WashU weekly Neuroscience publications

FAM222A encodes a protein which accumulates in plaques in Alzheimer’s disease
(2020) Nature Communications, 11 (1), art. no. 411, . 

Yan, T.^a , Liang, J.^b , Gao, J.^a , Wang, L.^a , Fujioka, H.^c , Weiner, M.W.^d , Schuff, N.^d , Rosen, H.J.^d , Miller, B.L.^d , Perry, D.^d , Aisen, P.^e , Toga, A.W.^e , Jimenez, G.^e , Donohue, M.^e , Gessert, D.^e , Harless, K.^e , Salazar, J.^e , Cabrera, Y.^e , Walter, S.^e , Hergesheimer, L.^e , Toga, A.W.^e , Crawford, K.^e , Neu, S.^e , Schneider, L.S.^e , Pawluczyk, S.^e , Becerra, M.^e , Teodoro, L.^e , Spann, B.M.^e , Aisen, P.^e , Petersen, R.^f , Jack, C.R.^f , Bernstein, M.^f , Borowski, B.^f , Gunter, J.^f , Senjem, M.^f , Vemuri, P.^f , Jones, D.^f , Kantarci, K.^f , Ward, C.^f , Mason, S.S.^f , Albers, C.S.^f , Knopman, D.^f , Johnson, K.^f , Graff-Radford, N.R.^g , Parfitt, F.^g , Poki-Walker, K.^g , Jagust, W.^h , Landau, S.^h , Trojanowki, J.Q.ⁱ , Shaw, L.M.ⁱ , Karlawish, J.H.ⁱ , Wolk, D.A.ⁱ , Vaishnavi, S.ⁱ , Clark, C.M.ⁱ , Arnold, S.E.ⁱ , Lee, V.ⁱ , Korecka, M.ⁱ , Figurski, M.ⁱ , Beckett, L.^j , Harvey, D.^j , DeCArli, C.^j , Fletcher, E.^j , Maillard, P.^j , Olichney, J.^j , Carmichael, O.^j , Green, R.C.^k , Sperling, R.A.^k , Johnson, K.A.^k , Marshall, G.A.^k , Saykin, A.J.^l , Foroud, T.M.^l , Shen, L.^l , Faber, K.^l , Kim, S.^l , Nho, K.^l , Farlow, M.R.^l , Hake, A.M.^l , Matthews, B.R.^l , Brosch, J.R.^l , Herring, S.^l , Morris, J.^m , Raichle, M.^m , Holtzman, D.^m , Morris, J.C.^m , Cairns, N.J.^m , Franklin, E.^m , Taylor-Reinwald, L.^m , Ances, B.^m , Winkfield, D.^m , Carroll, M.^m , Oliver, A.^m , Creech, M.L.^m , Mintun, M.A.^m , Schneider, S.^m , Kuller, L.ⁿ , Mathis, C.ⁿ , Lopez, O.L.ⁿ , Oakley, M.A.ⁿ , Simpson, D.M.ⁿ , Paul, S.^o , Relkin, N.^o , Chiang, G.^o , Lin, M.^o , Ravdin, L.^o , Davies, P.^p , Mesulam, M.M.^q , Mesulam, M.-M.^q , Rogalski, E.^q , Lipowski, K.^q , Weintraub, S.^q , Bonakdarpour, B.^q , Kerwin, D.^q , Wu, C.-K.^q , Johnson, N.^q , Snyder, P.J.^r , Montine, T.^s , Donohue, M.^t , Thal, L.^t , Brewer, J.^t , Vanderswag, H.^t , Fleisher, A.^t , Thompson, P.^u , Woo, E.^u , Silverman, D.H.S.^u , Teng, E.^u , Kremen, S.^u , Apostolova, L.^u , Tingus, K.^u , Lu, P.H.^u , Bartzokis, G.^u , Koeppe, R.A.^v , Ziolkowski, J.^v , Heidebrink, J.L.^v , Lord, J.L.^v , Foster, N.^w , Albert, M.^x , Onyike, C.^x , D’Agostino, D.^x , Kielb, S.^x , Quinn, J.^y , Silbert, L.C.^y , Lind, B.^y , Kaye, J.A.^y , Carter, R.^y , Dolen, S.^y , Villanueva-Meyer, J.^z , Pavlik, V.^z , Pacini, N.^z , Lamb, A.^z , Kass, J.S.^z , Doody, R.S.^z , Shibley, V.^z , Chowdhury, M.^z , Rountree, S.^z , Dang, M.^z , Stern, Y.^aa , Honig, L.S.^aa , Bell, K.L.^aa , Yeh, R.^aa , Marson, D.^ab , Geldmacher, D.^ab , Natelson, M.^ab , Griffith, R.^ab , Clark, D.^ab , Brockington, J.^ab , Grossman, H.^ac , Mitsis, E.^ac , Shah, R.C.^ad , Lamar, M.^ad , Samuels, P.^ad , Sadowski, M.^ae , Sheikh, M.O.^ae , Singleton-Garvin, J.^ae , Ulysse, A.^ae , Gaikwad, M.^ae , Doraiswamy, P.M.^af , James, O.^af , Borges-Neto, S.^af , Wong, T.Z.^af , Coleman, E.^af , Smith, C.D.^ag , Jicha, G.^ag , Hardy, P.^ag , El Khouli, R.^ag , Oates, E.^ag , Conrad, G.^ag , Porsteinsson, A.P.^ah , Martin, K.^ah , Kowalksi, N.^ah , Keltz, M.^ah , Goldstein, B.S.^ah , Makino, K.M.^ah , Ismail, M.S.^ah , Brand, C.^ah , Thai, G.^ai , Pierce, A.^ai , Yanez, B.^ai , Sosa, E.^ai , Witbracht, M.^ai , Potkin, S.^ai , Womack, K.^aj , Mathews, D.^aj , Quiceno, M.^aj , Levey, A.I.^ak , Lah, J.J.^ak , Cellar, J.S.^ak , Burns, J.M.^al , Swerdlow, R.H.^al , Brooks, W.M.^al , van Dyck, C.H.^am , Carson, R.E.^am , Varma, P.^am , Chertkow, H.^an , Bergman, H.^an , Hosein, C.^an , Turner, R.S.^ao , Johnson, K.^ao , Reynolds, B.^ao , Kowall, N.^ap , Killiany, R.^ap , Budson, A.E.^ap , Norbash, A.^ap , Johnson, P.L.^ap , Obisesan, T.O.^aq , Oyonumo, N.E.^aq , Allard, J.^aq , Ogunlana, O.^aq , Lerner, A.^ar , Ogrocki, P.^ar , Tatsuoka, C.^ar , Fatica, P.^ar , Johnson, S.^as , Asthana, S.^as , Carlsson, C.M.^as , Yesavage, J.^at , Taylor, J.L.^at , Chao, S.^at , Lane, B.^at , Rosen, A.^at , Tinklenberg, J.^at , Scharre, D.W.^au , Kataki, M.^au , Tarawneh, R.^au , Zimmerman, E.A.^av , Celmins, D.^av , Hart, D.^av , Flashman, L.A.^aw , Seltzer, M.^aw , Hynes, M.L.^aw , Santulli, R.B.^aw , Sink, K.M.^ax , Yang, M.^ax , Mintz, A.^ax , Miller, D.D.^ay , Smith, K.E.^ay , Koleva, H.^ay , Nam, K.W.^ay , Shim, H.^ay , Schultz, S.K.^ay , Smith, A.^az , Leach, C.^az , Raj, B.A.^az , Fargher, K.^az , Reiman, E.M.^ba , Chen, K.^ba , Tariot, P.^ba , Burke, A.^ba , Hetelle, J.^ba , DeMarco, K.^ba , Trncic, N.^ba , Fleisher, A.^ba , Reeder, S.^ba , Zamrini, E.^bb , Belden, C.M.^bb , Sirrel, S.A.^bb , Duara, R.^bc , Greig-Custo, M.T.^bc , Rodriguez, R.^bc , Bernick, C.^bd , Munic, D.^bd , Khachaturian, Z.^be , Buckholtz, N.^bf , Hsiao, J.^bf , Potter, W.^bg , Fillit, H.^bh , Hefti, F.^bi , Sadowsky, C.^bj , Villena, T.^bj , Hsiung, G.-Y.R.^bk , Mudge, B.^bk , Sossi, V.^bk , Feldman, H.^bk , Assaly, M.^bk , Finger, E.^bl , Pasternack, S.^bl , Pavlosky, W.^bl , Rachinsky, I.^bl , Drost, D.^bl , Kertesz, A.^bl , Black, S.^bm , Stefanovic, B.^bm , Heyn, C.^bm , Ott, B.R.^bn , Tremont, G.^bn , Daniello, L.A.^bn , Bodge, C.^bo , Salloway, S.^bo , Malloy, P.^bo , Correia, S.^bo , Lee, A.^bo , Pearlson, G.D.^bp , Blank, K.^bp , Anderson, K.^bp , Bates, V.^bq , Capote, H.^bq , Rainka, M.^bq , Mintzer, J.^br , Spicer, K.^br , Bachman, D.^br , Finger, E.^bs , Pasternak, S.^bs , Rachinsky, I.^bs , Rogers, J.^bs , Kertesz, A.^bs , Drost, D.^bs , Finger, E.^bs , Pasternak, S.^bs , Rachinsky, I.^bs , Rogers, J.^bs , Kertesz, A.^bs , Drost, D.^bs , Pomara, N.^bt , Hernando, R.^bt , Sarrael, A.^bt , Kittur, S.^bu , Borrie, M.^bv , Lee, T.-Y.^bv , Bartha, R.^bv , Frank, R.^bw , Fox, N.^bx , Logovinsky, V.^by , Corrillo, M.^bz , Sorensen, G.^ca , Zhu, X.^b , Wang, X.^a , The Alzheimer Disease Neuroimaging Initiative^cb

^a Department of Pathology, Case Western Reserve University, Cleveland, OH, United States
^b Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, United States
^c Electron Microscopy Core Facility, Case Western Reserve University, Cleveland, OH, United States
^d University of California, San Francisco, CA, United States
^e University of Southern California, San Francisco, CA, United States
^f Mayo Clinic, Rochester, MN, United States
^g Mayo Clinic, Jacksonville, FL, United States
^h University of California, Berkeley, CA, United States
ⁱ University of Pennsylvania, Philadelphia, PA, United States
^j University of California, Davis, CA, United States
^k Brigham and Women’s Hospital, Boston, MA, United States
^l Indiana University, Indianapolis, IN, United States
^m Washington University, St. Louis, MO, United States
ⁿ University of Pittsburgh, Pittsburgh, PA, United States
^o Cornell University, New York, NY, United States
^p Albert Einstein College of Medicine of Yeshiva University, New York, NY, United States
^q Northwestern University, Chicago, IL, United States
^r Brown University, Providence, RI, United States
^s University of Washington, Seattle, WA, United States
^t University of California, San Diego, CA, United States
^u University of California, Los Angeles, CA, United States
^v University of Michigan, Ann Arbor, MI, United States
^w University of Utah, Salt Lake City, UT, United States
^x Johns Hopkins University, Baltimore, MD, United States
^y Oregon Health & Science University, Portland, OR, United States
^z Baylor College of Medicine, Houston, TX, United States
^aa Columbia University Medical Center, New York, NY, United States
^ab University of Alabama, Birmingham, AL, United States
^ac Mount Sinai School of Medicine, New York, NY, United States
^ad Rush University Medical Center, Chicago, IL, United States
^ae New York University, New York, NY, United States
^af Duke University Medical Center, Durham, NC, United States
^ag University of Kentucky, Lexington, KY, United States
^ah University of Rochester Medical Center, Rochester, NY, United States
^ai University of California, Irvine, CA, United States
^aj University of Texas Southwestern Medical School, Dallas, TX, United States
^ak Emory University, Atlanta, GA, United States
^al University of Kansas Medical Center, Kansas City, KS, United States
^am Yale University School of Medicine, New Haven, CT, United States
^an McGill University Montreal-Jewish General Hospital, Montreal, QC, Canada
^ao Georgetown University Medical Center, Washington, DC, United States
^ap Boston University, Boston, MA, United States
^aq Howard University, Washington, DC, United States
^ar University Hospitals, Cleveland, OH, United States
^as University of Wisconsin, Madison, WI, United States
^at Stanford University, Stanford, CA, United States
^au Ohio State University, Columbus, OH, United States
^av Albany Medical College, Albany, NY, United States
^aw Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
^ax Wake Forest University Health Sciences, Winston-Salem, NC, United States
^ay University of Iowa College of Medicine, Iowa City, IA, United States
^az University of South Florida, Health Byrd Alzheimer’s Institute, Tampa, FL, United States
^ba Banner Alzheimer’s Institute, Phoenix, AZ, United States
^bb Banner Sun Health Research Institute, Sun City, AZ, United States
^bc Wien Center, Miami Beach, FL, United States
^bd Cleveland Clinic Lou Ruvo Center for Brain Health, Cleveland, OH, United States
^be Prevent Alzheimer’s Disease, Rockville, MD 2020, United States
^bf National Institute on Aging, Baltimore, MD, United States
^bg National Institute of Mental Health, Rockville, MD, United States
^bh AD Drug Discovery Foundation, New York, NY, United States
^bi Acumen Pharmaceuticals, Livermore, CA, United States
^bj Premiere Research Institute, Palm Beach Neurology, West Palm Beach, FL, United States
^bk U.B.C. Clinic for AD & Related Disorders, Vancouver, BC, Canada
^bl Cognitive Neurology – St. Joseph’s, London, ON, Canada
^bm Sunnybrook Health Sciences, Vancouver, ON, Canada
^bn Rhode Island Hospital, Providence, RI, United States
^bo Butler Hospital, Butler, PA, United States
^bp Hartford Hospital, Olin Neuropsychiatry Research Center, Hartford, CT, United States
^bq Dent Neurologic Institute, Orchard Park, NY, United States
^br Medical University South Carolina, Charleston, SC, United States
^bs St. Joseph’s Health Care, London, ON, Canada
^bt Nathan Kline Institute, Orangeburg, NY, United States
^bu Neurological Care of CNY, Liverpool, NY, United States
^bv Parkwood Institute, London, ON, Canada
^bw Richard Frank Consulting, London, United Kingdom
^bx University of London, London, United Kingdom
^by Eli Lilly and Company, Indianapolis, IN, United States
^bz Alzheimer’s Association, Chicago, IL, United States
^ca Siemens, Henkestr, DE, Germany

