WashU weekly Neuroscience publications: September 1, 2024

Mapping neural correlates of biological motion perception in autistic children using high-density diffuse optical tomography
(2024) Molecular Autism, 15 (1), art. no. 35, . 

Yang, D.^a , Svoboda, A.M.^a , George, T.G.^a , Mansfield, P.K.^a b , Wheelock, M.D.^a c d , Schroeder, M.L.^a e , Rafferty, S.M.^a , Sherafati, A.^a f g , Tripathy, K.^a d h , Burns-Yocum, T.^a i , Forsen, E.^a j , Pruett, J.R.^k , Marrus, N.M.^k , Culver, J.P.^{a c d f l m} , Constantino, J.N.^k n o , Eggebrecht, A.T.^{a c d f l m}

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^b Medical Education, Saint Louis University School of Medicine, St. Louis, MO 63104, United States
^c Department of Biomedical Engineering, Washington University School of Engineering, St. Louis, MO 63130, United States
^d Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Speech, Language, and Hearing Science, Purdue University, West Lafayette, IL 47907, United States
^f Department of Physics, Washington University School of Arts and Science, St. Louis, MO 63130, United States
^g Department of Neurology, University of California San Francisco, San Francisco, CA 94158, United States
^h University of Pittsburgh Medical Center, Western Psychiatric Hospital, Pittsburgh, PA 15213, United States
ⁱ Evolytics, Parkville, MO 64152, United States
^j Doctor of Medicine Program, Washington University School of Medicine, St. Louis, MO 63110, United States
^k Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^l Department of Electrical and System Engineering, Washington University School of Engineering, St. Louis, MO 63112, United States
^m Department Imaging Sciences Engineering, Washington University School of Engineering, St. Louis, MO 63112, United States
ⁿ Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, United States
^o Division of Behavioral and Mental Health, Children’s Healthcare of Atlanta, Atlanta, GA 30329, United States

Abstract
Background: Autism spectrum disorder (ASD), a neurodevelopmental disorder defined by social communication deficits plus repetitive behaviors and restricted interests, currently affects 1/36 children in the general population. Recent advances in functional brain imaging show promise to provide useful biomarkers of ASD diagnostic likelihood, behavioral trait severity, and even response to therapeutic intervention. However, current gold-standard neuroimaging methods (e.g., functional magnetic resonance imaging, fMRI) are limited in naturalistic studies of brain function underlying ASD-associated behaviors due to the constrained imaging environment. Compared to fMRI, high-density diffuse optical tomography (HD-DOT), a non-invasive and minimally constraining optical neuroimaging modality, can overcome these limitations. Herein, we aimed to establish HD-DOT to evaluate brain function in autistic and non-autistic school-age children as they performed a biological motion perception task previously shown to yield results related to both ASD diagnosis and behavioral traits. Methods: We used HD-DOT to image brain function in 46 ASD school-age participants and 49 non-autistic individuals (NAI) as they viewed dynamic point-light displays of coherent biological and scrambled motion. We assessed group-level cortical brain function with statistical parametric mapping. Additionally, we tested for brain-behavior associations with dimensional metrics of autism traits, as measured with the Social Responsiveness Scale-2, with hierarchical regression models. Results: We found that NAI participants presented stronger brain activity contrast (coherent > scrambled) than ASD children in cortical regions related to visual, motor, and social processing. Additionally, regression models revealed multiple cortical regions in autistic participants where brain function is significantly associated with dimensional measures of ASD traits. Limitations: Optical imaging methods are limited in depth sensitivity and so cannot measure brain activity within deep subcortical regions. However, the field of view of this HD-DOT system includes multiple brain regions previously implicated in both task-based and task-free studies on autism. Conclusions: This study demonstrates that HD-DOT is sensitive to brain function that both differentiates between NAI and ASD groups and correlates with dimensional measures of ASD traits. These findings establish HD-DOT as an effective tool for investigating brain function in autistic and non-autistic children. Moreover, this study established neural correlates related to biological motion perception and its association with dimensional measures of ASD traits. © The Author(s) 2024.

Author Keywords
Autism spectrum disorder;  Biological motion;  High-density diffuse optical tomography;  Neuroimaging;  Social perception

Document Type: Article
Publication Stage: Final
Source: Scopus

Cohort Expansion and Genotype-Phenotype Analysis of RAB11A-Associated Neurodevelopmental Disorder
(2024) Pediatric Neurology, 160, pp. 45-53. 

