carolina, Charleston, SC, United States
^ce St. Joseph’s Health Care, Toronto, ON, Canada
^cf Nathan Kline Institute, Orangeburg, SC, United States
^cg University of Iowa College of Medicine, Iowa City, IA, United States
^ch Cornell University, Ithaca, NY, United States
^ci University of South Florida, USF Health Byrd Alzheimer’s Institute, Tampa, FL, United States

Abstract
Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer’s disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHU01 AG024904
U.S. Department of DefenseDODW81XWH-12-2-0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s Disease Neuroimaging InitiativeADNI
Alzheimer Forschung InitiativeAFI15035
Horizon 2020 Framework ProgrammeH2020390857198, 666881, 667375, CRC 1123
Deutscher Akademischer AustauschdienstDAAD
Deutsche ForschungsgemeinschaftDFGINST 409/193-1 FUGG

Document Type: Article
Publication Stage: Final
Source: Scopus

“Developmental Delay and School Performance Among Retinoblastoma Survivors: Development/school morbidity among retinoblastoma survivors” (2021) American Journal of Ophthalmology

Developmental Delay and School Performance Among Retinoblastoma Survivors: Development/school morbidity among retinoblastoma survivors
(2021) American Journal of Ophthalmology, 229, pp. 266-273.

Reynolds, M.^a , Lueder, G.^a ^b , Gordon, M.^a , Hayashi, R.J.^b

^a Departments of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Purpose: The purpose of this study was to describe the academic performance of childhood retinoblastoma (RB) survivors. Design: Retrospective cohort study. Methods: Retrospective chart review of children followed in a survivorship clinic. Results: A total of 73 patients with RB (median age at diagnosis: 9.97 months; range: 0.29-65.1) were followed for a median of 6.4 years (0.2-1.76). A total of 48 patients (65.8%) had unilateral RB; 43 patients (63.0%) received systemic chemotherapy; and 57 patients (78.1%) underwent enucleation. At last follow-up, 5 children (6.8%) had bilateral visual acuity (VA) <20/70. Seventeen subjects (23.3%) reported school difficulties, and 10 subjects (13.7%) had an individualized education program (IEP). Multivariate analysis revealed that a history of receiving chemotherapy” Multivariate analysis revealed that a history of receiving chemotherapy was associated with self-reported school difficulties (odds ratio [CI]: 5.44; 95% confidence interval [CI]: 1.36-21.69; P =.016), and undergoing an IEP (OR: 11.47; 95% CI: 1.34-98.16; P =.03). The degree of visual impairment and history of enucleation did not influence the risk of self-reported school difficulties or the implementation of an IEP. Among unilateral RB patients, chemotherapy was an independent risk factor for self-reported school difficulties (OR: 12.8; 95% CI: 1.45-113; P =.009) and implementation of an IEP (OR: 15.2; 95% CI: 0.78-292; P =.02). Conclusions: Academic difficulties in childhood RB survivors are associated with chemotherapy treatment, a risk factor independent of VA. © 2021 Elsevier Inc.

Funding details
National Institutes of HealthNIHUL1 TR002345
Research to Prevent BlindnessRPB
National Center for Advancing Translational SciencesNCATS

Document Type: Article
Publication Stage: Final
Source: Scopus

“Associations of observed preschool performance monitoring with brain functional connectivity in adolescence” (2021) Cortex

Associations of observed preschool performance monitoring with brain functional connectivity in adolescence
(2021) Cortex, 142, pp. 15-27.

Gilbert, K.E.^a , Wheelock, M.D.^b , Kandala, S.^a , Eggebrecht, A.T.^b , Luby, J.L.^a , Barch, D.M.^a ^b ^c

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Monitoring one’s performance helps detect errors and adapt to prevent future mistakes. However, elevated performance monitoring is associated with increased checking behaviors and perfectionism and is characteristic of multiple psychiatric disorders. Understanding how heightened performance monitoring in early childhood relates to subsequent brain connectivity may elucidate mechanistic risk factors that influence brain and psychiatric outcomes. The aim of this study was to examine the association between performance monitoring in preschool-aged children and functional connectivity during adolescence. In the current prospective longitudinal study, we performed seed-based functional connectivity analysis using a dorsal anterior cingulate cortex (dACC) seed to assess brain–behavior relationships between observationally coded performance monitoring in preschool-aged children and adolescent functional connectivity (n = 79). We also utilized enrichment analysis to investigate network-level connectome-wide associations. Seed-based analysis revealed negative correlations between preschool performance monitoring and adolescent fc between dACC and orbitofrontal and dorsolateral prefrontal cortex while a positive correlation was observed between dACC-occipital cortex connectivity. Enrichment analysis revealed a negative correlation between preschool performance monitoring and connectivity between motor (MOT) – cingulo-opercular (CO) and salience (SN) – Reward (REW) and a positive correlation with MOT-DMN, and cerebellum (CB) – motor connectivity. Elevated performance monitoring in early childhood is associated with functional connectivity during adolescence in regions and networks associated with cognitive control, sensorimotor processing and cortico-striatal-thalamic-cortico (CTSC) aberrations. These regions and networks are implicated in psychiatric disorders characterized by elevated performance monitoring. Findings shed light on a mechanistic risk factor in early childhood with long-term associations with neural functioning. © 2021 Elsevier Ltd

Author Keywords
Development; fMRI; Functional connectivity; Network analysis; Performance monitoring

Funding details
National Institute of Mental HealthNIMHK01 MH103594, K23MH115074, K99 EB029343, R01 MH090786, T32 MH100019
Institute of Clinical and Translational SciencesICTS
Washington University School of Medicine in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

“International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management” (2021) Pain

International Association for the Study of Pain Presidential Task Force on Cannabis and Cannabinoid Analgesia: research agenda on the use of cannabinoids, cannabis, and cannabis-based medicines for pain management
(2021) Pain, 162, pp. S117-S124.