Abstract
Alzheimer’s disease (AD) is characterized by amyloid plaques and progressive cerebral atrophy. Here, we report FAM222A as a putative brain atrophy susceptibility gene. Our cross-phenotype association analysis of imaging genetics indicates a potential link between FAM222A and AD-related regional brain atrophy. The protein encoded by FAM222A is predominantly expressed in the CNS and is increased in brains of patients with AD and in an AD mouse model. It accumulates within amyloid deposits, physically interacts with amyloid-β (Aβ) via its N-terminal Aβ binding domain, and facilitates Aβ aggregation. Intracerebroventricular infusion or forced expression of this protein exacerbates neuroinflammation and cognitive dysfunction in an AD mouse model whereas ablation of this protein suppresses the formation of amyloid deposits, neuroinflammation and cognitive deficits in the AD mouse model. Our data support the pathological relevance of protein encoded by FAM222A in AD. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease
(2020) Nature Communications, 11 (1), art. no. 347, . 

Franzmeier, N.^a , Neitzel, J.^a , Rubinski, A.^a , Smith, R.^{b c} , Strandberg, O.^c , Ossenkoppele, R.^{c d} , Hansson, O.^{c e} , Ewers, M.^a , Weiner, M.^f , Aisen, P.^g , Petersen, R.^h , Jack, C.R., Jr.^h , Jagust, W.ⁱ , Trojanowki, J.Q.^j , Toga, A.W.^k , Beckett, L.^l , Green, R.C.^m , Saykin, A.J.ⁿ , Morris, J.^o , Shaw, L.M.^p , Liu, E.^q , Montine, T.^r , Thomas, R.G.^g , Donohue, M.^g , Walter, S.^g , Gessert, D.^g , Sather, T.^g , Jiminez, G.^g , Harvey, D.^l , Donohue, M.^g , Bernstein, M.^h , Fox, N.^s , Thompson, P.^t , Schuff, N.^u , DeCArli, C.^l , Borowski, B.^v , Gunter, J.^v , Senjem, M.^v , Vemuri, P.^v , Jones, D.^v , Kantarci, K.^v , Ward, C.^v , Koeppe, R.A.^w , Foster, N.^x , Reiman, E.M.^y , Chen, K.^y , Mathis, C.^z , Landau, S.ⁱ , Cairns, N.J.^o , Householder, E.^o , Reinwald, L.T.^o , Lee, V.^aa , Korecka, M.^aa , Figurski, M.^aa , Crawford, K.^k , Neu, S.^k , Foroud, T.M.ⁿ , Potkin, S.^ab , Shen, L.ⁿ , Kelley, F.ⁿ , Kim, S.ⁿ , Nho, K.ⁿ , 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.^ai , Heidebrink, J.L.^w , Lord, J.L.^w , Petersen, R.^h , Mason, S.S.^h , Albers, C.S.^h , Knopman, D.^h , Johnson, K.^h , 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 , Householder, E.^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.^p , Karlawish, J.H.^p , Wolk, D.^p , 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 , Ortiz, C.M.A.^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.ⁿ , Hake, A.M.ⁿ , Matthews, B.R.ⁿ , Herring, S.ⁿ , Hunt, C.ⁿ , 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 , Fleisher, A.^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.^f , Miller, B.L.^f , Mintzer, J.^cd , Spicer, K.^cd , Bachman, D.^cd , Finger, E.^ce , Pasternak, S.^ce , Rachinsky, I.^ce , Rogers, J.^ce , Kertesz, A.^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 , Alzheimer’s Disease Neuroimaging Initiative (ADNI)^cj

^a Institute for Stroke and Dementia Research, Klinikum der Universitat München, Ludwig-Maximilians-Universitat LMU, Munich, Germany
^b Department of Neurology, Skane University Hospital, Lund, Sweden
^c Clinical Memory Research Unit, Department of Clinical Sciences Malmo, Lund University, Lund, Sweden
^d Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
^e Memory Clinic, Skane University Hospital, Malmo, Sweden
^f UC San Francisco, San Francisco, CA, United States
^g UC San Diego, San Diego, CA, United States
^h Mayo Clinic, Rochester, NY, United States
ⁱ UC Berkeley, Berkeley, CA, United States
^j U Pennsylvania, Pennsylvania, CA, United States
^k USC, Los Angeles, CA, United States
^l UC Davis, Davis, CA, United States
^m Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
ⁿ Indiana University, Bloomington, IN, United States
^o Washington University St. Louis, St. Louis, MO, United States
^p University of Pennsylvania, Philadelphia, PA, United States
^q Janssen Alzheimer Immunotherapy, South San Francisco, CA, United States
^r University of Washington, Seattle, WA, United States
^s University of London, London, United Kingdom
^t USC School of Medicine, Los Angeles, CA, United States
^u UCSF MRI, San Francisco, CA, United States
^v Mayo Clinic, Rochester, NY, 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, city of 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 Univ., 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 Hosp, 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 HospitalRI, 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, 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 Floriday: USF Health Byrd Alzheimer’s Institute, Tampa, FL, United States

Abstract
In Alzheimer’s diseases (AD), tau pathology is strongly associated with cognitive decline. Preclinical evidence suggests that tau spreads across connected neurons in an activity-dependent manner. Supporting this, cross-sectional AD studies show that tau deposition patterns resemble functional brain networks. However, whether higher functional connectivity is associated with higher rates of tau accumulation is unclear. Here, we combine resting-state fMRI with longitudinal tau-PET in two independent samples including 53 (ADNI) and 41 (BioFINDER) amyloid-biomarker defined AD subjects and 28 (ADNI) vs. 16 (BioFINDER) amyloid-negative healthy controls. In both samples, AD subjects show faster tau accumulation than controls. Second, in AD, higher fMRI-assessed connectivity between 400 regions of interest (ROIs) is associated with correlated tau-PET accumulation in corresponding ROIs. Third, we show that a model including baseline connectivity and tau-PET is associated with future tau-PET accumulation. Together, connectivity is associated with tau spread in AD, supporting the view of transneuronal tau propagation. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons
(2020) Scientific Reports, 10 (1), art. no. 569, . 

Alquezar, C.^a , Felix, J.B.^b , McCandlish, E.^c , Buckley, B.T.^c , Caparros-Lefebvre, D.^d , Karch, C.M.^e , Golbe, L.I.^f , Kao, A.W.^a

^a Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA 94158, United States
^b Graduate Program, Department of Molecular and Cellular Biology Baylor College of Medicine, Houston, TX 77030, United States
^c Environmental and Occupational Health Sciences Institute (EOHSI), Rutgers University, 170, Frelinghuysen Road Piscataway NJ, New Brunswick, NJ 08854, United States
^d Centre Hospitalier de Wattrelos, 30 Rue Alexander Fleming, Wattrelos, cedex 59393, France
^e Department of Psychiatry, Washington University in St Louis, St Louis, MO 63110, United States
^f Division of Movement Disorders. Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States

Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by the presence of intracellular aggregates of tau protein and neuronal loss leading to cognitive and motor impairment. Occurrence is mostly sporadic, but rare family clusters have been described. Although the etiopathology of PSP is unknown, mutations in the MAPT/tau gene and exposure to environmental toxins can increase the risk of PSP. Here, we used cell models to investigate the potential neurotoxic effects of heavy metals enriched in a highly industrialized region in France with a cluster of sporadic PSP cases. We found that iPSC-derived iNeurons from a MAPT mutation carrier tend to be more sensitive to cell death induced by chromium (Cr) and nickel (Ni) exposure than an isogenic control line. We hypothesize that genetic variations may predispose to neurodegeneration induced by those heavy metals. Furthermore, using an SH-SY5Y neuroblastoma cell line, we showed that both heavy metals induce cell death by an apoptotic mechanism. Interestingly, Cr and Ni treatments increased total and phosphorylated tau levels in both cell types, implicating Cr and Ni exposure in tau pathology. Overall, this study suggests that chromium and nickel could contribute to the pathophysiology of tauopathies such as PSP by promoting tau accumulation and neuronal cell death. © 2020, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Dose-dependent induction of CPP or CPA by intra-pVTA ethanol: Role of mu opioid receptors and effects on NMDA receptors
(2020) Progress in Neuro-Psychopharmacology and Biological Psychiatry, 100, art. no. 109875, . 

Campos-Jurado, Y.^a , Martí-Prats, L.^a , Morón, J.A.^{b c} , Polache, A.^a , Granero, L.^a , Hipólito, L.^a

^a Department of Pharmacy and Pharmaceutical Tech. and Parasit., University of València, Spain
^b Department of Anesthesiology, Washington University Pain Center, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
The neurobiological mechanisms underlying alcohol motivational properties are still not fully understood, however, the mu-opioid receptors (MORs) have been evidenced as central elements in the manifestation of the alcohol reinforcing properties. Drug-associated environmental stimuli can trigger alcohol relapse and promote alcohol consumption whereby N-methyl-D-aspartate (NMDA) receptors play a pivotal role. Here we sought to demonstrate, for the first time, that ethanol induces conditioned place preference or aversion (CPP or CPA) when administered locally into the ventral tegmental area (VTA) and the associated role of MORs. We further analyzed the changes in the expression and mRNA levels of GluN1 and GluN2A subunits in designated brain areas. The expression of CPP or CPA was characterized following intra-VTA ethanol administration and we showed that either reinforcing (CPP) or aversive (CPA) properties are dependent on the dose administered (ranging here from 35 to 300 nmol). Furthermore, the critical contribution of local MORs in the acquisition of CPP was revealed by a selective antagonist, namely β-Funaltrexamine. Finally, modifications of the expression of NMDA receptor subunits in the Nucleus Accumbens (NAc) and Hippocampus after ethanol-induced CPP were analyzed at the proteomic and transcriptomic levels by western blot and In Situ Hybridation RNAscope techniques, respectively. Results showed that the mRNA levels of GluN2A but not GluN1 in NAc are higher after ethanol CPP. These novel results pave the way for further characterisation of the mechanisms by which ethanol motivational properties are associated with learned environmental cues. © 2020 Elsevier Inc.