Borroto, M.C.^a , Patel, H.^a , Srivastava, S.^b , Swanson, L.C.^c , Keren, B.^d , Whalen, S.^e , Mignot, C.^f , Wang, X.^g , Chen, Q.^h , Rosenfeld, J.A.^i ae , McLean, S.^i j , Littlejohn, R.O.^i j , Acosta, M.T.^ae , Adam, M.^ae , Adams, D.R.^ae , Alvarez, R.L.^ae , Alvey, J.^ae , Amendola, L.^ae , Andrews, A.^ae , Ashley, E.A.^ae , Bacino, C.A.^ae , Bademci, G.^ae , Balasubramanyam, A.^ae , Baldridge, D.^ae , Bale, J.^ae , Bamshad, M.^ae , Barbouth, D.^ae , Bayrak-Toydemir, P.^ae , Beck, A.^ae , Beggs, A.H.^ae , Behrens, E.^ae , Bejerano, G.^ae , Bellen, H.J.^ae , Bennett, J.^ae , Berg-Rood, B.^ae , Bernstein, J.A.^ae , Berry, G.T.^ae , Bican, A.^ae , Bivona, S.^ae , Blue, E.^ae , Bohnsack, J.^ae , Bonner, D.^ae , Botto, L.^ae , Boyd, B.^ae , Briere, L.C.^ae , Brokamp, E.^ae , Brown, G.^ae , Burke, E.A.^ae , Burrage, L.C.^i ae , Butte, M.J.^ae , Byers, P.^ae , Byrd, W.E.^ae , Carey, J.^ae , Carrasquillo, O.^ae , Cassini, T.^ae , Peter Chang, T.C.^ae , Chanprasert, S.^ae , Chao, H.-T.^ae , Clark, G.D.^ae , Coakley, T.R.^ae , Cobban, L.A.^ae , Cogan, J.D.^ae , Coggins, M.^ae , Cole, F.S.^ae , Colley, H.A.^ae , Cooper, C.M.^ae , Cope, H.^ae , Corona, R.^ae , Craigen, W.J.^ae , Crouse, A.B.^ae , Cunningham, M.^ae , D’Souza, P.^ae , Dai, H.^ae , Dasari, S.^ae , Davis, J.^ae , Dayal, J.G.^ae , Dell’Angelica, E.C.^ae , Dipple, K.^ae , Doherty, D.^ae , Dorrani, N.^ae , Doss, A.L.^ae , Douine, E.D.^ae , Duncan, L.^ae , Earl, D.^ae , Eckstein, D.J.^ae , Emrick, L.T.^ae , Eng, C.M.^ae , Falk, M.^ae , Fieg, E.L.^ae , Fisher, P.G.^ae , Fogel, B.L.^ae , Forghani, I.^ae , Gahl, W.A.^ae , Glass, I.^ae , Gochuico, B.^ae , Goddard, P.C.^ae , Godfrey, R.A.^ae , Golden-Grant, K.^ae , Grajewski, A.^ae , Hadley, D.^ae , Hahn, S.^ae , Halley, M.C.^ae , Hamid, R.^ae , Hassey, K.^ae , Hayes, N.^ae , High, F.^ae , Hing, A.^ae , Hisama, F.M.^ae , Holm, I.A.^ae , Hom, J.^ae , Horike-Pyne, M.^ae , Huang, A.^ae , Hutchison, S.^ae , Introne, W.^ae , Isasi, R.^ae , Izumi, K.^ae , Jamal, F.^ae , Jarvik, G.P.^ae , Jarvik, J.^ae , Jayadev, S.^ae , Jean-Marie, O.^ae , Jobanputra, V.^ae , Karaviti, L.^ae , Kennedy, J.^ae , Ketkar, S.^ae , Kiley, D.^ae , Kilich, G.^ae , Kobren, S.N.^ae , Kohane, I.S.^ae , Kohler, J.N.^ae , Korrick, S.^ae , Kozuira, M.^ae , Krakow, D.^ae , Krasnewich, D.M.^ae , Kravets, E.^ae , Lalani, S.R.^ae , Lam, B.^ae , Lam, C.^ae , Lanpher, B.C.^ae , Lanza, I.R.^ae , LeBlanc, K.^ae , Lee, B.H.^ae , Levitt, R.^ae , Lewis, R.A.^ae , Liu, P.^ae , Liu, X.Z.^ae , Longo, N.^ae , Loo, S.K.^ae , Loscalzo, J.^ae , Maas, R.L.^ae , Macnamara, E.F.^ae , MacRae, C.A.^ae , Maduro, V.V.^ae , Maghiro, A.^ae , Mahoney, R.^ae , Malicdan, M.C.V.^ae , Mamounas, L.A.^ae , Manolio, T.A.^ae , Mao, R.^ae , Maravilla, K.^ae , Marom, R.^ae , Marth, G.^ae , Martin, B.A.^ae , Martin, M.G.^ae , Martínez-Agosto, J.A.^ae , Marwaha, S.^ae , McCauley, J.^ae , McConkie-Rosell, A.^ae , McCray, A.T.^ae , McGee, E.^ae , Mefford, H.^ae , Merritt, J.L.^ae , Might, M.^ae , Mirzaa, G.^ae , Morava, E.^ae , Moretti, P.^ae , Mulvihill, J.^ae , Nakano-Okuno, M.^ae , Nelson, S.F.^ae , Newman, J.H.^ae , Nicholas, S.K.^ae , Nickerson, D.^ae , Nieves-Rodriguez, S.^ae , Novacic, D.^ae , Oglesbee, D.^ae , Orengo, J.P.^ae , Pace, L.^ae , Pak, S.^ae , Pallais, J.C.^ae , Palmer, C.G.S.^ae , Papp, J.C.^ae , Parker, N.H.^ae , Phillips, J.A., III^ae , Posey, J.E.^ae , Potocki, L.^ae , Pusey Swerdzewski, B.N.^ae , Quinlan, A.^ae , Rao, D.A.^ae , Raper, A.^ae , Raskind, W.^ae , Renteria, G.^ae , Reuter, C.M.^ae , Rives, L.^ae , Robertson, A.K.^ae , Rodan, L.H.^ae , Rosenwasser, N.^ae , Rossignol, F.^ae , Ruzhnikov, M.^ae , Sacco, R.^ae , Sampson, J.B.^ae , Saporta, M.^ae , Schaechter, J.^ae , Schedl, T.^ae , Schoch, K.^ae , Scott, D.A.^ae , Scott, C.R.^ae , Shashi, V.^ae , Shin, J.^ae , Silverman, E.K.^ae , Sinsheimer, J.S.^ae , Sisco, K.^ae , Smith, E.C.^ae , Smith, K.S.^ae , Solem, E.^ae , Solnica-Krezel, L.^ae , Solomon, B.^ae , Spillmann, R.C.^ae , Stoler, J.M.^ae , Sullivan, K.^ae , Sullivan, J.A.^ae , Sun, A.^ae , Sutton, S.^ae , Sweetser, D.A.^ae , Sybert, V.^ae , Tabor, H.K.^ae , Tan, Q.K.-G.^ae , Tan, A.L.M.^ae , Tekin, M.^ae , Telischi, F.^ae , Thorson, W.^ae , Tifft, C.J.^ae , Toro, C.^ae , Tran, A.A.^ae , Ungar, R.A.^ae , Urv, T.K.^ae , Vanderver, A.^ae , Velinder, M.^ae , Viskochil, D.^ae , Vogel, T.P.^ae , Wahl, C.E.^ae , Walker, M.^ae , Wallace, S.^ae , Walley, N.M.^ae , Wambach, J.^ae , Wan, J.^ae , Wang, L.-K.^ae , Wangler, M.F.^ae , Ward, P.A.^ae , Wegner, D.^ae , Hubshman, M.W.^ae , Wener, M.^ae , Wenger, T.^ae , Westerfield, M.^ae , Wheeler, M.T.^ae , Whitlock, J.^ae , Wolfe, L.A.^ae , Worley, K.^ae , Xiao, C.^ae , Yamamoto, S.^ae , Yang, J.^ae , Zhang, Z.^ae , Zuchner, S.^ae , Emrick, L.^k , Attali, R.^l , Lesca, G.^m , Acquaviva-Bourdain, C.ⁿ , Sarret, C.^o , Seaver, L.H.^p q , Platzer, K.^r , Bartolomaeus, T.^r , Wünsch, C.^s , Fischer, S.^s , Rodriguez Barreto, A.M.^t , Granadillo, J.L.^u , Schreiner, E.^v , Brunet, T.^w x , Schatz, U.A.^y , Thiffault, I.^z aa , Mullegama, S.V.^ab , Michaud, J.L.^a ac , Hamdan, F.F.^a ad , Rossignol, E.^a , Campeau, P.M.^a ad , Undiagnosed Diseases Network^af