Haroutounian, S.^a , Arendt-Nielsen, L.^b , Belton, J.^c , Blyth, F.M.^d , Degenhardt, L.^e , Di Forti, M.^f ^g ^h , Eccleston, C.ⁱ , Finn, D.P.^j , Finnerup, N.B.^k , Fisher, E.^l , Fogarty, A.E.^m , Gilron, I.ⁿ , Hohmann, A.G.^o , Kalso, E.^p , Krane, E.^q , Mohiuddin, M.^r , Moore, R.A.^s , Rowbotham, M.^t , Soliman, N.^u , Wallace, M.^v , Zinboonyahgoon, N.^w , Rice, A.S.C.^u

^a Division of Clinical and Translational Research and Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^b Center for Neuroplasticity and Pain (CNAP) and Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, School of Medicine, Aalborg University, Aalborg, Denmark
^c IASP Global Alliance of Partners for Pain Advocacy task force, Washington DC, United States
^d Sydney School of Public Health, Faculty of Medicine and Health, University of Sydney, NSW, Camperdown, Australia
^e National Drug and Alcohol Research Centre, University of New South Wales, NSW, Sydney, Australia
^f Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^g National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, United Kingdom
^h South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom
ⁱ Centre for Pain Research, The University of Bath, Bath, United Kingdom, Department of Clinical and Health Psychology, The University of Ghent, Ghent, Belgium
^j Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre and Centre for Pain Research, Human Biology Building, National University of Ireland Galway, University Road, Galway, Ireland
^k Danish Pain Research Center, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
^l Centre for Pain Research, University of Bath, Bath, United Kingdom
^m Department of Neurology, Division of Physical Medicine & Rehabilitation, Washington University School of Medicine, St Louis, MO, United States
ⁿ Departments of Anesthesiology & Perioperative Medicine and Biomedical & Molecular Sciences, Kingston Health Sciences Centre and Queen’s University, Centre for Neuroscience Studies, School of Policy Studies, Queen’s University, ONKingston, Canada
^o Department of Psychological and Brain Sciences, Program in Neuroscience, Gill Center for Biomolecular Science, Indiana University, IN, Bloomington, United States
^p Department of Pharmacology and SleepWell Research Programme, University of Helsinki, Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital Helsinki, Finland
^q Departments of Anesthesiology, Perioperative, and Pain Medicine, & Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
^r Department of Anesthesiology & Perioperative Medicine and, Queen’s University, ONKingston, Canada
^s Appledore, Court Road, Newton Ferrers, Plymouth, United Kingdom
^t Department of Anesthesia, University of California, San Francisco, CA, United States
^u Pain Research, Department of Surgery & Cancer, Faculty of Medicine, Imperial College London, United Kingdom
^v Division of Pain Medicine, Department of Anesthesiology, University of California, San Diego, CA, United States
^w Department of Anesthesiology, Siriraj Hospital, Mahidol UniversityBangkok, Thailand

Abstract
ABSTRACT: The President of the International Association for the Study of Pain established a task force on cannabis and cannabinoid analgesia to systematically examine the evidence on (1) analgesic pharmacology of cannabinoids and preclinical evidence on their efficacy in animal models of injury-related or pathological persistent pain; (2) the clinical efficacy of cannabis, cannabinoids, and cannabis-based medicines for pain; (3) harms related to long-term use of cannabinoids; as well as (4) societal issues and policy implications related to the use of these compounds for pain management. Here, we summarize key knowledge gaps identified in the task force outputs and propose a research agenda for generating high-quality evidence on the topic. The systematic assessment of preclinical and clinical literature identified gaps in rigor of study design and reporting across the translational spectrum. We provide recommendations to improve the quality, rigor, transparency, and reproducibility of preclinical and clinical research on cannabis and cannabinoids for pain, as well as for the conduct of systematic reviews on the topic. Gaps related to comprehensive understanding of the endocannabinoid system and cannabinoid pharmacology, including pharmacokinetics and drug formulation aspects, are discussed. We outline key areas where high-quality clinical trials with cannabinoids are needed. Remaining important questions about long-term and short-term safety of cannabis and cannabinoids are emphasized. Finally, regulatory, societal, and policy challenges associated with medicinal and nonmedicinal use of cannabis are highlighted, with recommendations for improving patient safety and reducing societal harms in the context of pain management. Copyright © 2021 International Association for the Study of Pain.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials” (2021) Pain

Cannabinoids, cannabis, and cannabis-based medicine for pain management: a systematic review of randomised controlled trials
(2021) Pain, 162, pp. S45-S66. Cited 1 time.

Fisher, E.^a ^b , Moore, R.A.^c , Fogarty, A.E.^d , Finn, D.P.^e , Finnerup, N.B.^f ^g , Gilron, I.^h ⁱ ^j , Haroutounian, S.^k , Krane, E.^l ^m , Rice, A.S.C.ⁿ , Rowbotham, M.^o ^p , Wallace, M.^q , Eccleston, C.^a ^b ^r

^a Centre for Pain Research, University of Bath, Bath, United Kingdom
^b Supportive Care Review Groups, Oxford University Hospitals, Oxford, United Kingdom
^c Appledore, Court Road, Newton Ferrers, Plymouth, United Kingdom
^d Department of Neurology, Division of Physical Medicine and Rehabilitation, Washington University in St. Louis School of Medicine, St Louis, MO, United States
^e Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre and Centre for Pain Research, Human Biology Building, National University of Ireland Galway, University Road, Galway, Ireland
^f Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
^g Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
^h Department of Anesthesiology and Perioperative Medicine, Kingston General Hospital, ONKingston, Canada
ⁱ Centre for Neuroscience Studies, Queen’s University, ONKingston, Canada
^j School of Policy Studies, Queen’s University, ONKingston, Canada
^k Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, Washington University Pain Center, St Louis, MO, United States
^l Department of Anesthesiology, Perioperative, and Pain Medicine, and Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
^m Palo Alto, Santa Clara, CA, United States
ⁿ Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom
^o Department of Anesthesia, University of California, San Francisco, CA, United States
^p Sutter Health, CPMC Research Institute, California Pacific Medical Center Research Institute, San Francisco, CA, United States
^q Division of Pain Medicine, Department of Anesthesiology, University of California, San Francisco, CA, United States
^r Department of Clinical and Health Psychology, Ghent University, Ghent, Belgium

Abstract
ABSTRACT: Cannabinoids, cannabis, and cannabis-based medicines (CBMs) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We summarised efficacy and adverse events (AEs) of these types of drugs for treating pain using randomised controlled trials: in people of any age, with any type of pain, and for any treatment duration. Primary outcomes were 30% and 50% reduction in pain intensity, and AEs. We assessed risk of bias of included studies, and the overall quality of evidence using GRADE. Studies of <7 and >7 days treatment duration were analysed separately. We included 36 studies (7217 participants) delivering cannabinoids (8 studies), cannabis (6 studies), and CBM (22 studies); all had high and/or uncertain risk of bias. Evidence of benefit was found for cannabis <7 days (risk difference 0.33, 95% confidence interval 0.20-0.46; 2 trials, 231 patients, very low-quality evidence) and nabiximols >7 days (risk difference 0.06, 95% confidence interval 0.01-0.12; 6 trials, 1484 patients, very low-quality evidence). No other beneficial effects were found for other types of cannabinoids, cannabis, or CBM in our primary analyses; 81% of subgroup analyses were negative. Cannabis, nabiximols, and delta-9-tetrahydrocannabinol had more AEs than control. Studies in this field have unclear or high risk of bias, and outcomes had GRADE rating of low- or very low-quality evidence. We have little confidence in the estimates of effect. The evidence neither supports nor refutes claims of efficacy and safety for cannabinoids, cannabis, or CBM in the management of pain. Copyright © 2020 International Association for the Study of Pain.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Societal issues and policy implications related to the use of cannabinoids, cannabis, and cannabis-based medicines for pain management” (2021) Pain

Societal issues and policy implications related to the use of cannabinoids, cannabis, and cannabis-based medicines for pain management
(2021) Pain, 162, pp. S110-S116.