Author Keywords
Alcohol;  Conditioned place preference;  GluN2A mRNA;  MORs;  VTA

Document Type: Article
Publication Stage: Final
Source: Scopus

Cues to stress in English spelling
(2020) Journal of Memory and Language, 112, art. no. 104089, . 

Treiman, R., Rosales, N., Cusner, L., Kessler, B.

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

Abstract
How do skilled readers of English decide which syllable of a word to stress? In four behavioral studies, we examined this issue using disyllabic nonwords that varied in number of initial and final consonants. The tasks included oral reading of sentences that contained the nonwords, pronunciation of isolated nonwords, and metalinguistic judgments about stress. Contrary to the influential view within linguistics that onsets are irrelevant to stress assignment, the rate of first-syllable stress increased with the number of consonants in the onset of the first syllable. Also influential were the number of consonants at the end of the nonword, the presence of letter strings that are potential prefixes, and the syntactic context of the nonword in a sentence. In our final study, which involved 3061 English words with the same general structure as the nonwords in the experiments, we found that stress could be predicted with a high degree of accuracy based on the same factors that influenced performance in the behavioral studies. The results are consistent with a statistical-learning view of reading according to which skilled readers have internalized cues to stress that exist in the language but less consistent with Rastle and Coltheart’s (2000) rule-based model of stress assignment in nonword reading. © 2020 Elsevier Inc.

Author Keywords
Lexical stress;  Nonword pronunciation;  Onsets;  Reading;  Statistical learning;  Syllables

Document Type: Article
Publication Stage: Final
Source: Scopus

Modifying genetic epilepsies – Results from studies on tuberous sclerosis complex
(2020) Neuropharmacology, 166, art. no. 107908, . 

Jozwiak, S.^a , Kotulska, K.^b , Wong, M.^c , Bebin, M.^d

^a Department of Pediatric Neurology, Medical University of Warsaw, Warsaw, Poland
^b Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder affecting approximately 1 in 6,000 in general population and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first year of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Recently TSC has been recognized as a model of genetic epilepsies. TSC is a genetic condition with known dysregulated mTOR pathway and is increasingly viewed as a model for human epileptogenesis. Moreover, TSC is characterized by a hyperactivation of mTOR (mammalian target of rapamycin) pathway, and mTOR activation was showed to be implicated in epileptogenesis in many animal models and human epilepsies. Recently published studies documented positive effect of preventive or disease modifying treatment of epilepsy in infants with high risk of epilepsy with significantly lower incidence of epilepsy and better cognitive outcome. Further studies on preventive treatment of epilepsy in other genetic epilepsies of early childhood are considered. © 2019 The Authors

Author Keywords
Children;  Disease modification;  Epileptogenesis;  Prevention;  Tuberous sclerosis complex

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Physical health composite and risk of cancer mortality in the REasons for Geographic and Racial Differences in Stroke Study
(2020) Preventive Medicine, 132, art. no. 105989, . 

Moore, J.X.^{a b} , Carter, S.J.^{c d e} , Williams, V.^{d f} , Khan, S.^b , Lewis-Thames, M.W.^b , Gilbert, K.^g , Howard, G.^h

^a Division of Epidemiology, Department of Population Health Sciences, Augusta University, Augusta, GA, United States
^b Division of Public Health Sciences, Department of Surgery, Washington University in Saint Louis School of Medicine, St Louis, MO, United States
^c School of Public Health, Department of Kinesiology, Indiana University, Bloomington, IN, United States
^d Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States
^e Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, United States
^f Department of Health Behavior, University of Alabama at Birmingham, Birmingham, AL, United States
^g Department of Behavioral Science and Health Education, Saint Louis University, St. Louis, MO, United States
^h Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
It is unclear how resting myocardial workload, as indexed by baseline measures of rate-pressure product (RPP) and physical activity (PA), is associated with the overall risk of cancer mortality. We performed prospective analyses among 28,810 men and women from the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. We used a novel physical health (PH) composite index and categorized participants into one of four groups based on combinations from self-reported PA and RPP: 1) No PA and High RPP; 2) No PA and Low RPP; 3) Yes PA and High RPP; and 4) Yes PA and Low RPP. We examined the association between baseline PH composite and cancer mortality adjusted for potential confounders using Cox regression. A total of 1191 cancer deaths were observed over the 10-year observation period, with the majority being lung (26.87%) and gastrointestinal (21.49%) cancers. Even after controlling for sociodemographics, health behaviors, baseline comorbidity score, and medications, participants with No PA and High RPP had 71% greater risk of cancer mortality when compared to participants with PA and Low RPP (adjusted HR: 1.71, 95% CI: 1.42–2.06). These associations persisted after examining BMI, smoking, income, and gender as effect modifiers and all-cause mortality as a competing risk. Poorer physical health composite, including the novel RPP metric, was associated with a nearly 2-fold long-term risk of cancer mortality. The physical health composite has important public health implications as it provides a measure of risk beyond traditional measure of obesity and physical activity. © 2020 Elsevier Inc.

Author Keywords
Cancer;  Mortality;  Physical activity;  Rate-pressure product

Document Type: Article
Publication Stage: Final
Source: Scopus

Progeny in an Inhospitable Milieu—Solitary Intraventricular Metastasis From a Triple-Negative Breast Cancer Mimicking Central Neurocytoma: Case Report and Review of Diagnostic Pitfalls and Management Strategies
(2020) World Neurosurgery, 135, pp. 309-315. 

Shenoy, S.^a , Shenoy, S.N.^b

^a Brown School, Washington University, St. Louis, MO, United States
^b Tarun Neuro Clinic, Thane, India

Abstract
Background: Triple-negative breast cancer (TNBC) is one of the most invasive subtypes of breast cancer, with high rates of visceral metastases and recurrence. Choroid plexus metastasis from breast cancer is infrequent despite a high incidence of brain parenchymal metastasis. Methods: We report a case of solitary metastasis to the choroid plexus from a TNBC that masqueraded as central neurocytoma, and we review the PubMed database for similar cases focusing on their diagnostic challenges and management strategies. Results: A 28-year-old woman with a history of TNBC presented with recurrent seizures, headache, and vomiting. Imaging studies depicted a well-defined lesion in the right anterior lateral ventricle that was attached to the septum pellucidum. After an initial radiological diagnosis of central neurocytoma, she deteriorated rapidly with intraventricular hemorrhage requiring emergency transcallosal microsurgical tumor decompression. Histopathological examination and immunohistochemistry confirmed breast carcinoma as the origin of the intraventricular mass. A review of the PubMed database identified only 2 case reports of choroid plexus metastases from breast cancer reported thus far. Conclusions: Choroid plexus metastases are exceedingly infrequent and can be mistaken for the more common central neurocytoma. The intraventricular milieu is inhospitable suggesting some extracranial carcinomas develop traits that help them to thrive in the acellular cerebrospinal fluid. Intraventricular mass lesions with a history of primary neoplasm should raise suspicion for choroid plexus metastases. A high index of suspicion despite excellent control of the primary tumor and the absence of systemic metastases is indispensable. © 2019 Elsevier Inc.

Author Keywords
Brain metastases;  Choroid plexus metastases;  Hydrocephalus;  Intraventricular metastases;  Metaplastic breast carcinoma;  Triple-negative breast cancer

Document Type: Article
Publication Stage: Final
Source: Scopus

Neurocardiac Injury Assessed by Strain Imaging Is Associated With In-Hospital Mortality in Patients With Subarachnoid Hemorrhage
(2020) JACC: Cardiovascular Imaging, 13 (2P2), pp. 535-546. Cited 3 times.

Kagiyama, N.^a , Sugahara, M.^b , Crago, E.A.^c , Qi, Z.^b , Lagattuta, T.F.^c , Yousef, K.M.^{c d} , Friedlander, R.M.^e , Hravnak, M.T.^c , Gorcsan, J., III^a

^a Division of Cardiology, Washington University in St. Louis, St. Louis, MO, United States
^b Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, PA, United States
^c School of Nursing, University of Pittsburgh, Pittsburgh, PA, United States
^d School of Nursing, University of Jordan, Jordan
^e Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Objectives: This study sought to test the hypothesis that speckle tracking strain echocardiography can quantify neurocardiac injuries in patients with aneurysmal subarachnoid hemorrhage (SAH), which is associated with worse clinical outcome. Background: SAH may be a life-threatening disease associated with variable degrees of neurocardiac injury. Strain imaging has the potential to detect subtle myocardial dysfunction which is additive to conventional measurements. Methods: A total of 255 consecutive patients were prospectively enrolled with acute SAH, who were admitted to the intensive care unit with echocardiography studies within 72 h. Left ventricular (LV) and right ventricular (RV) strains were acquired from standard apical views. Abnormal LV global longitudinal strain (GLS) and RV free-wall strain were pre-defined as <17% and <23% (absolute values), respectively. Results: Performing LV GLS was feasible in 221 patients (89%) 53 ± 10 years of age, 71% female, after excluding those with previous cardiac disease. Abnormal LV GLS findings were observed in 53 patients (24%) and were associated with worse clinical severity, including a Hunt-Hess grade >3 (34% vs. 15%; p = 0.005) and biomarker evidence of neurocardiac injury and higher troponin values (1.50 [interquartile range (IQR): 0.01 to 3.87] vs. 0.01 [IQR: 0.01 to 0.22] ng/ml; p < 0.001). A reverse Takotsubo pattern of segmental strain was observed in 49% of patients (apical sparing and reduced basal strain). Importantly, LV GLS was more strongly associated with in-hospital mortality than left ventricular ejection fraction (LVEF), even after adjusting for clinical severity (odds ratio [OR]: 3.11; 95% confidence interval [CI]: 1.12 to 8.63; p = 0.029). RV strain was measured in 159 subjects (72%); abnormal RV strain was added to LV GLS for predicting in-hospital mortality (p = 0.007). Conclusions: Neurocardiac injury can be detected by LV GLS and RV strain in patients with acute SAH. LV GLS was significantly associated with in-hospital mortality. RV strain, when available, added prognostic value to LV GLS. Abnormal myocardial strain is a marker for increased risk of in-hospital mortality in SAH and has clinical prognostic utility. © 2020

Author Keywords
global longitudinal strain;  prognosis;  right ventricle;  speckle tracking echocardiography;  subarachnoid hemorrhage

Document Type: Article
Publication Stage: Final
Source: Scopus

Structural and Functional Abnormities of Amygdala and Prefrontal Cortex in Major Depressive Disorder With Suicide Attempts
(2020) Frontiers in Psychiatry, 10, art. no. 923, . 

Wang, L.^{a b c} , Zhao, Y.^{a b c} , Edmiston, E.K.^d , Womer, F.Y.^e , Zhang, R.^b , Zhao, P.^b , Jiang, X.^{c f} , Wu, F.^b , Kong, L.^b , Zhou, Y.^{b g} , Tang, Y.^{b g} , Wei, S.^{c f}

^a Department of Psychiatry, China Medical University, Shenyang, China
^b Department of Psychiatry, First Affiliated Hospital, China Medical University, Shenyang, China
^c Brain Function Research Section, First Affiliated Hospital, China Medical University, Shenyang, China
^d Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Radiology, First Affiliated Hospital, China Medical University, Shenyang, China
^g Department of Geriatric Medicine, First Affiliated Hospital, China Medical University, Shenyang, China

Abstract
Finding neural features of suicide attempts (SA) in major depressive disorder (MDD) may be helpful in preventing suicidal behavior. The ventral and medial prefrontal cortex (PFC), as well as the amygdala form a circuit implicated in emotion regulation and the pathogenesis of MDD. The aim of this study was to identify whether patients with MDD who had a history of SA show structural and functional connectivity abnormalities in the amygdala and PFC relative to MDD patients without a history of SA. We measured gray matter volume in the amygdala and PFC and amygdala-PFC functional connectivity using structural and functional magnetic resonance imaging (MRI) in 158 participants [38 MDD patients with a history of SA, 60 MDD patients without a history of SA, and 60 healthy control (HC)]. MDD patients with a history of SA had decreased gray matter volume in the right and left amygdala (F = 30.270, P = 0.000), ventral/medial/dorsal PFC (F = 15.349, P = 0.000), and diminished functional connectivity between the bilateral amygdala and ventral and medial PFC regions (F = 22.467, P = 0.000), compared with individuals who had MDD without a history of SA, and the HC group. These findings provide evidence that the amygdala and PFC may be closely related to the pathogenesis of suicidal behavior in MDD and implicate the amygdala-ventral/medial PFC circuit as a potential target for suicide intervention. © Copyright © 2020 Wang, Zhao, Edmiston, Womer, Zhang, Zhao, Jiang, Wu, Kong, Zhou, Tang and Wei.