^a Centre de recherche Azrieli du CHU Sainte-Justine, Montreal, Québec, Canada
^b Department of Neurology, Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^c Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^d Département de génétique, APHP-Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Assistance Publique des Hôpitaux de Paris, Paris, France
^e UF de Génétique Clinique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs, APHP, Sorbonne Université, Hôpital Trousseau, Paris, France
^f Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière and Hôpital Trousseau, APHP, Sorbonne Université, Paris, France
^g Cipher Gene Ltd., Beijing, China
^h Children’s Hospital, Capital Institute of Pediatrics, Beijing, China
ⁱ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^j Department of Pediatrics, Baylor College of Medicine, San Antonio, TX, United States
^k Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
^l Genomic Research Department, Emedgene, an Illumina Company, Tel Aviv, Israel
^m Department of Medical Genetics, Lyon University Hospital, University Claude Bernard Lyon 1, Lyon, France
ⁿ Hospices civils de Lyon, service biochimie et biologie moléculaire, UF maladies héréditaires du métabolisme, Bron, France
^o CHU Estaing, Pôle Pédiatrie, Service de Génétique, Clermont-Ferrand, France
^p Corewell Health Helen DeVos Children’s Hospital, Grand Rapids, MI, United States
^q Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Grand Rapids, MI, United States
^r Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
^s Sozialpädiatrisches Zentrum Leipzig – Frühe Hilfe Leipzig e.V., Leipzig, Germany
^t Division of Clinical Genetics, Nicklaus Children’s Hospital, Miami, FL, United States
^u Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^v Diagnostic and Research Institute of Human Genetics, Medical University of Graz, Graz, Austria
^w Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany
^x Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s Hospital, LMU – University of Munich, Munich, Germany
^y Institute of Human Genetics, Technical University of Munich, Munich, Germany
^z Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, MO, United States
^aa Department of Pathology and Laboratory Medicine, Children’s Mercy Kansas City, Kansas City, MO, United States
^ab GeneDx, Gaithersburg, MD, United States
^ac Departments of Pediatrics and Neurosciences, Université de Montréal, Montreal, Québec, Canada
^ad Department of Pediatrics, University of Montreal, Montreal, Québec, Canada