Haroutounian, S.^a ^b , Gilron, I.^c ^d ^e , Belton, J.^f ^g , Degenhardt, L.^h , Di Forti, M.ⁱ ^j ^k , Finn, D.P.^l , Fogarty, A.^m , Kalso, E.ⁿ ^o , Krane, E.^p , Moore, R.A.^q , Rowbotham, M.^r , Wallace, M.^s , Rice, A.S.C.^t

^a Division of Clinical and Translational Research, Washington University Pain Center, St. Louis, MO, United States
^b Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^c Departments of Anesthesiology and Perioperative Medicine and Biomedical and Molecular Sciences, Kingston Health Sciences Centre, Queen’s UniversityKingston, Canada
^d Centre for Neuroscience Studies, Queen’s UniversityKingston, Canada
^e School of Policy Studies, Queen’s UniversityKingston, Canada
^f CO, Fraser, United States
^g International Association for the Study of Pain, DCWA, United States
^h National Drug and Alcohol Research Centre, University of New South Wales, NSW, Sydney, Australia
ⁱ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^j National Institute for Health Research (NIHR), Mental Health Biomedical Research Centre at South London, Maudsley NHS Foundation Trust, King’s College, London, United Kingdom
^k South London and Maudsley NHS Mental Health Foundation Trust, London, United Kingdom
^l Department of Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre and Centre for Pain Research, NCBES, Human Biology Building, National University of Ireland Galway, Galway, Ireland
^m Department of Neurology, Division of Physical Medicine & Rehabilitation, Washington University School of Medicine, St Louis, MO, United States
ⁿ Department of Pharmacology and SleepWell Research Programme, University of Helsinki, Helsinki, Finland
^o Department of Anaesthesiology, Intensive Care and Pain Medicine, Helsinki University Hospital, Helsinki, Finland
^p Departments of Anesthesiology, Perioperative, and Pain Medicine, & Pediatrics, Stanford University School of Medicine, Stanford, CA, United States
^q Appledore, Newton Ferrers, Plymouth, United Kingdom
^r Department of Anesthesia, University of California, San Francisco, CA, United States
^s Division of Pain Medicine, Department of Anesthesiology, University of California San Diego, San Diego, CA, United States
^t Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom

Document Type: Article
Publication Stage: Final
Source: Scopus

“Weekend light shifts evoke persistent drosophila circadian neural network desynchrony” (2021) Journal of Neuroscience

Weekend light shifts evoke persistent drosophila circadian neural network desynchrony
(2021) Journal of Neuroscience, 41 (24), pp. 5173-5189.

Nave, C.^a , Roberts, L.^a , Hwu, P.^a , Estrella, J.D.^a , Vo, T.C.^a , Nguyen, T.H.^a , Bui, T.T.^a , Rindner, D.J.^a , Pervolarakis, N.^b , Shaw, P.J.^c , Leise, T.L.^d , Holmes, T.C.^a

^a Department of Physiology and Biophysics, University of California, Irvine, Irvine, CA 92697, United States
^b Center for Complex Biological Systems, University of California, Irvine, Irvine, CA 92697, United States
^c Department of Anatomy and Neurobiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Department of Mathematics and Statistics, Amherst College, Amherst, MA 01002, United States

Abstract
We developed a method for single-cell resolution longitudinal bioluminescence imaging of PERIOD (PER) protein and TIMELESS (TIM) oscillations in cultured male adult Drosophila brains that captures circadian circuit-wide cycling under simulated day/night cycles. Light input analysis confirms that CRYPTOCHROME (CRY) is the primary circadian photoreceptor and mediates clock disruption by constant light (LL), and that eye light input is redundant to CRY; 3-h light phase delays (Friday) followed by 3-h light phase advances (Monday morning) simulate the common practice of staying up later at night on weekends, sleeping in later on weekend days then returning to standard schedule Monday morning [weekend light shift (WLS)]. PER and TIM oscillations are highly synchronous across all major circadian neuronal subgroups in unshifted light schedules for 11 d. In contrast, WLS significantly dampens PER oscillator synchrony and rhythmicity in most circadian neurons during and after exposure. Lateral ventral neuron (LNv) oscillations are the first to desynchronize in WLS and the last to resynchronize in WLS. Surprisingly, the dorsal neuron group-3 (DN3s) increase their within-group synchrony in response to WLS. In vivo, WLS induces transient defects in sleep stability, learning, and memory that temporally coincide with circuit desynchrony. Our findings suggest that WLS schedules disrupt circuit-wide circadian neuronal oscillator synchrony for much of the week, thus leading to observed behavioral defects in sleep, learning, and memory. Copyright © 2021 Nave, Roberts et al.

Author Keywords
Circadian rhythm; Drosophila; Learning; Memory; Neural circuits; Sleep

Funding details
National Institutes of HealthNIHR35 GM127102
University of California, San DiegoUCSD

Document Type: Article
Publication Stage: Final
Source: Scopus

“Evaluation of artificial signal peptides for secretion of two lysosomal enzymes in CHO cells” (2021) Biochemical Journal

Evaluation of artificial signal peptides for secretion of two lysosomal enzymes in CHO cells
(2021) Biochemical Journal, 478 (12), pp. 2309-2319.

Cheng, K.-W.^a , Wang, F.^a , Lopez, G.A.^a , Singamsetty, S.^b , Wood, J.^b , Dickson, P.I.^c , Chou, T.-F.^a

^a Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States
^b Phoenix Nest Inc., Brooklyn, NY 11232, United States
^c Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Enzyme replacement therapy (ERT) is a scientifically rational and clinically proven treatment for lysosomal storage diseases. Most enzymes used for ERT are purified from the culture supernatant of mammalian cells. However, it is challenging to purify lysosomal enzymes with sufficient quality and quantity for clinical use due to their low secretion levels in mammalian cell systems. To improve the secretion efficiency of recombinant lysosomal enzymes, we evaluated the impact of artificial signal peptides on the production of recombinant lysosomal enzymes in Chinese hamster ovary (CHO) cell lines. We engineered two recombinant human lysosomal enzymes, N-acetyl-α-glucosaminidase (rhNAGLU) and glucosamine (N-acetyl)-6-sulfatase (rhGNS), by replacing their native signal peptides with nine different signal peptides derived from highly secretory proteins and expressed them in CHO K1 cells. When comparing the native signal peptides, we found that rhGNS was secreted into media at higher levels than rhNAGLU. The secretion of rhNAGLU and rhGNS can, however, be carefully controlled by altering signal peptides. The secretion of rhNAGLU was relatively higher with murine Igκ light chain and human chymotrypsinogen B1 signal peptides, whereas Igκ light chain signal peptide 1 and human chymotrypsinogen B1 signal peptides were more effective for rhGNS secretion, suggesting that human chymotrypsinogen B1 signal peptide is the most appropriate for increasing lysosomal enzyme secretion. Collectively, our results indicate that altering signal peptide can modulate the secretion of recombinant lysosome enzymes and will enable lysosomal enzyme production for clinical use. © 2021 The Author(s).