Author Keywords
amygdala;  functional connectivity;  gray matter volume;  major depressive disorder;  prefrontal cortex;  suicide attempts

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Genome-wide gene-environment analyses of major depressive disorder and reported lifetime traumatic experiences in UK Biobank
(2020) Molecular Psychiatry, . 

Coleman, J.R.I.^{a b} , Peyrot, W.J.^c , Purves, K.L.^a , Davis, K.A.S.^{b d} , Rayner, C.^a , Choi, S.W.^a , Hübel, C.^{a b} , Gaspar, H.A.^{a b} , Kan, C.^d , Van der Auwera, S.^e , Adams, M.J.^f , Lyall, D.M.^g , Choi, K.W.^{h i j k} , Wray, N.R.^{q r} , Ripke, S.^{s t u} , Mattheisen, M.^{v w x} , Trzaskowski, M.^q , Byrne, E.M.^q , Abdellaoui, A.^y , Adams, M.J.^z , Agerbo, E.^{aa ab ac} , Air, T.M.^ad , Andlauer, T.F.M.^{ae af} , Bacanu, S.-A.^ag , Bækvad-Hansen, M.^{ac fk} , Beekman, A.T.F.^ah , Bigdeli, T.B.^{ag ai} , Binder, E.B.^{ae aj} , Bryois, J.^ak , Buttenschøn, H.N.^{ac al am} , Bybjerg-Grauholm, J.^{ac fk} , Cai, N.^{an ao} , Castelao, E.^ap , Christensen, J.H.^{x ac am} , Clarke, T.-K.^z , Coleman, J.R.I.^aq , Colodro-Conde, L.^ar , Couvy-Duchesne, B.^{r as} , Craddock, N.^at , Crawford, G.E.^{au av} , Davies, G.^aw , Deary, I.J.^aw , Degenhardt, F.^ax , Derks, E.M.^ar , Direk, N.^{ay az} , Dolan, C.V.^y , Dunn, E.C.^{ba bb bc} , Eley, T.C.^aq , Escott-Price, V.^bd , Kiadeh, F.F.H.^be , Finucane, H.K.^{bf bg} , Foo, J.C.^bh , Forstner, A.J.^{ax bi bj bk} , Frank, J.^bh , Gaspar, H.A.^aq , Gill, M.^bl , Goes, F.S.^bm , Gordon, S.D.^ar , Grove, J.^{x ac am bn} , Hall, L.S.^{z bo} , Hansen, C.S.^{ac fk} , Hansen, T.F.^{bp bq br} , Herms, S.^{ax bj} , Hickie, I.B.^bs , Hoffmann, P.^{ax bj} , Homuth, G.^bt , Horn, C.^bu , Hottenga, J.-J.^y , Hougaard, D.M.^ac , Howard, D.M.^{z aq} , Ising, M.^bv , Jansen, R.^ah , Jones, I.^bw , Jones, L.A.^bx , Jorgenson, E.^by , Knowles, J.A.^bz , Kohane, I.S.^{ca cb cc} , Kraft, J.^t , Kretzschmar, W.W.^cd , Kutalik, Z.^{ce cf} , Li, Y.^cd , Lind, P.A.^ar , MacIntyre, D.J.^{cg ch} , MacKinnon, D.F.^bm , Maier, R.M.^r , Maier, W.^ci , Marchini, J.^cj , Mbarek, H.^y , McGrath, P.^ck , McGuffin, P.^aq , Medland, S.E.^ar , Mehta, D.^{r cl} , Middeldorp, C.M.^{y cm cn} , Mihailov, E.^co , Milaneschi, Y.^ah , Milani, L.^co , Mondimore, F.M.^bm , Montgomery, G.W.^q , Mostafavi, S.^{cp cq} , Mullins, N.^aq , Nauck, M.^{cr cs} , Ng, B.^cq , Nivard, M.G.^y , Nyholt, D.R.^ct , O’Reilly, P.F.^aq , Oskarsson, H.^cu , Owen, M.J.^bw , Painter, J.N.^ar , Pedersen, C.B.^{aa ab ac} , Pedersen, M.G.^{aa ab ac} , Peterson, R.E.^{ag cv} , Pettersson, E.^ak , Peyrot, W.J.^ah , Pistis, G.^ap , Posthuma, D.^{cw cx} , Quiroz, J.A.^cy , Qvist, P.^{x ac am} , Rice, J.P.^cz , Riley, B.P.^ag , Rivera, M.^{aq da} , Mirza, S.S.^ay , Schoevers, R.^db , Schulte, E.C.^{dc dd} , Shen, L.^by , Shi, J.^de , Shyn, S.I.^df , Sigurdsson, E.^dg , Sinnamon, G.C.B.^dh , Smit, J.H.^ah , Smith, D.J.^di , Stefansson, H.^dj , Steinberg, S.^dj , Streit, F.^bh , Strohmaier, J.^bh , Tansey, K.E.^dk , Teismann, H.^dl , Teumer, A.^dm , Thompson, W.^{ac bq dn do} , Thomson, P.A.^dp , Thorgeirsson, T.E.^dj , Traylor, M.^dq , Treutlein, J.^bh , Trubetskoy, V.^t , Uitterlinden, A.G.^dr , Umbricht, D.^ds , Van der Auwera, S.^dt , van Hemert, A.M.^du , Viktorin, A.^ak , Visscher, P.M.^{q r} , Wang, Y.^{ac bq do} , Webb, B.T.^dv , Weinsheimer, S.M.^{ac bq} , Wellmann, J.^dl , Willemsen, G.^y , Witt, S.H.^bh , Wu, Y.^q , Xi, H.S.^dw , Yang, J.^{r dx} , Zhang, F.^q , Arolt, V.^dy , Baune, B.T.^{dz ea eb} , Berger, K.^dl , Boomsma, D.I.^y , Cichon, S.^{ax bj ec ed} , Dannlowski, U.^dy , de Geus, E.J.C.^{y ee} , DePaulo, J.R.^bm , Domenici, E.^ef , Domschke, K.^{eg eh} , Esko, T.^{u co} , Grabe, H.J.^dt , Hamilton, S.P.^ei , Hayward, C.^ej , Heath, A.C.^cz , Kendler, K.S.^ag , Kloiber, S.^{bv ek el} , Lewis, G.^em , Li, Q.S.^en , Lucae, S.^bv , Madden, P.A.F.^cz , Magnusson, P.K.^ak , Martin, N.G.^ar , McIntosh, A.M.^{z aw} , Metspalu, A.^{co eo} , Mors, O.^{ac ep} , Mortensen, P.B.^{aa ab ac am} , Müller-Myhsok, B.^{ae eq er} , Nordentoft, M.^{ac es} , Nöthen, M.M.^ax , O’Donovan, M.C.^bw , Paciga, S.A.^et , Pedersen, N.L.^ak , Penninx, B.W.J.H.^ah , Perlis, R.H.^{ba eu} , Porteous, D.J.^dp , Potash, J.B.^ev , Preisig, M.^ap , Rietschel, M.^bh , Schaefer, C.^by , Schulze, T.G.^{bh dd ew ex ey} , Smoller, J.W.^{ba bb bc} , Stefansson, K.^{dj ez} , Tiemeier, H.^{ay fa fb} , Uher, R.^fc , Völzke, H.^dm , Weissman, M.M.^{ck fd} , Werge, T.^{ac bq fe} , Lewis, C.M.^{aq ff} , Levinson, D.F.^fg , Breen, G.^{aq fh} , Børglum, A.D.^{x ac am} , Sullivan, P.F.^{ak fi fj} , Dunn, E.C.^{j k l} , Vassos, E.^{a b} , Danese, A.^{a m n} , Maughan, B.^a , Grabe, H.J.^e , Lewis, C.M.^{a b} , O’Reilly, P.F.^a , McIntosh, A.M.^f , Smith, D.J.^g , Wray, N.R.^{o p} , Hotopf, M.^{b d} , Eley, T.C.^{a b} , Breen, G.^{a b} , on the behalf of Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium^fk