Abstract
Background: GTPases of the Rab family are important orchestrators of membrane trafficking, and their dysregulation has been linked to a variety of neuropathologies. In 2017, we established a causal link between RAB11A variants and developmental and epileptic encephalopathy. In this study, we expand the phenotype of RAB11A-associated neurodevelopmental disorder and explore genotype-phenotype correlations. Methods: We assessed 16 patients with pathogenic or likely pathogenic RAB11A variants, generally de novo, heterozygous missense variants. One individual had a homozygous nonsense variant, although concomitant with a pathogenic LAMA2 variant, which made their respective contributions to the phenotype difficult to discriminate. Results: We reinforce the finding that certain RAB11A missense variants lead to intellectual disability and developmental delays. Other clinical features might include gait disturbances, hypotonia, magnetic resonance imaging abnormalities, visual anomalies, dysmorphisms, early adrenarche, and obesity. Epilepsy seems to be less common and linked to variants outside the binding sites. Individuals with variants in the binding sites seem to have a more multisystemic, nonepileptic phenotype. Conclusions: Similar to other Rab-related disorders, RAB11A-associated neurodevelopmental disorder can also impact gait, tonus, brain anatomy and physiology, vision, adrenarche, and body weight and structure. Epilepsy seems to affect the minority of patients with variants outside the binding sites. © 2024 The Author(s)

Author Keywords
Epileptic encephalopathy;  GTPase;  Neurodevelopmental disorder;  RAB11

Document Type: Article
Publication Stage: Final
Source: Scopus

Increased periventricular thalamic damage gradient in multiple sclerosis detected by quantitative gradient echo MRI
(2024) Multiple Sclerosis and Related Disorders, 90, art. no. 105834, . 

Samara, A.^a , Xiang, B.^a , Judge, B.^b , Ciotti, J.R.^c , Yablonskiy, D.A.^b , Cross, A.H.^a , Brier, M.R.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, St. Louis, MO 63110, United States
^c Department of Neurology, University of South Florida, Tampa, FL, United States

Abstract
Objective: Thalamic tissue damage in multiple sclerosis (MS) follows a ‘surface-in’ gradient from the ventricular surface. The clinical consequences of this gradient are not completely understood. Using quantitative gradient-recalled echo (qGRE) MRI, we evaluated a periventricular thalamic gradient of tissue integrity in MS and its relationship with clinical variables. Methods: Structural and qGRE MRI scans were acquired for a cohort of MS patients and healthy controls (HC). qGRE-derived R2t* values were used as a measure of tissue integrity. Thalamic segmentations were divided into 1-mm concentric bands radiating from the ventricular surface, excluding the CSF-adjacent band. Median R2t* values within these bands were used to calculate the periventricular thalamic gradient. Results: We included 44 MS patients and 17 HC. R2t* increased slightly with distance from the ventricular surface in HC. MS patients had a steeper periventricular thalamic gradient compared to HC (mean slope 0.55 vs. 0.36; p < 0.001), which correlated with longer disease duration (β = 0.001 /year; p = 0.027) and higher Expanded Disability Status Scale (EDSS) score (β = 0.07 /EDSS point; p = 0.019). Left and right thalamus were symmetrically affected. Conclusions: We detected an increased thalamic gradient in MS in vivo using qGRE MRI, which correlated with disease duration and greater clinical disability. These findings further support the ‘surface-in’ pathology hypothesis in MS and suggest a CSF-mediated process given symmetric bi-thalamic involvement. © 2024 The Author(s)

Author Keywords
MRI;  Multiple sclerosis;  Quantitative gradient-recalled echo (qGRE);  Thalamus

Document Type: Article
Publication Stage: Final
Source: Scopus

The Undiagnosed Diseases Network: Characteristics of solvable applicants and diagnostic suggestions for nonaccepted ones
(2024) Genetics in Medicine, 26 (10), art. no. 101203, . 