Funding details
National Institute of Neurological Disorders and StrokeNINDSU44NS089061

Document Type: Article
Publication Stage: Final
Source: Scopus

“Detection of optic neuritis on routine brain MRI without and with the assistance of an image postprocessing algorithm” (2021) American Journal of Neuroradiology

Detection of optic neuritis on routine brain MRI without and with the assistance of an image postprocessing algorithm
(2021) American Journal of Neuroradiology, 42 (6), pp. 1130-1135.

Schroeder, A.^a , Van Stavern, G.^b ^c , Orlowski, H.L.P.^d , Stunkel, L.^b ^c , Parsons, M.S.^d , Rhea, L.^e , Sharma, A.^d

^a Washington University in Saint Louis School of Medicine, St. LouisMO, United States
^b Department of Ophthalmology and Visual Sciences, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
^d Mallinckrodt Institute of Radiology, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States
^e Department of Biostatistics, Washington University in Saint Louis School of Medicine, St. Louis, MO, United States

Abstract
Background and Purpose: At times, there is a clinical need for using routine brain MR imaging performed close to the time of onset of patients’ visual symptoms to firmly establish the diagnosis of optic neuritis. Our aim was to assess the diagnostic performance of radiologists in detecting optic neuritis on routine brain MR images and whether this performance could be enhanced using a postprocessing algorithm. Materials and Methods: In this retrospective case-control study of 60 patients (37 women, 23 men; mean age, 47.2 [SD, 17.9] years), 2 blinded neuroradiologists evaluated T2-weighted FLAIR and contrast-enhanced T1WI from brain MR imaging for the presence of imaging evidence of optic neuritis. Images were processed using an image-processing algorithm that aimed to selectively accentuate the signal intensity of diseased optic nerves. We assessed the effect of image processing on the contrast-to-noise ratio between the optic nerves and normal-appearing white matter and on the diagnostic performance of the neuroradiologists, including the interobserver reliability. Results: The average sensitivity of readers was 55%, 56.5%, and 30.0% on FLAIR, coronal contrast-enhanced T1WI, and axial contrast- enhanced T1WI, respectively. Sensitivities were lower in the absence of fat saturation on FLAIR (P = .001) and coronal contrast- enhanced T1WI (P = .04). Processing increased the contrast-to-noise ratio of diseased (P value range = .03 to <.001) but not of control optic nerves. Processing did not improve the sensitivity but improved the specificity and positive predictive value. Interobserver agreement improved from slight to good. Conclusions: Detection of optic neuritis on routine brain MR imaging is challenging. Specificity, positive predictive value, and interobserver agreement can be improved by postprocessing of MR images. © 2021 American Society of Neuroradiology. All rights reserved.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

“Polygenic risk scores for alcohol involvement relate to brain structure in substance-naïve children: Results from the ABCD study” (2021) Genes, Brain and Behavior

Polygenic risk scores for alcohol involvement relate to brain structure in substance-naïve children: Results from the ABCD study
(2021) Genes, Brain and Behavior, .

Hatoum, A.S.^a , Johnson, E.C.^a , Baranger, D.A.A.^c , Paul, S.E.^b , Agrawal, A.^a , Bogdan, R.^b

^a Department of Psychiatry, Washington University St. Louis Medical School, St. Louis, MO, United States
^b Department of Psychology & Brain Sciences, Washington University St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA, United States

Abstract
Brain imaging-derived structural correlates of alcohol involvement have largely been speculated to arise as a consequence of alcohol exposure. However, they may also reflect predispositional risk. In substance naïve children of European ancestry who completed the baseline session of the Adolescent Brain Cognitive Development (ABCD) Study (n = 3013), mixed-effects models estimated whether polygenic risk scores (PRS) for problematic alcohol use (PAU-PRS) and drinks per week (DPW-PRS) are associated with magnetic resonance imaging-derived brain structure phenotypes (i.e., total and regional: cortical thickness, surface area and volume; subcortical volume; white matter volume, fractional anisotropy, mean diffusivity). Follow-up analyses evaluated whether any identified regions were also associated with polygenic risk among substance naïve children of African ancestry (n = 898). After adjustment for multiple testing correction, polygenic risk for PAU was associated with lower volume of the left frontal pole and greater cortical thickness of the right supramarginal gyrus (|βs| > 0.009; ps < 0.001; psfdr < 0.046; r2s < 0.004). PAU PRS and DPW PRS showed nominally significant associations with a host of other regional brain structure phenotypes (e.g., insula surface area and volume). None of these regions showed any, even nominal association among children of African ancestry. Genomic liability to alcohol involvement may manifest as variability in brain structure during middle childhood prior to alcohol use initiation. Broadly, alcohol-related variability in brain morphometry may partially reflect predisposing genomic influence. Larger discovery genome-wide association studies and target samples of diverse ancestries are needed to determine whether observed associations may generalize across ancestral origins. © 2021 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Author Keywords
adolescence; alcohol use; alcohol use disorder; cortical gray matter; drug naive; DTI; imaging genetics; multi-site study; polygenic risk scores; subcortical gray matter

Funding details
National Institutes of HealthNIH
U.S. Department of Veterans AffairsVAU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
Office of Research and DevelopmentORD
Health Services Research and DevelopmentHSR&D

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Fast volumetric imaging of neural activity in deep brain” (2021) Progress in Biomedical Optics and Imaging – Proceedings of SPIE

Fast volumetric imaging of neural activity in deep brain
(2021) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 11629, art. no. 116290M, .