^a Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
^b NIHR Maudsley Biomedical Research Centre, South London and Maudsley NHS Trust, London, United Kingdom
^c Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Medical Center, Amsterdam, Netherlands
^d Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
^e Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany
^f Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
^g Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
^h Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
ⁱ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^j Stanley Center for Psychiatric Research, The Broad Institute of Harvard and MIT, Cambridge, MA, United States
^k Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^l Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^m Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
ⁿ National and Specialist CAMHS Trauma and Anxiety Clinic, South London and Maudsley NHS Foundation Trust, London, United Kingdom
^o Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
^p Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
^q Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
^r Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
^s Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
^t Department of Psychiatry and Psychotherapy, Universitätsmedizin Berlin Campus Charité Mitte, Berlin, Germany
^u Medical and Population Genetics, Broad Institute, Cambridge, MA, United States
^v Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wurzburg, Wurzburg, Germany
^w Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
^x Department of Biomedicine, Aarhus University, Aarhus, Denmark
^y Dept of Biological Psychology & EMGO+ Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^z Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
^aa Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark
^ab National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark
^ac iPSYCH, The Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
^ad Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia
^ae Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany
^af Department of Neurology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
^ag Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^ah Department of Psychiatry, Vrije Universiteit Medical Center and GGZ inGeest, Amsterdam, Netherlands
^ai Virginia Institute for Psychiatric and Behavior Genetics, Richmond, VA, United States
^aj Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
^ak Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^al Department of Clinical Medicine, Translational Neuropsychiatry Unit, Aarhus University, Aarhus, Denmark
^am iSEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark
^an Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom
^ao Statistical Genomics and Systems Genetics, European Bioinformatics Institute (EMBL-EBI), Cambridge, United Kingdom
^ap Department of Psychiatry, University Hospital of Lausanne, Prilly, VD, Switzerland
^aq Social Genetic and Developmental Psychiatry Centre, King’s College London, London, United Kingdom
^ar Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^as Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
^at Psychological Medicine, Cardiff University, Cardiff, United Kingdom
^au Center for Genomic and Computational Biology, Duke University, Durham, NC, United States
^av Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, NC, United States
^aw Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
^ax Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
^ay Department of Epidemiology, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
^az Department of Psychiatry, School Of Medicine, Dokuz Eylul University, Izmir, Turkey
^ba Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^bb Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, United States
^bc Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, United States
^bd Neuroscience and Mental Health, Cardiff University, Cardiff, United Kingdom
^be Department of Bioinformatics, University of British Columbia, Vancouver, BC, Canada
^bf Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^bg Department of Mathematics, Massachusetts Institute of Technology, Cambridge, MA, United States
^bh Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Baden-Württemberg, Germany
^bi Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
^bj Department of Biomedicine, University of Basel, Basel, Switzerland
^bk Centre for Human Genetics, University of Marburg, Marburg, Germany
^bl Department of Psychiatry, Trinity College Dublin, Dublin, Ireland
^bm Psychiatry & Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
^bn Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
^bo Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
^bp Department of Neurology, Danish Headache Centre, Rigshospitalet, Glostrup, Denmark
^bq Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services Capital Region of Denmark, Copenhagen, Denmark
^br iPSYCH, The Lundbeck Foundation Initiative for Psychiatric Research, Copenhagen, Denmark
^bs Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia
^bt Interfaculty Institute for Genetics and Functional Genomics, Department of Functional Genomics, University Medicine and Ernst Moritz Arndt University Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
^bu Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
^bv Max Planck Institute of Psychiatry, Munich, Germany
^bw MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
^bx Department of Psychological Medicine, University of Worcester, Worcester, United Kingdom
^by Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
^bz Psychiatry & The Behavioral Sciences, University of Southern California, Los Angeles, CA, United States
^ca Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
^cb Department of Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^cc Informatics Program, Boston Children’s Hospital, Boston, MA, United States
^cd Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
^ce Institute of Social and Preventive Medicine (IUMSP), University Hospital of Lausanne, Lausanne, VD, Switzerland
^cf Swiss Institute of Bioinformatics, Lausanne, VD, Switzerland
^cg Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
^ch Mental Health, NHS 24, Glasgow, United Kingdom
^ci Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany
^cj Department of Statistics, University of Oxford, Oxford, United Kingdom
^ck Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^cl School of Psychology and Counseling, Queensland University of Technology, Brisbane, QLD, Australia
^cm Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Service, South Brisbane, QLD, Australia
^cn Child Health Research Centre, University of Queensland, Brisbane, QLD, Australia
^co Estonian Genome Center, University of Tartu, Tartu, Estonia
^cp Medical Genetics, University of British Columbia, Vancouver, BC, Canada
^cq Department of Statistics, University of British Columbia, Vancouver, BC, Canada
^cr DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, University Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
^cs Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
^ct Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia
^cu Humus, Reykjavik, Iceland
^cv Virginia Institute for Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^cw Clinical Genetics, Vrije Universiteit Medical Center, Amsterdam, Netherlands
^cx Complex Trait Genetics, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^cy Solid Biosciences, Boston, MA, United States
^cz Department of Psychiatry, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
^da Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
^db Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
^dc Department of Psychiatry and Psychotherapy, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
^dd Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, Ludwig Maximilian University Munich, Munich, Germany
^de Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, United States
^df Behavioral Health Services, Kaiser Permanente Washington, Seattle, WA, United States
^dg Faculty of Medicine, Department of Psychiatry, University of Iceland, Reykjavik, Iceland
^dh School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
^di Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom
^dj deCODE Genetics/Amgen, Reykjavik, Iceland
^dk College of Biomedical and Life Sciences, Cardiff University, Cardiff, United Kingdom
^dl Institute of Epidemiology and Social Medicine, University of Münster, Münster, Nordrhein-Westfalen, Germany
^dm Institute for Community Medicine, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
^dn Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
^do KG Jebsen Centre for Psychosis Research, Norway Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
^dp Medical Genetics Section, CGEM, IGMM, University of Edinburgh, Edinburgh, United Kingdom
^dq Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom
^dr Internal Medicine, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
^ds Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases Discovery & Translational Medicine Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
^dt Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Mecklenburg-Vorpommern, Germany
^du Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands
^dv Virginia Institute for Psychiatric & Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^dw Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, United States
^dx Institute for Molecular Bioscience; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
^dy Department of Psychiatry, University of Münster, Münster, Nordrhein-Westfalen, Germany
^dz Department of Psychiatry, University of Münster, Münster, Germany
^ea Department of Psychiatry, Melbourne Medical School, University of Melbourne, Melbourne, Australia
^eb Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia
^ec Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
^ed Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Juelich, Germany
^ee Amsterdam Public Health Institute, Vrije Universiteit Medical Center, Amsterdam, Netherlands
^ef Centre for Integrative Biology, Università degli Studi di Trento, Trento, Trentino-Alto Adige, Italy
^eg Department of Psychiatry and Psychotherapy, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^eh Center for NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^ei Psychiatry, Kaiser Permanente Northern California, San Francisco, CA, United States
^ej Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
^ek Department of Psychiatry, University of Toronto, Toronto, ON, Canada
^el Centre for Addiction and Mental Health, Toronto, ON, Canada
^em Division of Psychiatry, University College London, London, United Kingdom
^en Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, United States
^eo Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
^ep Psychosis Research Unit, Aarhus University Hospital, Risskov, Aarhus, Germany
^eq Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^er University of Liverpool, Liverpool, United Kingdom
^es Mental Health Center Copenhagen, Copenhagen Universtity Hospital, Copenhagen, Denmark
^et Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, United States
^eu Psychiatry, Harvard Medical School, Boston, MA, United States
^ev Psychiatry, University of Iowa, Iowa City, IA, United States
^ew Department of Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States
^ex Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Goettingen, Niedersachsen, Germany
^ey Human Genetics Branch, NIMH Division of Intramural Research Programs, Bethesda, MD, United States
^ez Faculty of Medicine, University of Iceland, Reykjavik, Iceland
^fa Child and Adolescent Psychiatry, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
^fb Department of Psychiatry, Erasmus MC, Rotterdam, Zuid-Holland, Netherlands
^fc Department of Psychiatry, Dalhousie University, Halifax, NS, Canada
^fd Division of Epidemiology, New York State Psychiatric Institute, New York, NY, United States
^fe Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK, Denmark
^ff Department of Medical & Molecular Genetics, King’s College London, London, United Kingdom
^fg Psychiatry & Behavioral Sciences, Stanford University, Stanford, CA, United States
^fh NIHR Maudsley Biomedical Research Centre, King’s College London, London, United Kingdom
^fi Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^fj Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^fk Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

Abstract
Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094–92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10−7 versus rg = −0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10−4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD. © 2020, The Author(s), under exclusive licence to Springer Nature Limited.

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

When medical information comes from Nazi atrocities
(2020) The BMJ, 368, art. no. l7075, . 

Mackinnon, S.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MI, United States

Document Type: Review
Publication Stage: Final
Source: Scopus

Advances in the repair of segmental nerve injuries and trends in reconstruction
(2020) Muscle and Nerve, . 

Pan, D., Mackinnon, S.E., Wood, M.D.

Division of Plastic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Despite advances in surgery, the reconstruction of segmental nerve injuries continues to pose challenges. In this review, current neurobiology regarding regeneration across a nerve defect is discussed in detail. Recent findings include the complex roles of nonneuronal cells in nerve defect regeneration, such as the role of the innate immune system in angiogenesis and how Schwann cells migrate within the defect. Clinically, the repair of nerve defects is still best served by using nerve autografts with the exception of small, noncritical sensory nerve defects, which can be repaired using autograft alternatives, such as processed or acellular nerve allografts. Given current clinical limits for when alternatives can be used, advanced solutions to repair nerve defects demonstrated in animals are highlighted. These highlights include alternatives designed with novel topology and materials, delivery of drugs specifically known to accelerate axon growth, and greater attention to the role of the immune system. © 2020 Wiley Periodicals, Inc.

Author Keywords
acellular nerve allograft;  autograft;  nerve gap;  nerve guidance conduit;  peripheral nerve

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

Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing–Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study
(2020) CNS Drugs, . 

Naismith, R.T.^a , Wundes, A.^b , Ziemssen, T.^c , Jasinska, E.^d , Freedman, M.S.^e , Lembo, A.J.^f , Selmaj, K.^{g h} , Bidollari, I.ⁱ , Chen, H.^j , Hanna, J.^k , Leigh-Pemberton, R.ⁱ , Lopez-Bresnahan, M.ⁱ , Lyons, J.^j , Miller, C.^j , Rezendes, D.ⁱ , Wolinsky, J.S.^l , The EVOLVE-MS-2 Study Group^m

^a Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, University of Washington Medical Center, Seattle, WA, United States
^c Center of Clinical Neuroscience, Carl Gustav Carus University Hospital, Dresden, Germany
^d Collegium Medicum UJK, and Clinical Center, RESMEDICA, Kielce, Poland
^e University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, ON, Canada
^f Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
^g Center of Neurology, Lodz, Poland
^h Department of Neurology, University of Warmia and Mazury, Olsztyn, Poland
ⁱ Alkermes Inc., Waltham, MA, United States
^j Biogen, 225 Binney St, Cambridge, MA 02142, United States
^k Biogen, Maidenhead, United Kingdom
^l Department of Neurology, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, TX, United States

Abstract
Background: Diroximel fumarate (DRF) is a novel oral fumarate approved in the USA for relapsing forms of multiple sclerosis. DRF is converted to monomethyl fumarate, the pharmacologically active metabolite of dimethyl fumarate (DMF). DRF 462 mg and DMF 240 mg produce bioequivalent exposure of monomethyl fumarate and are therefore expected to have similar efficacy/safety profiles; the distinct chemical structure of DRF may contribute to its tolerability profile. Objectives: The objective of this study was to compare the gastrointestinal tolerability of DRF and DMF over 5 weeks in patients with relapsing–remitting multiple sclerosis. Methods: EVOLVE-MS-2 was a phase III, randomized, double-blind, head-to-head, 5-week study evaluating the gastrointestinal tolerability of DRF 462 mg vs DMF 240 mg, administered twice daily in patients with relapsing–remitting multiple sclerosis, using two self-administered gastrointestinal symptom scales: Individual Gastrointestinal Symptom and Impact Scale (IGISIS) and Global Gastrointestinal Symptom and Impact Scale (GGISIS). The primary endpoint was the number of days with an IGISIS intensity score ≥ 2 relative to exposure. Other endpoints included the degree of gastrointestinal symptom severity measured by IGISIS/GGISIS and assessment of safety/tolerability. Results: DRF-treated patients experienced a statistically significant reduction (46%) in the number of days with an IGISIS symptom intensity score ≥ 2 compared with DMF-treated patients (rate ratio [95% confidence interval]: 0.54 [0.39–0.75]; p = 0.0003). Lower rates of gastrointestinal adverse events (including diarrhea, nausea, vomiting, and abdominal pain) were observed with DRF than DMF (34.8% vs 49.0%). Fewer patients discontinued DRF than DMF because of adverse events (1.6% vs 5.6%) and gastrointestinal adverse events (0.8% vs 4.8%). Conclusions: DRF demonstrated an improved gastrointestinal tolerability profile compared with DMF, with less severe gastrointestinal events and fewer days of self-assessed gastrointestinal symptoms, fewer gastrointestinal adverse events, and lower discontinuation rates because of gastrointestinal adverse events. Clinical Trials Registration: ClinicalTrials.gov (NCT03093324). © 2020, The Author(s).

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

How good are the outcomes of instrumented debulking operations for symptomatic spinal metastases and how long do they stand? A subgroup analysis in the global spine tumor study group database
(2020) Acta Neurochirurgica, . 

Depreitere, B.^a , Ricciardi, F.^b , Arts, M.^c , Balabaud, L.^d , Bunger, C.^e , Buchowski, J.M.^f , Chung, C.K.^g , Coppes, M.H.^h , Fehlings, M.G.ⁱ , Kawahara, N.^j , Martin-Benlloch, J.A.^k , Massicotte, E.M.ⁱ , Mazel, C.^l , Meyer, B.^m , Oner, F.C.ⁿ , Peul, W.^o , Quraishi, N.^p , Tokuhashi, Y.^q , Tomita, K.^r , Verlaan, J.-J.ⁿ , Wang, M.^s , Crockard, H.A.^t , Choi, D.^t

^a Division of Neurosurgery, University Hospitals Leuven, Herestraat 49, Leuven, 3000, Belgium
^b Department of Statistical Science, University College London, London, United Kingdom
^c Department of Neurosurgery, Medical Center Haaglanden, Haaglanden, Netherlands
^d Orthopaedics and Traumatology Centre, Clinique Mutualiste de la Porte de L’Orient, L’Orient, France
^e Department of Orthopedic Surgery, University Hospital of Aarhus, Aarhus, Denmark
^f Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurosurgery, Seoul National University Hospital, Seoul, South Korea
^h Department of Neurosurgery, University Medical Centre Groningen, Groningen, Netherlands
ⁱ Division of Neurosurgery and Spinal Program, University of Toronto and Toronto Western Hospital, Toronto, Canada
^j Department of Orthopedic Surgery, Kanazawa Medical University Hospital, Kanazawa, Japan
^k Spinal Unit, Hospital Universitario Dr Peset, Valencia, Spain
^l Department of Orthopedic surgery, L’Institut Mutualiste Montsouris, Paris, France
^m Department of Neurosurgery, Technische Universität München, Munich, Germany
ⁿ Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, Netherlands
^o Department of Neurosurgery, Leiden University Medical Centre, Leiden, Netherlands
^p Centre for Spine Studies and Surgery, Queens Medical Centre, Nottingham, United Kingdom
^q Department of Orthopaedic Surgery, Nihon University School of Medicine, Tokyo, Japan
^r Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
^s Department of Neurosurgery, Jackson Memorial Hospital, University of Miami, Miami, United States
^t Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom

Abstract
Background: The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as cancer treatments improve and overall survival lengths increase, the incidence of recurrent spinal cord compression after debulking may increase. The aim of the current paper is to document the postoperative evolution of neurological function, pain, and quality of life following debulking and instrumentation in the Global Spine Tumor Study Group (GSTSG) database. Methods: The GSTSG database is a prospective multicenter data repository of consecutive patients that underwent surgery for a symptomatic spinal metastasis. For the present analysis, patients were selected from the database that underwent decompressive debulking surgery with instrumentation. Preoperative tumor type, Tomita and Tokuhashi scores, EQ-5D, Frankel, Karnofsky, and postoperative complications, survival, EQ-5D, Frankel, Karnofsky, and pain numeric rating scores (NRS) at 3, 6, 12, and 24 months were analyzed. Results: A total of 914 patients underwent decompressive debulking surgery with instrumentation and had documented follow-up until death or until 2 years post surgery. Median preoperative Karnofsky performance index was 70. A total of 656 patients (71.8%) had visceral metastases and 490 (53.6%) had extraspinal bone metastases. Tomita scores were evenly distributed above (49.1%) and below or equal to 5 (50.9%), and Tokuhashi scores almost evenly distributed below or equal to 8 (46.3%) and above 8 (53.7%). Overall, 12-month survival after surgery was 56.3%. The surgery resulted in EQ-5D health status improvement and NRS pain reduction that was maintained throughout follow-up. Frankel scores improved at first follow-up in 25.0% of patients, but by 12 months neurological deterioration was observed in 18.8%. Conclusion: We found that palliative debulking and instrumentation surgeries were performed throughout all Tomita and Tokuhashi categories. These surgeries reduced pain scores and improved quality of life up to 2 years after surgery. After initial improvement, a proportion of patients experienced neurological deterioration by 1 year, but the majority of patients remained stable. © 2020, Springer-Verlag GmbH Austria, part of Springer Nature.