Mulvihill, J.J.^a b j , Findley, L.^a , Ni, W.^c , Sinsheimer, J.S.^d , Cole, F.S.^e , Esteves, C.^f , Bernstein, J.A.^g j , Newman, J.H.^h , Wheeler, M.T.^g j , Mokry, J.R.ⁱ , Acosta, M.T.^j , Adams, D.R.^j , Afzali, B.^j , Al-Beshri, A.^j , Allworth, A.^j , Alvarez, R.L.^j , Alvey, J.^j , Andrews, A.^j , Ashley, E.A.^j , Bacino, C.A.^j , Bademci, G.^j , Balasubramanyam, A.^j , Baldridge, D.^j , Bale, J.^j , Bamshad, M.^j , Barbouth, D.^j , Bayrak-Toydemir, P.^j , Beck, A.^j , Beggs, A.H.^j , Behrens, E.^j , Bejerano, G.^j , Bellen, H.J.^j , Bennett, J.^j , Berry, G.T.^j , Bican, A.^j , Bivona, S.^j , Blue, E.^j , Bohnsack, J.^j , Bonner, D.^j , Borja, N.^j , Botto, L.^j , Briere, L.C.^j , Burke, E.A.^j , Burrage, L.C.^j , Butte, M.J.^j , Byers, P.^j , Byrd, W.E.^j , Callaway, K.^j , Carey, J.^j , Carvalho, G.^j , Cassini, T.^j , Chanprasert, S.^j , Chao, H.-T.^j , Chinn, I.^j , Clark, G.D.^j , Coakley, T.R.^j , Cobban, L.A.^j , Cogan, J.D.^j , Coggins, M.^j , Cole, F.S.^j , Corner, B.^j , Corona, R.I.^j , Craigen, W.J.^j , Crouse, A.B.^j , Cuddapah, V.^j , Cunningham, M.^j , D’Souza, P.^j , Dai, H.^j , Dasari, S.^j , Davis, J.^j , Delgado, M.^j , Dell’Angelica, E.C.^j , Dipple, K.^j , Doherty, D.^j , Dorrani, N.^j , Douglas, J.^j , Douine, E.D.^j , Earl, D.^j , Emrick, L.T.^j , Eng, C.M.^j , Ezell, K.^j , Fieg, E.L.^j , Fisher, P.G.^j , Fogel, B.L.^j , Fu, J.^j , Gahl, W.A.^j , Ganetzky, R.^j , Glanton, E.^j , Glass, I.^j , Goddard, P.C.^j , Gonzalez, J.M.^j , Gropman, A.^j , Halley, M.C.^j , Hamid, R.^j , Hanchard, N.^j , Hassey, K.^j , Hayes, N.^j , High, F.^j , Hing, A.^j , Hisama, F.M.^j , Holm, I.A.^j , Hom, J.^j , Horike-Pyne, M.^j , Huang, A.^j , Huang, Y.^j , Hurst, A.^j , Introne, W.^j , Jarvik, G.P.^j , Jarvik, J.^j , Jayadev, S.^j , Marie, O.J.^j , Jobanputra, V.^j , Kaitryn, E.^j , Kanca, O.^j , Karasozen, Y.^j , Ketkar, S.^j , Kiley, D.^j , Kilich, G.^j , Kobren, S.N.^j , Kohane, I.S.^j , Kohler, J.N.^j , Korf, B.^j , Korrick, S.^j , Krakow, D.^j , Kravets, E.^j , Lalani, S.R.^j , Lam, C.^j , Lanpher, B.C.^j , Lanza, I.R.^j , Latchman, K.^j , LeBlanc, K.^j , Lee, B.H.^j , Lewis, R.A.^j , Liu, P.^j , Longo, N.^j , Loscalzo, J.^j , Maas, R.L.^j , Macnamara, E.F.^j , MacRae, C.A.^j , Maduro, V.V.^j , Maghiro, A.S.^j , Mahoney, R.^j , Malicdan, M.C.V.^j , Mao, R.^j , Marom, R.^j , Marth, G.^j , Martin, B.A.^j , Martin, M.G.^j , Martínez-Agosto, J.A.^j , Marwaha, S.^j , McConkie-Rosell, A.^j , McCray, A.T.^j , Might, M.^j , Mikati, M.^j , Miller, D.^j , Mirzaa, G.^j , Morava, E.^j , Moretti, P.^j , Morimoto, M.^j , Nakano-Okuno, M.^j , Nelson, S.F.^j , Neumann, S.^j , Novacic, D.^j , Oglesbee, D.^j , Orengo, J.P.^j , Pace, L.^j , Pak, S.^j , Pallais, J.C.^j , Parker, N.H.^j , Peart, L.S.^j , Petcharet, L.^j , Phillips, J.A., III^j , Posey, J.E.^j , Potocki, L.^j , Pusey Swerdzewski, B.N.^j , Quinlan, A.^j , Rajagopalan, R.^j , Rao, D.A.^j , Raper, A.^j , Raskind, W.^j , Rebelo, A.^j , Reuter, C.M.^j , Rives, L.^j , Robertson, A.K.^j , Rodan, L.H.^j , Rodriguez, M.^j , Rosenfeld, J.A.^j , Rosenthal, E.^j , Rossignol, F.^j , Ruzhnikov, M.^j , Sabaii, M.^j , Sampson, J.B.^j , Schedl, T.^j , Schoch, K.^j , Scott, D.A.^j , Seto, E.^j , Shashi, V.^j , Shelkowitz, E.^j , Sheppeard, S.^j , Shin, J.^j , Silverman, E.K.^j , Sisco, K.^j , Skelton, T.^j , Skraban, C.^j , Smith, C.A.^j , Smith, K.S.^j , Solnica-Krezel, L.^j , Solomon, B.^j , Spillmann, R.C.^j , Stergachis, A.^j , Stoler, J.M.^j , Sullivan, K.^j , Sutton, S.^j , Sweetser, D.A.^j , Sybert, V.^j , Tabor, H.K.^j , Tan, Q.K.-G.^j , Tan, A.L.M.^j , Tarakad, A.^j , Taylor, H.^j , Tekin, M.^j , Thorson, W.^j , Tifft, C.J.^j , Toro, C.^j , Tran, A.A.^j , Ungar, R.A.^j , Vanderver, A.^j , Velinder, M.^j , Viskochil, D.^j , Vogel, T.P.^j , Wahl, C.E.^j , Walker, M.^j , Walley, N.M.^j , Wambach, J.^j , Wangler, M.F.^j , Ward, P.A.^j , Wegner, D.^j , Hubshman, M.W.^j , Wener, M.^j , Wenger, T.^j , Westerfield, M.^j , Whitlock, J.^j , Wolfe, L.A.^j , Wood, H.^j , Worley, K.^j , Yamamoto, S.^j , Zhang, Z.^j , Zuchner, S.^j , Undiagnosed Diseases Network^k