Chang, C.-P.J.^a , Holy, T.E.^a ^b

^a Department of Biomedical engineering, Washington University in St. Louis, United States
^b Department of Neuroscience, School of Medicine, Washington University in St. Louis, United States

Abstract
Calcium imaging is a widely-used technique for recording neuronal activity. For deep-brain imaging, light scattering degrades image acquisition. To avoid imaging through thick tissue, one common approach is to implant a small lens system (a microendoscope) into the brain. But there is no technique to achieve fast volumetric imaging through such lenses, and this lack forces a choice between abandoning optical sectioning or sampling with risk of confusion from overlaps (when labeling is dense) or being limited to modest neural population size (when labeling is sparse). To address these limitations, we designed a novel imaging technique, RE-imaging Axial Light-sheet Microscopy (REALM), suitable for fast three-dimensional imaging through a microendoscope. REALM images via a tilted light-sheet, illuminating and collecting fluorescence emission with single objective. The first-stage “Maxwell theorem” microscope employs a matching pair of objectives to reimage sample volume onto a sawtooth mirror, which consists of a series of sub-micrometer scale angled surfaces. The sawtooth mirror redirects the light horizontally into the second-stage microscope, forming a crisp image of the illuminated near-axial plane. The whole second microscope system collects over 40% of light reflected by the sawtooth mirror, compared to previous studies 28% of light collection efficiency at numerical apertures that are unavailable for microendoscopy. This microscope will combine the speed and resolution advantages of light-sheet microscopy with the capabilities of microendoscopes for deep-brain imaging, providing the ability to perform fast three-dimensional imaging in deep tissue. © 2021 SPIE.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

“Automated craniotomy with impedance-sensitive skull curvature profiling” (2021) Progress in Biomedical Optics and Imaging – Proceedings of SPIE

Automated craniotomy with impedance-sensitive skull curvature profiling
(2021) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 11629, art. no. 116292C, .

Hedlund, M.^a , Banks, H.^a , Bice, A.^a , Chen, S.^b , Culver, J.^a ^b ^c

^a Dept. of Radiology, Washington University in St. Louis, 1 Brookings Dr., St. Louis, MO 63105, United States
^b Dept. of Biomedical Engineering, Washington University in St. Louis, 1 Brookings Dr., St. Louis, MO 63105, United States
^c Dept. of Physics, Washington University in St. Louis, 1 Brookings Dr., St. Louis, MO 63105, United States

Abstract
Scattering in the skull limits spatial resolution in optical neuroimaging experiments in mice, so it is necessary to excise a portion of the skull. Such craniotomy procedures have traditionally been done manually, but automating the process provides greater control of the cutting path and depth. A computer numerical controlled (CNC) milling machine can perform craniotomies of arbitrary shape and position with high precision. Automating the procedure improves repeatability and consistency, poses fewer risks for damaging the brain, and makes the procedure easier to learn. We have developed an automated craniotomy procedure which utilizes a CNC machine to obtain a curvature profile of the skull with an impedance-sensitive probing circuit and to interpolate a cut path along this profile to remove a portion of a mouse’s skull. This procedure does not damage the underlying brain tissue and can be performed in under two hours. © 2021 SPIE.

Author Keywords
Computer numerical control; Craniotomy; Surface profiling

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

“Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome” (2021) NeuroImage: Clinical

Neurofibrillary tau depositions emerge with subthreshold cerebral beta-amyloidosis in down syndrome
(2021) NeuroImage: Clinical, 31, art. no. 102740, .

Zammit, M.D.^a ^b , Tudorascu, D.L.^c , Laymon, C.M.^d ^e , Hartley, S.L.^a , Ellison, P.A.^b , Zaman, S.H.^f , Ances, B.M.^g , Johnson, S.C.^h , Stone, C.K.ⁱ , Sabbagh, M.N.^j , Mathis, C.A.^c , Klunk, W.E.^c , Cohen, A.D.^c , Handen, B.L.^c , Christian, B.T.^a ^b

^a University of Wisconsin-Madison Waisman Center, Madison, WI, United States
^b University of Wisconsin-Madison Department of Medical Physics, Madison, WI, United States
^c University of Pittsburgh Department of Psychiatry, Pittsburgh, PA, United States
^d University of Pittsburgh Department of Radiology, Pittsburgh, PA, United States
^e University of Pittsburgh, Department of Bioengineering, Pittsburgh, PA, United States
^f Cambridge Intellectual Disability Research Group, University of Cambridge, Cambridge, United Kingdom
^g Washington University in St. Louis Department of Neurology, St. LouisMO, United States
^h University of Wisconsin-Madison Alzheimer’s Disease Research Center, Madison, WI, United States
ⁱ University of Wisconsin-Madison Department of Medicine, Madison, WI, United States
^j Cleveland Clinic Nevada, Las Vegas, NV, United States

Abstract
Introduction: Adults with Down syndrome are genetically predisposed to develop Alzheimer’s disease and accumulate beta-amyloid plaques (Aβ) early in life. While Aβ has been heavily studied in Down syndrome, its relationship with neurofibrillary tau is less understood. The aim of this study was to evaluate neurofibrillary tau deposition in individuals with Down syndrome with varying levels of Aβ burden. Methods: A total of 161 adults with Down syndrome (mean age = 39.2 (8.50) years) and 40 healthy, non-Down syndrome sibling controls (43.2 (12.6) years) underwent T1w-MRI, [C-11]PiB and [F-18]AV-1451 PET scans. PET images were converted to units of standardized uptake value ratios (SUVrs). Aβ burden was calculated using the amyloid load metric (AβL); a measure of global Aβ burden that improves quantification from SUVrs by suppressing the nonspecific binding signal component and computing the specific Aβ signal from all Aβ-carrying voxels from the image. Regional tau was assessed using control-standardized AV-1451 SUVr. Control-standardized SUVrs were compared across Down syndrome groups of Aβ-negative (A-) (AβL < 13.3), subthreshold A+ (13.3 ≤ AβL < 20) and conventionally A+ (AβL ≥ 20) individuals. The subthreshold A + group was identified as having significantly higher Aβ burden compared to the A- group, but not high enough to satisfy a conventional A + classification. Results: A large-sized association that survived adjustment for chronological age, mental age (assessed using the Peabody Picture Vocabulary Test), and imaging site was observed between AβL and AV-1451 within each Braak region (p < .05). The A + group showed significantly higher AV-1451 retention across all Braak regions compared to the A- and subthreshold A + groups (p < .05). The subthreshold A + group showed significantly higher AV-1451 retention in Braak regions I-III compared to an age-matched sample from the A- group (p < .05). Discussion: These results show that even the earliest detectable Aβ accumulation in Down syndrome is accompanied by elevated tau in the early Braak stage regions. This early detection of tau can help characterize the tau accumulation phase during preclinical Alzheimer’s disease progression in Down syndrome and suggests that there may be a relatively narrow window after Aβ accumulation begins to prevent the downstream cascade of events that leads to Alzheimer’s disease. © 2021 The Authors

Author Keywords
Amyloid; Down syndrome; Early detection; Neurofibrillary tau

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAR01AG031110, U01AG051406, U54HD090256
National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Final
Source: Scopus

“A fresh look at the two visual streams” (2021) Journal of Consciousness Studies

A fresh look at the two visual streams
(2021) Journal of Consciousness Studies, 28 (5-6), pp. 198-207.

Henke, B.