Author Keywords
Debulking surgery;  Frankel score;  Metastasis;  Quality of life;  Spine

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

The effect of a scheduled regimen of acetaminophen and ibuprofen on opioid use following cesarean delivery
(2020) Journal of Perinatal Medicine, pp. 153-156. 

Poljak, D.^a , Chappelle, J.^b

^a Washington University, Mail Stop 8064-37-1005, 4901 Forest Park Ave, St Louis, MO 63108, United States
^b Stony Brook University Hospital, 101 Nicolls Rd, HSC 9-090, Stony Brook, NY 11794, United States

Abstract
The primary objective was to evaluate if the administration of ibuprofen and acetaminophen at regularly scheduled intervals impacts pain scores and total opioid consumption, when compared to administration based on patient demand. A retrospective chart review was performed comparing scheduled vs. as-needed acetaminophen and ibuprofen regimens, with 100 women included in each arm. Demographics and delivery characteristics were collected in addition to pain scores and total ibuprofen, acetaminophen and oxycodone use at 24, 48 and 72 h postoperatively. The scheduled dosing group was found to have a statistically significant decrease in pain scores at all time intervals. Acetaminophen and ibuprofen usage were also noted to be higher in this group while narcotic use was reduced by 64%. Scheduled dosing of non-narcotic pain medications can substantially decrease opioid usage after cesarean delivery and improve post-operative pain. © 2020 Walter de Gruyter GmbH, Berlin/Boston.

Author Keywords
cesarean;  NSAIDs;  opioid;  pain control

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

From Research Training to Scientific Advancement-Contributions from the Implementation Research Institute: An Introduction to the Special Issue
(2020) Administration and Policy in Mental Health and Mental Health Services Research, . 

Landsverk, J.^b , Proctor, E.K.^a

^a Brown School of Social Work, Washington University in St. Louis, 1 Brookings Drive, Campus Box 1196, St. Louis, MO 63130, United States
^b Oregon Social Learning Center, 10 Shelton McMurphy Blvd., Eugene, OR 97401, United States

Abstract
The special series is designed to provide examples of funded implementation research conducted by alumni of the first four cohorts of the Implementation Research Institute (IRI). The introduction links the six substantive papers to the conceptual and methodological challenges laid out in a 2009 publication in this journal which led to the IRI training program in the emerging science of implementation with a special focus on behavior health settings. The 7th paper in the series illustrates an innovative evaluative approach to design and measurement of IRI fellow publications and grants informed by the training program such as bibliometrics. The introduction also notes some elements identified in the 2009 foundational paper not represented in these papers such as costs as well as important developments and foci in the decade since 2009 such as de-implementation, sustainability, dynamic adaptation processes, and hybrid designs that need to be an integral part of training programs in implementation research. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Bibliometrics;  De-implementation;  Dynamic adaptation;  Hybrid designs;  Implementation science;  Sustainability

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

Future perspectives: What lies ahead for Neuronal Ceroid Lipofuscinosis research?
(2020) Biochimica et Biophysica Acta – Molecular Basis of Disease, art. no. 165681, . 

Cooper, J.D.^a , Mole, S.E.^b

^a Pediatric Storage Disorders Laboratory, Department of Pediatrics, Division of Genetics and Genomics, Washington University in St. Louis, School of Medicine, St Louis, MO 63110, United States
^b UCL MRC Laboratory for Molecular Cell Biology and UCL Great Ormond Street Institute of Child Health, University College London, London, WC1E 6BT, United Kingdom

Abstract
Progress is being made in all aspects of Neuronal Ceroid Lipofuscinosis (NCL) research, resulting in many recent advances. These advances encompass several areas that were previously thought intractable, ranging from basic science, through to a better understanding of the clinical presentation of different forms of NCL, therapeutic development, and new clinical trials that are underway. Increasing numbers of original NCL research papers continue to be published, and this new sense of momentum is greatly encouraging for the field. Here, we make some predictions as to what we can anticipate in the next few years. © 2020

Author Keywords
Batten disease;  Future perspectives;  International congress;  Neuronal Ceroid Lipofuscinoses

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

Predictors of intracranial hypertension in children undergoing ICP monitoring after severe traumatic brain injury
(2020) Child’s Nervous System, . 

Miles, D.K.^a , Ponisio, M.R.^b , Colvin, R.^c , Limbrick, D.^d , Greenberg, J.K.^d , Brancato, C.^c , Leonard, J.R.^d , Pineda, J.A.^c

^a Department of Pediatrics, Division of Critical Care, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9063, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pediatrics, Division of Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Intracranial hypertension (ICH) is a common and treatable complication after severe traumatic brain injury (sTBI) in children. Describing the incidence and risk factors for developing ICH after sTBI could impact clinical practice. Methods: Retrospective cohort study from 2006 to 2015 at two university-affiliated level I pediatric trauma centers of children admitted with accidental or abusive TBI, a post-resuscitation Glasgow Coma Score (GCS) of 8 or less, and an invasive intracranial pressure (ICP) monitor. Bivariate and multivariable logistic regression analysis were performed to identify demographic, injury, and imaging characteristics in patients who received ICP directed therapies for ICH (ICP > 20 mmHg). Results: Eight to 5% (271/321) of monitored patients received ICP directed therapy for ICH during their PICU stay. Ninety-seven percent of patients had an abnormality on CT scan by either the Marshall or the Rotterdam score. Of the analyzed clinical and radiologic variables, only presence of hypoxia prior to PICU arrival, female sex, and a higher Injury Severity Score (ISS) were associated with increased risk of ICH (p < 0.05). Conclusions: In this retrospective study of clinical practice of ICP monitoring in children after sTBI, the vast majority of children had an abnormal CT scan and experienced ICH requiring clinical intervention. Commonly measured clinical variables and radiologic classification scores did not significantly add to the prediction for developing of ICH and further efforts are needed to define low-risk populations that would not develop ICH. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
CT imaging;  Intracranial hypertension;  Pediatric;  Traumatic brain injury

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

A management algorithm for adult patients with both brain oxygen and intracranial pressure monitoring: the Seattle International Severe Traumatic Brain Injury Consensus Conference (SIBICC)
(2020) Intensive Care Medicine, . 

Chesnut, R.^{a b} , Aguilera, S.^{c d} , Buki, A.^{e f} , Bulger, E.^g , Citerio, G.^{h i} , Cooper, D.J.^{j k} , Arrastia, R.D.^l , Diringer, M.^m , Figaji, A.ⁿ , Gao, G.^o , Geocadin, R.^p , Ghajar, J.^q , Harris, O.^r , Hoffer, A.^s , Hutchinson, P.^t , Joseph, M.^u , Kitagawa, R.^v , Manley, G.^w , Mayer, S.^x , Menon, D.K.^y , Meyfroidt, G.^z , Michael, D.B.^aa , Oddo, M.^ab , Okonkwo, D.^ac , Patel, M.^ad , Robertson, C.^ae , Rosenfeld, J.V.^{af ag} , Rubiano, A.M.^{ah ai} , Sahuquillo, J.^aj , Servadei, F.^{ak al} , Shutter, L.^am , Stein, D.^an , Stocchetti, N.^{ao ap} , Taccone, F.S.^aq , Timmons, S.^ar , Tsai, E.^as , Ullman, J.S.^at , Vespa, P.^au , Videtta, W.^av , Wright, D.W.^aw , Zammit, C.^ax , Hawryluk, G.W.J.^ay