^a National Human Genome Research Institute (National Institutes of Health), Bethesda, MD, United States
^b Department of Pediatrics, University of Oklahoma, Oklahoma City, OK, United States
^c Department of Computer Science and Mathematics, Arcadia University, Glenside, PA, United States
^d Departments of Human Genetics and of Computational Medicine and Biostatistics, University of California, Los Angeles, CA, United States
^e Department of Pediatrics, Washington University, St. Louis, MO, United States
^f Department of Biomedical Informatics, Harvard Medical School, Boston, MA, United States
^g Department of Pediatrics, Stanford University, Stanford, CA, United States
^h Department of Medicine, Vanderbilt University, Nashville, TN, United States
ⁱ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States

Abstract
Purpose: Can certain characteristics identify as solvable some undiagnosed patients who seek extensive evaluation and thorough record review, such as by the Undiagnosed Diseases Network (UDN)? Methods: The UDN is a national research resource to solve medical mysteries through team science. Applicants provide informed consent to access to their medical records. After review, expert panels assess if applicants meet inclusion and exclusion criteria to select participants. When not accepting applicants, UDN experts may offer suggestions for diagnostic efforts. Using minimal information from initial applications, we compare features in applicants who are not accepted with those who are accepted and either solved or still not solved by the UDN. The diagnostic suggestions offered to nonaccepted applicants and their clinicians were tallied. Results: Nonaccepted applicants were more often female, older at first symptoms and application, and longer in review compared with accepted applicants. The accepted and successfully diagnosed applicants were younger, shorter in review time, more often non-White, of Hispanic ethnicity, and presenting with nervous system features. Half of nonaccepted applicants were given suggestions for further local diagnostic evaluation. A few seemed to have 2 major diagnoses or a provocative environmental exposure history. Conclusion: Comprehensive UDN record review generates possibly helpful advice. © 2024

Author Keywords
Clinical diagnosis;  Environmental exposures;  Record review;  Undiagnosed and rare diseases

Document Type: Article
Publication Stage: Final
Source: Scopus

Caregiver Wellness after Traumatic Brain Injury (CG-Well): Protocol for a randomized clinical trial
(2024) Contemporary Clinical Trials Communications, 41, art. no. 101356, . 