Washington University in St. Louis MO, United States

Abstract
According to what I’ll call the ‘two visual systems account’ (TWO-SYSTEMS), visual processing is divided into two independent sub-systems, a ventral system implementing ‘vision for perception’ and a dorsal system implementing ‘vision for action’ (Milner and Goodale, 2006). TWO-SYSTEMS is widely discussed in philosophy due to the counter-intuitive role that it posits for conscious experience in the control of actions. However, recent evidence undermines the model’s core tenets: it no longer appears that the ventral and dorsal streams constitute isolated processing systems, and there is now evidence for the involvement of both streams in conscious experience and online motor control. I articulate a new ‘direct dorsal control account’ (DORSAL-CONTROL), show that it is immune to three empirical challenges facing TWO-SYSTEMS, and show that it nonetheless has similarly significant implications for the perceiving mind. © 2021, Imprint Academic. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

“The foraging gene as a modulator of division of labour in social insects” (2021) Journal of Neurogenetics

The foraging gene as a modulator of division of labour in social insects
(2021) Journal of Neurogenetics, .

Lucas, C.^a , Ben-Shahar, Y.^b

^a Institut de Recherche sur la Biologie de l’Insecte (UMR7261), CNRS–University of Tours, Tours, France
^b Department of Biology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The social ants, bees, wasps, and termites include some of the most ecologically-successful groups of animal species. Their dominance in most terrestrial environments is attributed to their social lifestyle, which enable their colonies to exploit environmental resources with remarkable efficiency. One key attribute of social insect colonies is the division of labour that emerges among the sterile workers, which represent the majority of colony members. Studies of the mechanisms that drive division of labour systems across diverse social species have provided fundamental insights into the developmental, physiological, molecular, and genomic processes that regulate sociality, and the possible genetic routes that may have led to its evolution from a solitary ancestor. Here we specifically discuss the conserved role of the foraging gene, which encodes a cGMP-dependent protein kinase (PKG). Originally identified as a behaviourally polymorphic gene that drives alternative foraging strategies in the fruit fly Drosophila melanogaster, changes in foraging expression and kinase activity were later shown to play a key role in the division of labour in diverse social insect species as well. In particular, foraging appears to regulate worker transitions between behavioural tasks and specific behavioural traits associated with morphological castes. Although the specific neuroethological role of foraging in the insect brain remains mostly unknown, studies in genetically tractable insect species indicate that PKG signalling plays a conserved role in the neuronal plasticity of sensory, cognitive and motor functions, which underlie behaviours relevant to division of labour, including appetitive learning, aggression, stress response, phototaxis, and the response to pheromones. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
behaviour; division of labour; foraging gene; insects; sociality

Document Type: Review
Publication Stage: Article in Press
Source: Scopus

“Integrated functional characterization and optical tagging for cell-type identification” (2021) Progress in Biomedical Optics and Imaging – Proceedings of SPIE

Integrated functional characterization and optical tagging for cell-type identification
(2021) Progress in Biomedical Optics and Imaging – Proceedings of SPIE, 11663, art. no. 116630I, .

Lee, D.^a ^b , Kume, M.^a , Holy, T.E.^a

^a Washington University in St. Louis, Departments of Neuroscience and Biomedical Engineering, St. Louis, MO 63110, United States
^b Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Abstract
Imaging has become one of the most important tools for categorizing neurons based on their function. However, for a cell type identified only by its pattern of activity, the process of identifying molecular markers remains laborious. We developed physiological optical tagging sequencing (PhOTseq), a technique for tagging and ex- pression profiling of cells on the basis of their functional properties. We developed a reporter combining a green calcium indicator (GCaMP) with a photoactivatable red reporter (PAmCherry). When visualizing neuronal activity in such animals, real-time analysis allowed digital selection of cells exhibiting specific activity patterns, and photoactivation was directed specifically to those cells to tag them for later harvesting and analysis. We found that PhOTseq was capable of selecting rare cell types and enriching them by nearly 100-fold. We applied PhOTseq to the challenge of mapping receptor-ligand pairings among pheromone-sensing neurons in mice, and densely mapped the cell types responsible for encoding a specific portion of the sensory world. © 2021 SPIE. All rights reserved.

Author Keywords
Calcium imaging; Cell types; Gene expression; Optical tagging; Real-time analysis; Single-cell sequencing

Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDDC010381, R01 DC005964
Bio-oriented Technology Research Advancement InstitutionBRAIN1UF1NS108176

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

“Markers of early changes in cognition across cohorts of adults with down syndrome at risk of alzheimer’s disease” (2021) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring

Markers of early changes in cognition across cohorts of adults with down syndrome at risk of alzheimer’s disease
(2021) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 13 (1), art. no. e12184, .

Aschenbrenner, A.J.^a , Asaad Baksh, R.^b ^c , Benejam, B.^d , Beresford-Webb, J.A.^e , Coppus, A.^f , Fortea, J.^d ^g ^h , Handen, B.L.ⁱ , Hartley, S.^j , Head, E.^k , Jaeger, J.^l ^m , Levin, J.ⁿ ^o ^p , Loosli, S.V.ⁿ , Rebillat, A.-S.^q , Sacco, S.^q , Schmitt, F.A.^r ^s , Thurlow, K.E.^b , Zaman, S.^e ^t , Hassenstab, J.^a , Strydom, A.^b ^c ^u

^a Washington University in St. Louis, Department of Neurology, St. Louis, MO, United States
^b Institute of Psychiatry, Psychology, and Neuroscience, Department of Forensic and Neurodevelopmental Sciences, King’s College London, London, United Kingdom
^c The London Down Syndrome (LonDownS) Consortium, London, United Kingdom
^d Barcelona Down Medical Center, Fundació Catalana Síndrome de Down, Barcelona, Spain
^e Cambridge Intellectual and Developmental Disabilities Research Group, Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
^f Department of Primary and Community Care, Radboud University Medical Center, Nijmegen, Netherlands
^g Memory Unit and Biomedical Research Institute Sant Pau (IIB Sant Pau), Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^h Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
ⁱ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^j Department of Human Development & Family Studies, University of Wisconsin-Madison, Madison, WI, United States
^k Department of Pathology & Laboratory Medicine, University of California, Irvine, CA, United States
^l CognitionMetrics, LLC, Wilmington, DE, United States
^m Deptment of Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States
ⁿ Department of Neurology, Ludwig-Maximilians-UniversitätMünchen, Munich, Germany
^o German Center for Neurodegenerative Diseases, Munich, Germany
^p Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^q Jerome Lejeune Institute, Paris, France
^r Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, United States
^s Departments of Neurology, Neurosurgery, Behavioral Science, Psychology, Psychiatry, University of Kentucky, Lexington, KY, United States
^t Cambridgeshire & Peterborough NHS Foundation Trust, Cambridge, United Kingdom
^u South London and the Maudsley NHS Foundation Trust, London, United Kingdom

Abstract
Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer’s disease (AD), lacks a suitable outcome measure for prevention trials targeting predementia stages. Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composites that were sensitive to change over time.We then conducted additional analyses to provide support for the utility of the composites. The composites were presented to an expert panel to determine the most optimal cognitive battery based on predetermined criteria. Results: There were common cognitive domains across site composites, which were sensitive to early decline. The final composite consisted ofmemory, language/executive functioning, selective attention, orientation, and praxis tests. Discussion:We have identified a composite that is sensitive to early decline and thus may have utility as an outcome measure in trials to prevent or delay symptoms of AD in DS. © 2021 The Authors.