^a Department of Neurological Surgery, Harborview Medical Center, University of Washington, 325 Ninth Ave, Mailstop 359766, Seattle, WA 98104-2499, United States
^b Department of Orthopaedic Surgery, Harborview Medical Center, University of Washington, 325 Ninth Ave, Mailstop 359766, Seattle, WA 98104-2499, United States
^c Almirante Nef Naval Hospital, Viña del Mar, Chile
^d Valparaiso University, Valparaiso, Chile
^e Department of Neurosurgery, Medical School and Szentágothai Research Centre, Ifjúság útja 20, Pécs, 7624, Hungary
^f University of Pécs, Pécs, Hungary
^g Department of Surgery, Harborview Medical Center, University of Washington, 325 Ninth Ave, Seattle, WA 98104-2499, United States
^h School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy
ⁱ Neuro-Intensive Care, Department of Emergency and Intensive Care, ASST, San Gerardo Hospital, Monza, Italy
^j Intensive Care Medicine, Australian and New Zealand Intensive Care Research Centre, Monash University, Monash, Australia
^k Department of Intensive Care, Alfred Hospital, Melbourne, VIC, Australia
^l University of Pennsylvania Perelman School of Medicine, Penn Presbyterian Medical Center, 51 North 39th Street, Philadelphia, PA 19104, United States
^m Department of Neurology, Barnes-Jewish Hospital, Washington University School of Medicine, 1 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110, United States
ⁿ Division of Neurosurgery and Neuroscience Institute, University of Cape Town, H53 Old Main Building, Groote Schuur Hospital, Main Road, Observatory, 7925, South Africa
^o Department of Neurosurgery, Renji Hospital, Shanghai Institute of Head Trauma, Shanghai Jiaotong University School of Medicine, 1630 Dongfang Road, Shanghai, 200127, China
^p Johns Hopkins University School of Medicine, 1800 Orleans St. Sheikh Zayed Tower, Baltimore, MD 21287, United States
^q Stanford Neuroscience Health Center, 213 Quarry Rd 4th Fl MC 5958, Palo Alto, CA 94304, United States
^r Department of Neurosurgery, Pasteur Drive, Room R205, Edward’s Building, MC 5327, Stanford, CA 94305, United States
^s Department of Neurological Surgery, School of Medicine, Case Western Reserve University, 11100 Euclid Avenue, HAN 5042, Cleveland, OH 44106, United States
^t Division of Neurosurgery, Department of Clinical Neurosciences, Addenbrooke’s Hospital and University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB20QQ, United Kingdom
^u Department of Neurological Sciences, Christian Medical College, Ida Scudder Road, Vellore, Tamil Nadu, India
^v Vivian L Smith Department of Neurosurgery, McGovern Medical School at UTHealth, 6400 Fannin St, Suite 2800, Houston, TX 77030, United States
^w University of California San Francisco, San Francisco General Hospital and Trauma Center, 1001 Potrero Ave., Bldg 1, Room 101, San Francisco, CA 94110, United States
^x Neurology, K-11, Henry Ford Hospital, 2799 W Grand Blvd, Detroit, MI 48202, United States
^y Division of Anaesthesia, University of Cambridge and Addenbrooke’s Hospital, Addenbrooke’s Hospital, Hills Road, Box 93, Cambridge, CB2 0QQ, United Kingdom
^z Department and Laboratory of Intensive Care Medicine, University Hospitals Leuven and KU Leuven, Herestraat 49, Box 7003 63, Leuven, 3000, Belgium
^aa Oakland University William Beaumont School of Medicine, Beaumont Health, Michigan Head and Spine Institute, Southfield, MI, United States
^ab Department of Intensive Care Medicine, CHUV-Lausanne University Hospital, University of Lausanne, Faculty of Biology and Medicine, Lausanne, Switzerland
^ac Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^ad Vanderbilt University Medical Center, Nashville, United States
^ae Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, United States
^af Department of Neurosurgery, Alfred Hospital, Melbourne, Australia
^ag Department of Surgery, Monash University, Melbourne, Australia
^ah INUB/MEDITECH Research Group, Neurosciences Institute, El Bosque University, Bogotá, Colombia
^ai MEDITECH Foundation, Clinical Research, Calle 7-A # 44-95, Cali, 760036, Colombia
^aj University Hospital Vall D’Hebron, Barcelona, Spain
^ak Department of Neurosurgery, Humanitas University and Research Hospital, Milan, Italy
^al World Federation of Neurosurgical Societies, Nyon, Switzerland
^am University of Pittsburgh Medical Center, 3550 Terrace St, Room 646, Pittsburgh, PA 15261, United States
^an Zuckerberg San Francisco General Hospital and Trauma Center, University of California, San Francisco, 1001 Potrero Ave., Ward 3A, San Francisco, CA 94110, United States
^ao Department of Physiopathology and Transplantation, Milan University, Milan, Italy
^ap Neuroscience Intensive Care Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
^aq Department of Intensive Care, Hospital Erasme, Université Libre de Bruxelles (ULB), Brussels, Belgium
^ar Department of Neurological Surgery, Penn State University Milton S. Hershey Medical Center, 30 Hope Dr., Suite 1200 | Building B, Hershey, PA 17033, United States
^as Suruchi Bhargava Chair in Spinal Cord and Brain Regeneration Research, University of Ottawa, The Ottawa Hospital, C2 Neurosciences Unit, The Ottawa Hosptial, Civic Campus, 1053 Carling Avenue, Ottawa, ON K1Y 4E9, Canada
^at Department of Neurosurgery, Donald and Barbara Zucker School of Medicine At Hofstra/Northwell North, Shore University Hospital, 300 Community Drive, 9 Tower, Manhasset, NY, United States
^au Ronald Reagan UCLA Medical Center, UCLA Medical Center, Santa Monica, Santa Monica, United States
^av Posadas Hospital, Buenos Aires, Argentina
^aw Emory University School of Medicine, 49 Jesse Hill Jr Dr, Atlanta, GA 30303, United States
^ax School of Medicine and Dentistry, University of Rochester Medical Center, 601 Elmwood Ave, Box 655C, Rochester, NY 14642, United States
^ay Section of Neurosurgery, University of Manitoba, GB1, 820 Sherbrook Street, Winnipeg, MB R3A 1R9, Canada

Abstract
Background: Current guidelines for the treatment of adult severe traumatic brain injury (sTBI) consist of high-quality evidence reports, but they are no longer accompanied by management protocols, as these require expert opinion to bridge the gap between published evidence and patient care. We aimed to establish a modern sTBI protocol for adult patients with both intracranial pressure (ICP) and brain oxygen monitors in place. Methods: Our consensus working group consisted of 42 experienced and actively practicing sTBI opinion leaders from six continents. Having previously established a protocol for the treatment of patients with ICP monitoring alone, we addressed patients who have a brain oxygen monitor in addition to an ICP monitor. The management protocols were developed through a Delphi-method-based consensus approach and were finalized at an in-person meeting. Results: We established three distinct treatment protocols, each with three tiers whereby higher tiers involve therapies with higher risk. One protocol addresses the management of ICP elevation when brain oxygenation is normal. A second addresses management of brain hypoxia with normal ICP. The third protocol addresses the situation when both intracranial hypertension and brain hypoxia are present. The panel considered issues pertaining to blood transfusion and ventilator management when designing the different algorithms. Conclusions: These protocols are intended to assist clinicians in the management of patients with both ICP and brain oxygen monitors but they do not reflect either a standard-of-care or a substitute for thoughtful individualized management. These protocols should be used in conjunction with recommendations for basic care, management of critical neuroworsening and weaning treatment recently published in conjunction with the Seattle International Brain Injury Consensus Conference. © 2020, The Author(s).

Author Keywords
Algorithm;  Brain injury;  Brain oxygen;  Consensus;  Head trauma;  Intracranial pressure;  PbtO2;  Protocol;  Seattle;  SIBICC;  Tiers

Document Type: Conference Paper
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

A Multi-Institutional Analysis of Factors Influencing Surgical Outcomes for Patients with Newly Diagnosed Grade I Gliomas
(2020) World Neurosurgery, . 

Yahanda, A.T.^a , Patel, B.^a , Sutherland, G.^c , Honeycutt, J.^d , Jensen, R.L.^e , Smyth, M.D.^a , Limbrick, D.D., Jr.^a , Dacey, R.G., Jr.^a , Dowling, J.L.^a , Dunn, G.P.^a , Kim, A.H.^a , Leuthardt, E.C.^a , Rich, K.M.^a , Zipfel, G.J.^a , Leonard, J.R.^f , Cahill, D.P.^g , Shah, M.V.^h , Abram, S.R.ⁱ , Evans, J.^a , Tao, Y.^b , Chicoine, M.R.^a

^a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Neurological Surgery, University of Calgary School of Medicine, Calgary, Alberta, Canada
^d Department of Neurological Surgery, Cook Children’s Medical Center, Fort Worth, TX, United States
^e Department of Neurological Surgery, University of Utah School of Medicine, Salt Lake City, UT, United States
^f Department of Neurological Surgery, Ohio State University College of Medicine, Columbus, OH, United States
^g Department of Neurological Surgery, Massachusetts General Hospital, Boston, MA, United States
^h Department of Neurological Surgery, Goodman Campbell Brain and Spine, Indianapolis, IN, United States
ⁱ Department of Neurological Surgery, St. Thomas Hospital, Nashville, TN, United States

Abstract
Objective: To assess the impact of intraoperative magnetic resonance imaging (iMRI), extent of resection (EOR), and other factors on overall survival (OS) and progression-free survival (PFS) for patients with newly diagnosed grade I gliomas. Methods: A multicenter database was queried to identify patients with grade I gliomas. Retrospective analyses assessed the impact of patient, treatment, and tumor characteristics on OS and PFS. Results: A total of 284 patients underwent treatment for grade I gliomas, including 248 resections (205 with iMRI, 43 without), 23 biopsies, and 13 laser interstitial thermal therapy treatments. Log-rank analyses of Kaplan-Meier plots showed improved 5-year OS (P = 0.0107) and PFS (P = 0.0009) with increasing EOR, and a trend toward improved 5-year OS for patients with lower American Society of Anesthesiologists score (P = 0.0528). Greater EOR was associated with significantly increased 5-year PFS for pilocytic astrocytoma (P < 0.0001), but not for ganglioglioma (P = 0.10) or dysembryoplastic neuroepithelial tumor (P = 0.57). Temporal tumors (P = 0.04) and location of “other” (P = 0.04) were associated with improved PFS, and occipital/parietal tumors (P = 0.02) were associated with decreased PFS compared with all other locations. Additional tumor resection was performed after iMRI in 49.7% of cases using iMRI, which produced gross total resection in 64% of these additional resection cases. Conclusions: Patients with grade I gliomas have extended OS and PFS, which correlates positively with increasing EOR, especially for patients with pilocytic astrocytoma. iMRI may increase EOR, indicated by the rate of gross total resection after iMRI use but was not independently associated with increased OS or PFS. © 2019 Elsevier Inc.

Author Keywords
Clinical research;  Grade I glioma;  Intraoperative magnetic resonance imaging;  Neurosurgery;  Registry;  Treatment outcomes

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

Using the DRM paradigm to assess language processing in monolinguals and bilinguals
(2020) Memory and Cognition, . 

Bialystok, E.^a , Dey, A.^b , Sullivan, M.D.^c , Sommers, M.S.^d

^a Department of Psychology, York University, 4700 Keele St., Toronto, ON M3J 1P3, Canada
^b Center for Vital Longevity, University of Texas at Dallas, Richardson, TX, United States
^c Department of Psychology, Ryerson University, Toronto, ON, Canada
^d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Both languages are jointly activated in the bilingual brain, requiring bilinguals to select the target language while avoiding interference from the unwanted language. This cross-language interference is similar to the within-language interference created by the Deese–Roediger–McDermott false memory paradigm (DRM; Roediger & McDermott, 1995, Journal of Experimental Psychology: Learning, Memory, and Cognition, 21[4], 803–814). Although the mechanisms mediating false memory in the DRM paradigm remain an area of investigation, two of the more prominent theories—implicit associative response (IAR) and fuzzy trace—provide frameworks for using the DRM paradigm to advance our understanding of bilingual language processing. Three studies are reported comparing accuracy of monolingual and bilingual participants on different versions of the DRM. Study 1 presented lists of phonological associates and found that bilinguals showed higher rates of false recognition than did monolinguals. Study 2 used the standard semantic variant of the task and found that bilinguals showed lower false recognition rates than did monolinguals. Study 3 replicated and extended the findings in Experiment 2 in another semantic version of the task presented to younger and older adult monolingual and bilingual participants. These results are discussed within the frameworks of IAR and fuzzy-trace theories as further explicating differences between monolingual and bilingual processing. © 2020, The Psychonomic Society, Inc.

Author Keywords
Aging;  Bilingualism;  False memory;  Phonology;  Selective attention;  Semantics

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

Can CSF biomarkers predict future MS disease activity and severity?
(2020) Multiple Sclerosis Journal, . 

Magliozzi, R.^a , Cross, A.H.^b

^a Department of Neurosciences, Biomedicine and Movement Science, University of Verona, Verona, Italy
^b Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Multiple sclerosis (MS) is a heterogeneous disease. With several disease modifying treatments of different mechanisms of action in use now and in development, it is important to identify reliable biomarkers to identify those higher risk MS patients in whom stronger but riskier treatments might be used, as well as to identify those for whom safer treatments of lower efficacy would be sufficient. Here we review cerebrospinal fluid (CSF) and blood biomarkers that show promise for differentiating people with MS who are at risk for severe disease and disability from those with more benign disease. We reviewed published literature for studies reporting biomarkers with predictive value in MS. Most studies of MS CSF found the presence of oligoclonal bands (both IgG and IgM), high IgG index and high levels of kappa light chains to each be associated with worse prognosis. Neurofilament light chain (NfL) and two markers of glial activation, glial fibrillary acidic protein (GFAP) and YKL-40, were higher in CSF of people with subsequent clinical progression or imaging evidence for neurodegeneration. Few reports have been made yet on the prognostic significance of blood NfL, but in one early report baseline, serum NfL (sNfL) predicted subsequent brain volume loss. © The Author(s), 2020.

Author Keywords
biomarkers;  cerebrospinal fluid;  Multiple sclerosis;  neurofilaments;  prognosis

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

Partial Validation of the Sleep Health Construct in the Medical Outcomes Study Sleep Questionnaire
(2020) Journal of Clinical Psychology in Medical Settings, . 