Kreitzer, N.^a , Fink, S.^a , Adeoye, O.^b , Kurowski G, B.^c , Wade, S.^c , Sucharew, H.^a , Bakas, T.^d

^a Department of Emergency Medicine, University of Cincinnati, Medical Sciences Building Room 1654 231, Albert Sabin Way, PO Box 670769, Cincinnati, OH 45267-0769, United States
^b Department of Emergency Medicine, Washington University, 660 S. Euclid Ave., Campus Box 8072, Saint Louis, MO 63110, United States
^c Departments of Pediatrics and Neurology and Rehabilitation Medicine, Division of Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3026, United States
^d College of Nursing, University of Cincinnati, 3110 Vine St., Cincinnati, OH 45221, United States

Abstract
Introduction: After injury, survivors of moderate to severe traumatic brain injury (msTBI) depend on informal family caregivers. Upwards of 77 % of family caregivers experience poor outcomes, such as adverse life changes, poor health-related quality of life, and increased depressive symptoms. Caregivers frequently report minimal support or training to prepare them for their new role. The majority of previously developed caregiver and caregiver/survivor dyad interventions after msTBI focus on providing information to either survivors only, or to long-term caregivers, rather than to the new caregiver. This manuscript describes the protocol of an ongoing randomized control trial, Caregiver Wellness after TBI (CG-Well), developed to provide education, support, and skill-building to caregivers of adults with msTBI, beginning when the survivor is early in the clinical course. Methods: Within two weeks of admission to the ICU, participants are randomized to CG-Well online modules (intervention group, n = 50 dyads) or information, support, and referral (ISR) e-bulletins that exist in the public domain (control group, n = 50 dyads) over the first six months after their family member’s msTBI. Both groups receive regular phone calls. The primary outcome is intervention satisfaction at six months. Results: Enrollment began in March 2022 and is projected to complete October 2024. We have enrolled approximately 70 % of participants at this time. Primary analysis completion is anticipated April 2025. Discussion: This RCT is designed to evaluate caregiver satisfaction by addressing the need for tailored supportive care for caregivers of msTBI beginning during the ICU admission. Trial registration: Clinicaltrials. gov Registration Number: NCT05307640. © 2024 The Authors

Author Keywords
Anxiety;  Caregiver;  Depression;  Pilot trial;  Protocol;  Traumatic brain injury

Document Type: Article
Publication Stage: Final
Source: Scopus

Performance of upper limb entry item to predict forced vital capacity in dysferlin-deficient limb girdle muscular dystrophy
(2024) Neuromuscular Disorders, 43, pp. 20-28. 

Borland, H.^a , Moore, U.^a , Dressman, H.G.^b c , Human, A.^d , Mayhew, A.G.^a , Hilsden, H.^a , Rufibach, L.E.^e , Duong, T.^f , Maron, E.^g , DeWolf, B.^h , Rose, K.ⁱ , Siener, C.^j , Thiele, S.^k , Práxedes, N.S.-A.^l , Canal, A.^m , Holsten, S.ⁿ , Sakamoto, C.^o , Pedrosa-Hernández, I.^p , Bello, L.^q , Alfano, L.N.^r , Lowes, L.P., The Jain COS Consortium^r , James, M.K.^a , Straub, V.^a

^a The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon, Tyne, United Kingdom
^b Center for Translational Science, Division of Biostatistics and Study Methodology, Children’s National Health System, Washington, DC, United States
^c Pediatrics, Epidemiology and Biostatistics, George Washington University, Washington, DC, United States
^d University of Pretoria, Pretoria, South Africa
^e Jain Foundation, Seattle, United States
^f Stanford University, Palo Alto, United States
^g Elan Physio, Berlin, Germany
^h Children’s National Health System, Washington, DC, United States
ⁱ Discipline of Physiotherapy, Faculty of Medicine and Health, University of Sydney and the Sydney Children’s Hospitals Network, Sydney, Australia
^j Washington University School of Medicine, St. Louis, MO, United States
^k Friedrich Baur Institute, Munich, Germany
^l Hospital Universitario Virgen del Rocío, Sevilla, Spain
^m Institute of Myology, Paris, France
ⁿ Carolinas HealthCare System, Charlotte, United States
^o National Center of Neurology and Psychiatry, Tokyo, Japan
^p Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
^q University of Padova, Padova, Italy
^r Nationwide Children’s Hospital, Abigail Wexner Research Inst., Columbus, OH, United States