Author Keywords
Alzheimer’s disease; Clinical trial outcome; Composite measure; Down syndrome; Early cognitive decline

Funding details
National Institutes of HealthNIH
Roche
National Institute on Handicapped ResearchNIHR
Stiftung VERUM
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD064993
Wellcome TrustWT098330/Z/12/Z
Medical Research CouncilMRCMR/R024901/1, MR/S005145/1, MR/S011277/1
National Institute for Health ResearchNIHR
Deutsche ForschungsgemeinschaftDFG390857198
Fondation Jérôme Lejeune
UCLH Biomedical Research CentreNIHR BRCBRC-1215-20014, R01AG031110, U01AG051406

Document Type: Article
Publication Stage: Final
Source: Scopus

“Social and non-social sensory responsivity in toddlers at high-risk for autism spectrum disorder” (2021) Autism Research

Social and non-social sensory responsivity in toddlers at high-risk for autism spectrum disorder
(2021) Autism Research, .

Gunderson, J.^a , Worthley, E.^a , Grzadzinski, R.^b , Burrows, C.^a , Estes, A.^c , Zwaigenbaum, L.^d , Botteron, K.^e , Dager, S.^c , Hazlett, H.^b , Schultz, R.^f , Piven, J.^b , Wolff, J.^a , IBIS Network^g

^a University of Minnesota, Minneapolis, MN, United States
^b University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^c University of Washington, Seattle, WA, United States
^d University of Alberta, Edmonton, AB, Canada
^e Washington University in St. Louis, St. Louis, MO, United States
^f Children’s Hospital of Philadelphia, Philadelphia, PA, United States

Abstract
Empirical evidence concerning sensory responsivity in young children who later develop autism spectrum disorder (ASD) remains relatively limited. It is unclear whether specific patterns or aspects of sensory responsivity underlay the emergence of the disorder. The goals of this study were to (a) examine whether social versus non-social context impacted the expression of sensory responsivity in infants at high risk for ASD, and (b) examine if sensory responsivity in social or non-social contexts was associated with severity of ASD symptoms. The Sensory Experiences Questionnaire 2.1 was collected for 338 infants (131 females, 207 males) at high-risk for ASD at 12 and/or 24 months of age. High-risk toddlers meeting diagnostic criteria for ASD (n = 75) showed elevated sensory responsivity in both social and non-social contexts at 12 months of age and differences widened over the second year of life. Individuals with ASD demonstrate higher responsivity in both contexts suggestive of generalized atypical sensory responsivity in ASD. Lay Summary: Behaviors such as avoiding or noticing sensory input (e.g., sounds, touches) are often different in individuals with autism spectrum disorder (ASD) than those without. The reason for this is widely unknown. The findings from this study show that in toddlers, sensory responsivity increased in both social and non-social situations. Therefore, the setting of sensory input does not explain these differences. © 2021 International Society for Autism Research and Wiley Periodicals LLC.

Author Keywords
autism spectrum disorder; context; environment; sensory functioning; sensory responsivity; social

Funding details
National Institutes of HealthNIHP30HD03110, R01HD05574, R01MH116961, T32HD040127
Autism SpeaksAS
Simons FoundationSF

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“Diffusion basis spectrum imaging measures anti-inflammatory and neuroprotective effects of fingolimod on murine optic neuritis” (2021) NeuroImage: Clinical

Diffusion basis spectrum imaging measures anti-inflammatory and neuroprotective effects of fingolimod on murine optic neuritis
(2021) NeuroImage: Clinical, 31, art. no. 102732, .

Yang, R.^a ^b , Lin, T.-H.^b , Zhan, J.^b , Lai, S.^c , Song, C.^b , Sun, P.^b , Ye, Z.^b , Wallendorf, M.^d , George, A.^b , Cross, A.H.^e ^f , Song, S.-K.^b ^e ^g

^a Department of Radiology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, Guangdong 510640, China
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Medical Equipment, Guangdong Food and Drug Vocational College, Guangzhou, Guangdong 510520, China
^d Department of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Objective: To prospectively determine whether diffusion basis spectrum imaging (DBSI) detects, differentiates and quantitates coexisting inflammation, demyelination, axonal injury and axon loss in mice with optic neuritis (ON) due to experimental autoimmune encephalomyelitis (EAE), and to determine if DBSI accurately measures effects of fingolimod on underlying pathology. Methods: EAE was induced in 7-week-old C57BL/6 female mice. Visual acuity (VA) was assessed daily to detect onset of ON after which daily oral-treatment with either fingolimod (1 mg/kg) or saline was given for ten weeks. In vivo DBSI scans of optic nerves were performed at baseline, 2-, 6- and 10-weeks post treatment. DBSI-derived metrics including restricted isotropic diffusion tensor fraction (putatively reflecting cellularity), non-restricted isotropic diffusion tensor fraction (putatively reflecting vasogenic edema), DBSI-derived axonal volume, axial diffusivity, λ∥ (putatively reflecting axonal integrity), and increased radial diffusivity, λ⊥ (putatively reflecting demyelination). Mice were killed immediately after the last DBSI scan for immunohistochemical assessment. Results: Optic nerves of fingolimod-treated mice exhibited significantly better (p < 0.05) VA than saline-treated group at each time point. During ten-week of treatment, DBSI-derived non-restricted and restricted-isotropic-diffusion-tensor fractions, and axonal volumes were not significantly different (p > 0.05) from the baseline values in fingolimod-treated mice. Transient DBSI-λ∥ decrease and DBSI-λ⊥ increase were detected during Fingolimod treatment. DBSI-derived metrics assessed in vivo significantly correlated (p < 0.05) with the corresponding histological markers. Conclusion: DBSI was used to assess changes of the underlying optic nerve pathologies in EAE mice with ON, exhibiting great potential as a noninvasive outcome measure for monitoring disease progression and therapeutic efficacy for MS. © 2021 The Author(s)

Author Keywords
Axonal loss; Demyelination; Fingolimod; Multiple sclerosis, diffusion basis spectrum imaging; Optic neuritis

Funding details
National Institutes of HealthNIHP01-NS059560, R01-NS047592, U01- EY025500
U.S. Department of DefenseDODW81XWH-12-1-0457
National Multiple Sclerosis SocietyFG-1507-05315, RG 4549A4/1, RG1701-26617
Foundation for Barnes-Jewish Hospital
National Natural Science Foundation of ChinaNSFC81971574
Natural Science Foundation of Guangdong Province2018A030313282
Natural Science Foundation of Jiangxi Province20202BABL216038, 202110018
Education Department of Jiangxi ProvinceGJJ180133
Guangzhou Municipal Science and Technology Project202002030268

Document Type: Article
Publication Stage: Final
Source: Scopus

“Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging” (2021) Multiple Sclerosis Journal

Characterization of multiple sclerosis neuroinflammation and neurodegeneration with relaxation and diffusion basis spectrum imaging
(2021) Multiple Sclerosis Journal, .