Bliwise, D.L.^a , Howard, L.E.^b , Moreira, D.M.^c , Andriole, G.L.^d , Hopp, M.L.^e , Freedland, S.J.^e

^a Department of Neurology, Emory University School of Medicine, Sleep Center 12 Executive Park Drive, Room 435, Atlanta, GA 30329, United States
^b Department of Statistics, Duke University School of Medicine, Durham, United States
^c Department of Urology, University of Illinois at Chicago School of Medicine, Chicago, United States
^d Department of Urology, Washington University School of Medicine, St. Louis, United States
^e Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, United States

Abstract
Sleep health is postulated as a multi-dimensional construct comprised of sleepiness/alertness, timing, duration, efficiency, and satisfaction. New questionnaires for its measurement have been proposed. We performed secondary data analyses and analyzed responses on a widely used, well-established sleep questionnaire to determine whether the construct might be detectable with an existing questionnaire. Healthy men (n = 7604) aged 55–75 completed the six-item Medical Outcomes Study Sleep Questionnaire (MOSSQ) at baseline in a large, randomized clinical trial [the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial). Two components clearly emerged from a Principal Components Analysis, suggesting that both sleep disturbance and sleep satisfaction are differentiated by the MOSSQ. Selected elements of sleep health are accessible with relatively few questionnaire items. Widespread previous usage of the MOSSQ in both descriptive and interventional research suggests that many previously collected databases could address at least two components of this construct. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Medical Outcomes Study;  Principal components analysis;  Questionnaires;  REDUCE trial;  Sleep health

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

The influence of pain, agitation, and their management on the immature brain
(2020) Pediatric Research, . 

McPherson, C.^{a b} , Miller, S.P.^c , El-Dib, M.^d , Massaro, A.N.^e , Inder, T.E.^d

^a Department of Pharmacy, St. Louis Children’s Hospital, St. Louis, MO, United States
^b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Paediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, ON, Canada
^d Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^e Department of Pediatrics—Neonatology Division, The George Washington University School of Medicine and Children’s National Health System, Washington, DC, United States

Abstract
Preterm infants are exposed to frequent painful procedures and agitating stimuli over the many weeks of their hospitalization in the neonatal intensive care unit (NICU). The adverse neurobiological impact of pain and stress in the preterm infant has been well documented, including neuroimaging and neurobehavioral outcomes. Although many tools have been validated to assess acute pain, few methods are available to assess chronic pain or agitation (a clinical manifestation of neonatal stress). Both nonpharmacologic and pharmacologic approaches are used to reduce the negative impact of pain and agitation in the preterm infant, with concerns emerging over the adverse effects of analgesia and sedatives. Considering benefits and risks of available treatments, units must develop a stepwise algorithm to prevent, assess, and treat pain. Nonpharmacologic interventions should be consistently utilized prior to mild to moderately painful procedures. Sucrose may be utilized judiciously as an adjunctive therapy for minor painful procedures. Rapidly acting opioids (fentanyl or remifentanil) form the backbone of analgesia for moderately painful procedures. Chronic sedation during invasive mechanical ventilation represents an ongoing challenge; appropriate containment and an optimal environment should be standard; when indicated, low-dose morphine infusion may be utilized cautiously and dexmedetomidine infusion may be considered as an emerging adjunct. © 2020, International Pediatric Research Foundation, Inc.

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

Machine Learning With Neuroimaging: Evaluating Its Applications in Psychiatry
(2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . 

Nielsen, A.N.^{a b} , Barch, D.M.^{c d} , Petersen, S.E.^{e f g} , Schlaggar, B.L.^{h i j} , Greene, D.J.^{d g}

^a Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL, United States
^b Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^g Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^h Kennedy Krieger Institute, Baltimore, MD, United States
ⁱ Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^j Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
Psychiatric disorders are complex, involving heterogeneous symptomatology and neurobiology that rarely involves the disruption of single, isolated brain structures. In an attempt to better describe and understand the complexities of psychiatric disorders, investigators have increasingly applied multivariate pattern classification approaches to neuroimaging data and in particular supervised machine learning methods. However, supervised machine learning approaches also come with unique challenges and trade-offs, requiring additional study design and interpretation considerations. The goal of this review is to provide a set of best practices for evaluating machine learning applications to psychiatric disorders. We discuss how to evaluate two common efforts: 1) making predictions that have the potential to aid in diagnosis, prognosis, and treatment and 2) interrogating the complex neurophysiological mechanisms underlying psychopathology. We focus here on machine learning as applied to functional connectivity with magnetic resonance imaging, as an example to ground discussion. We argue that for machine learning classification to have translational utility for individual-level predictions, investigators must ensure that the classification is clinically informative, independent of confounding variables, and appropriately assessed for both performance and generalizability. We contend that shedding light on the complex mechanisms underlying psychiatric disorders will require consideration of the unique utility, interpretability, and reliability of the neuroimaging features (e.g., regions, networks, connections) identified from machine learning approaches. Finally, we discuss how the rise of large, multisite, publicly available datasets may contribute to the utility of machine learning approaches in psychiatry. © 2019 Society of Biological Psychiatry

Author Keywords
Computational psychiatry;  Feature selection;  Functional connectivity;  Machine learning;  Neurophysiological mechanisms;  Prediction

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

Protective role of brain derived neurotrophic factor (BDNF) in obstructive sleep apnea syndrome (OSAS) patients
(2020) PLoS ONE, 15 (1), art. no. e0227834, . 

Flores, K.R.^a , Viccaro, F.^a , Aquilini, M.^a , Scarpino, S.^a , Ronchetti, F.^a , Mancini, R.^a , Di Napoli, A.^a , Scozzi, D.^b , Ricci, A.^a

^a Department of Clinical and Molecular Medicine, Division of Respiratory Diseases, Sant’Andrea Hospital, Sapienza University, Rome, Italy
^b Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by repeated episodes of upper airways collapse during the sleep. The following intermittent hypoxia triggers a state of chronic inflammation, which also interests the nervous system leading to neuronal damage and increased risk of cognitive impairment. Brain derived neurotrophic factor (BDNF) is a growth factor often associated with neuroplasticity and neuroprotection whose levels increase in several condition associated with neuronal damage. However, whether patients affected by OSAS have altered BDNF levels and whether such alteration may be reflective of their cognitive impairment is still controversial. Here we show that, when compared to healthy control volunteers, OSAS patients have increased serum levels of BDNF. Moreover, OSAS patients with the higher levels of BDNF also have reduced neurocognitive impairment as measured by The Montreal Cognitive Assessment (MoCA) questionnaire. Treatment with standard non-invasive mechanical ventilation (CPAP) also was able to ameliorate the level of cognitive impairment. Altogether our results indicate that BDNF levels represent a neuroprotective response to intermittent hypoxia in OSAS patients. © 2020 Flores et al.

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Circulating ceramide ratios and risk of vascular brain aging and dementia
(2020) Annals of Clinical and Translational Neurology, . 

McGrath, E.R.^{a b c} , Himali, J.J.^{c d e f} , Xanthakis, V.^{c d e} , Duncan, M.S.^g , Schaffer, J.E.^h , Ory, D.S.^h , Peterson, L.R.^h , DeCarli, C.ⁱ , Pase, M.P.^{c j k} , Satizabal, C.L.^{c f} , Vasan, R.S.^{c e} , Beiser, A.S.^{c d e} , Seshadri, S.^{c e f}

^a Department of Neurology, Brigham & Women’s Hospital, Boston, MA, United States
^b Harvard Medical School, Boston, MA, United States
^c Framingham Heart Study, Framingham, MA, United States
^d School of Public Health, Boston University, Boston, MA, United States
^e Boston University School of Medicine, Boston, MA, United States
^f Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX, United States
^g Vanderbilt University Medical Center, Nashville, TN, United States
^h Washington University School of Medicine, St Louis, MO, United States
ⁱ Department of Neurology, University of California, Davis, CA, United States
^j Melbourne Dementia Research Centre, The Florey Institute for Neuroscience and Mental HealthVIC, Australia
^k The University of MelbourneVIC, Australia

Abstract
Background: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer’s disease (AD) dementia in a large, community-based sample. Methods: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes. Results: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were diagnosed with AD dementia. In multivariable Cox-proportional hazards analyses, each standard deviation (SD) increment in the ratio of ceramides C24:0/C16:0 was associated with a 27% reduction in the risk of dementia (HR 0.73, 95% CI 0.56–0.96) and AD dementia (HR 0.73, 95% CI 0.53–1.00). The ratio of ceramides C22:0/C16:0 was also inversely associated with incident dementia (HR per SD 0.75, 95% CI 0.57–0.98), and approached statistical significance for AD (HR 0.73, 95% CI 0.53–1.01, P = 0.056). Higher ratios of ceramides C24:0/C16:0 and C22:0/C16:0 were also cross-sectionally associated with lower white matter hyperintensity burden on MRI (−0.05 ± 0.02, P = 0.02; −0.06 ± 0.02, P = 0.003; respectively per SD increase), but not with other MRI brain measures. Conclusions: Higher plasma ratios of very long-chain to long-chain ceramides are associated with a reduced risk of incident dementia and AD dementia in our community-based sample. Circulating ceramide ratios may serve as potential biomarkers for predicting dementia risk in cognitively healthy adults. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

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

Perspective on Systematic Medical Literature Reviews and Meta-Analyses
(2020) American Journal of Ophthalmology, . 

Pepose, J.S.^a , Foulks, G.N.^b , Nelson, J.D.^c , Erickson, S.^d , Lemp, M.A.^e

^a Pepose Vision Institute and Washington University School of Medicine, St. Louis, MO, United States
^b Department of Ophthalmology, University of Louisville, Louisville, KY, United States
^c Health Partners Institute, Bloomington, MN, United States
^d Medical Editor/Writer, Brookline, MA, United States
^e Department of Ophthalmology, Georgetown University School of Medicine, Washington, DC, United States

Abstract
Purpose: This study sought to identify factors contributing to the inadequacies of systematic reviews and meta-analyses (SRMAs) published in the ophthalmology literature. Design: Perspective. Methods: Review and synthesis of selective literature, with interpretation and perspective. Results: Although recommendations for the design, conduct, assessment of quality, and risk of bias of systematic reviews have been widely available, some recent publications illustrate a serious potential failing in this domain: inclusion of refuted science, lack of citation of post-publication correspondence and failure to use ≥1 alternative search strategy. Conclusions: Examples of inadequacies of peer review in medical literature and perpetuation of erroneous science by unfiltered inclusion in subsequent systematic reviews have been identified, and the problem can be traced to authors, peer reviewers, and editors of journals. This perspective identifies and analyzes several possible causes of the problem and recommends some specific corrective actions to improve the quality and accuracy of such reviews. © 2019 Elsevier Inc.

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

Cerebral blood flow in 5- to 8-month-olds: Regional tissue maturity is associated with infant affect
(2019) Developmental Science, art. no. e12928, . 

Catalina Camacho, M.^a , King, L.S.^b , Ojha, A.^b , Garcia, C.M.^b , Sisk, L.M.^b , Cichocki, A.C.^b , Humphreys, K.L.^c , Gotlib, I.H.^b

^a Washington University in St. Louis, St. Louis, MO, United States
^b Stanford University, Stanford, CA, United States
^c Vanderbilt University, Nashville, TN, United States

Abstract
Infancy is marked by rapid neural and emotional development. The relation between brain function and emotion in infancy, however, is not well understood. Methods for measuring brain function predominantly rely on the BOLD signal; however, interpretation of the BOLD signal in infancy is challenging because the neuronal-hemodynamic relation is immature. Regional cerebral blood flow (rCBF) provides a context for the infant BOLD signal and can yield insight into the developmental maturity of brain regions that may support affective behaviors. This study aims to elucidate the relations among rCBF, age, and emotion in infancy. One hundred and seven mothers reported their infants’ (infant age M ± SD = 6.14 ± 0.51 months) temperament. A subsample of infants completed MRI scans, 38 of whom produced usable perfusion MRI during natural sleep to quantify rCBF. Mother-infant dyads completed the repeated Still-Face Paradigm, from which infant affect reactivity and recovery to stress were quantified. We tested associations of infant age at scan, temperament factor scores, and observed affect reactivity and recovery with voxel-wise rCBF. Infant age was positively associated with CBF in nearly all voxels, with peaks located in sensory cortices and the ventral prefrontal cortex, supporting the formulation that rCBF is an indicator of tissue maturity. Temperamental Negative Affect and recovery of positive affect following a stressor were positively associated with rCBF in several cortical and subcortical limbic regions, including the orbitofrontal cortex and inferior frontal gyrus. This finding yields insight into the nature of affective neurodevelopment during infancy. Specifically, infants with relatively increased prefrontal cortex maturity may evidence a disposition toward greater negative affect and negative reactivity in their daily lives yet show better recovery of positive affect following a social stressor. © 2019 John Wiley & Sons Ltd

Author Keywords
cerebral blood flow;  emotion;  infant brain development;  still-face;  temperament

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