Vavasour, I.M.^a ^j , Sun, P.^b , Graf, C.^c , Yik, J.T.^c , Kolind, S.H.^d ^k ^l ^m , Li, D.K.B.^e ^p , Tam, R.^f ^o , Sayao, A.-L.^g , Schabas, A.^g , Devonshire, V.^g , Carruthers, R.^g , Traboulsee, A.^g , Moore, G.R.W.^h ⁿ , Song, S.-K.^b , Laule, C.ⁱ ^q ^r ^s

^a Department of Radiology, The University of British Columbia, UBC Hospital, Vancouver, BC, Canada
^b Department of Radiology, Washington University, St. Louis, MO, United States
^c Department of Physics & Astronomy, The University of British Columbia, Vancouver, BC, Canada
^d Department of Radiology, The University of British Columbia, Vancouver, BC, Canada
^e Department of Radiology, The University of British Columbia, Vancouver, BC, Canada
^f Department of Radiology, The University of British Columbia, Vancouver, BC, Canada
^g Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
^h Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
ⁱ Department of Radiology, The University of British Columbia, Vancouver, BC, Canada
^j International Collaboration on Repair Discoveries (ICORD), The University of British Columbia, Vancouver, BC, Canada
^k International Collaboration on Repair Discoveries (ICORD), The University of British Columbia, Vancouver, BC, Canada
^l Department of Physics Astronomy, The University of British Columbia, Vancouver, BC, Canada
^m Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
ⁿ Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada
^o School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada
^p Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
^q International Collaboration on Repair Discoveries (ICORD), The University of British Columbia, Vancouver, BC, Canada
^r Department of Physics Astronomy, The University of British Columbia, Vancouver, BC, Canada
^s Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada

Abstract
Background: Advanced magnetic resonance imaging (MRI) methods can provide more specific information about various microstructural tissue changes in multiple sclerosis (MS) brain. Quantitative measurement of T1 and T2 relaxation, and diffusion basis spectrum imaging (DBSI) yield metrics related to the pathology of neuroinflammation and neurodegeneration that occurs across the spectrum of MS. Objective: To use relaxation and DBSI MRI metrics to describe measures of neuroinflammation, myelin and axons in different MS subtypes. Methods: 103 participants (20 clinically isolated syndrome (CIS), 33 relapsing-remitting MS (RRMS), 30 secondary progressive MS and 20 primary progressive MS) underwent quantitative T1, T2, DBSI and conventional 3T MRI. Whole brain, normal-appearing white matter, lesion and corpus callosum MRI metrics were compared across MS subtypes. Results: A gradation of MRI metric values was seen from CIS to RRMS to progressive MS. RRMS demonstrated large oedema-related differences, while progressive MS had the most extensive abnormalities in myelin and axonal measures. Conclusion: Relaxation and DBSI-derived MRI measures show differences between MS subtypes related to the severity and composition of underlying tissue damage. RRMS showed oedema, demyelination and axonal loss compared with CIS. Progressive MS had even more evidence of increased oedema, demyelination and axonal loss compared with CIS and RRMS. © The Author(s), 2021.

Author Keywords
brain; diffusion basis spectrum imaging; multiple sclerosis; T1 relaxation; T2 relaxation

Funding details
Genzyme
Novartis
Roche
Natural Sciences and Engineering Research Council of CanadaNSERC
Michael Smith Foundation for Health ResearchMSFHR
Multiple Sclerosis Society of CanadaMSSOC2302
Mitacs
MedImmune
Vancouver Coastal Health Research InstituteVCHRI

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

“College Mental Health Before and During the COVID-19 Pandemic: Results From a Nationwide Survey” (2021) Cognitive Therapy and Research

College Mental Health Before and During the COVID-19 Pandemic: Results From a Nationwide Survey
(2021) Cognitive Therapy and Research, .

Kim, H.^a , Rackoff, G.N.^b , Fitzsimmons-Craft, E.E.^c , Shin, K.E.^d , Zainal, N.H.^b , Schwob, J.T.^b , Eisenberg, D.^e , Wilfley, D.E.^c , Taylor, C.B.^f ^g , Newman, M.G.^b

^a Department of Psychiatry, Michigan Medicine, Ann Arbor, MI, United States
^b Department of Psychology, The Pennsylvania State University, 371 Moore Building, University Park, PA, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychology, Teachers College, Columbia University, New York City, NY, United States
^e Department of Health Policy and Management, Fielding School of Public Health, University of California at Los Angeles, Los Angeles, CA, United States
^f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^g Center for m2 Health, Palo Alto University, Palo Alto, CA, United States

Abstract
Background: The COVID-19 pandemic could affect college students’ mental health. We examined screening rates for psychological disorders before and during the pandemic. Methods: Undergraduates were surveyed before (n = 3643) or during the pandemic (n = 4970). Logistic regression adjusting for participant demographics was conducted. Results: Frequencies of depression [OR 1.32, 95% CI (1.17, 1.48)], alcohol use disorder [OR 1.70, 95% CI (1.50, 1.93)], bulimia nervosa/binge-eating disorder [OR 1.54, 95% CI (1.28, 1.85)], and comorbidity [OR 1.19, 95% CI (1.04, 1.35)] were greater during (vs. before) the pandemic. Frequencies of posttraumatic stress disorder were lower during the pandemic [OR 0.86, 95% CI (0.75, 0.98)]. The upward trend in alcohol use disorder was stronger among women than men [OR 1.47, 95% CI (1.18, 1.83)]. The upward trend in depression was stronger among Black students than White students [OR 1.72, 95% CI (1.19, 2.49)]. Anxiety disorders, insomnia, anorexia nervosa, and suicidality showed no significant trends. Conclusions: Depression, alcohol use disorder, bulimia nervosa/binge-eating disorder, and comorbidity were higher, whereas posttraumatic stress disorder was lower during the pandemic. Women and Black students could face especially heightened risk for alcohol use disorder and depression, respectively, during the pandemic. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
College students; COVID-19; Pandemic; Psychological disorders

Funding details
National Institutes of HealthNIH5R01MH115128-03

Document Type: Article
Publication Stage: Article in Press
Source: Scopus