Abstract
Dysferlin-deficient limb girdle muscular dystrophy (LGMD R2), also referred to as dysferlinopathy, can be associated with respiratory muscle weakness as the disease progresses. Clinical practice guidelines recommend biennial lung function assessments in patients with dysferlinopathy to screen for respiratory impairment. However, lack of universal access to spirometry equipment and trained specialists makes regular monitoring challenging. This study investigated the use of the Performance of Upper Limb (PUL) clinical scale entry item as a low-cost screening tool to identify patients with dysferlinopathy at risk of respiratory impairment. Using data from 193 patients from the Jain Foundation’s International Clinical Outcomes Study, modelling identified a significant positive relationship between the PUL entry item and forced vital capacity (FVC). Eighty-eight percent of patients with the lowest PUL entry item score of 1 presented with FVC % predicted values of <60 %, suggestive of respiratory impairment. By contrast, only 10 % of the remainder of the cohort (PUL entry item of 2 or more) had an FVC of <60 %. This relationship also held true when accounting for ambulatory status, age, and sex as possible confounding factors. In summary, our results suggest that the PUL entry item could be implemented in clinical practice to screen for respiratory impairment where spirometry is not readily available. © 2024 The Authors

Author Keywords
Dysferlin;  Forced vital capacity;  Limb girdle muscular dystrophy;  Miyoshi myopathy;  Performance of upper limb (PUL);  Respiratory function

Document Type: Article
Publication Stage: Final
Source: Scopus

Effect of Human Head Shape on the Risk of Traumatic Brain Injury: A Gaussian Process Regression-Based Machine Learning Approach
(2024) Military Medicine, 189 (Supplement_3), pp. 608-617. 

Upadhyay, K.^a , Jagani, R.^b , Giovanis, D.G.^c , Alshareef, A.^d , Knutsen, A.K.^e , Johnson, C.L.^f , Carass, A.^g , Bayly, P.V.^h , Shields, M.D.^c , Ramesh, K.T.^b

^a Department of Mechanical and Industrial Engineering, Louisiana State University, Baton Rouge, LA 70803, United States
^b Department of Mechanical Engineering, Johns Hopkins University, Baltimore, MD 21218, United States
^c Department of Civil and Systems Engineering, Johns Hopkins University, Baltimore, MD 21218, United States
^d Department of Mechanical Engineering, University of South Carolina, Columbia, SC 29208, United States
^e Center for Neuroscience and Regenerative Medicine, Henry M. Jackson Foundation, Bethesda, MD 20817, United States
^f Department of Biomedical Engineering, University of Delaware, Newark, DE 19713, United States
^g Department of Electrical and Computer Engineering, Johns Hopkins University, Baltimore, MD 21218, United States
^h Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Introduction: Computational head injury models are promising tools for understanding and predicting traumatic brain injuries. However, most available head injury models are “average”models that employ a single set of head geometry (e.g., 50th-percentile U.S. male) without considering variability in these parameters across the human population. A significant variability of head shapes exists in U.S. Army soldiers, evident from the Anthropometric Survey of U.S. Army Personnel (ANSUR II). The objective of this study is to elucidate the effects of head shape on the predicted risk of traumatic brain injury from computational head injury models. Materials and Methods: Magnetic resonance imaging scans of 25 human subjects are collected. These images are registered to the standard MNI152 brain atlas, and the resulting transformation matrix components (called head shape parameters) are used to quantify head shapes of the subjects. A generative machine learning model is used to generate 25 additional head shape parameter datasets to augment our database. Head injury models are developed for these head shapes, and a rapid injurious head rotation event is simulated to obtain several brain injury predictor variables (BIPVs): Peak cumulative maximum principal strain (CMPS), average CMPS, and the volume fraction of brain exceeding an injurious CMPS threshold. A Gaussian process regression model is trained between head shape parameters and BIPVs, which is then used to study the relative sensitivity of the various BIPVs on individual head shape parameters. We distinguish head shape parameters into 2 types: Scaling components,, and that capture the breadth, length, and height of the head, respectively, and shearing components (, and) that capture the relative skewness of the head shape. Results: An overall positive correlation is evident between scaling components and BIPVs. Notably, a very high, positive correlation is seen between the BIPVs and the head volume. As an example, a 57% increase in peak CMPS was noted between the smallest and the largest investigated head volume parameters. The variation in shearing components, and on average does not cause notable changes in the BIPVs. From the Gaussian process regression model, all 3 BIPVs showed an increasing trend with each of the 3 scaling components, but the BIPVs are found to be most sensitive to the height dimension of the head. From the Sobol sensitivity analysis, the scaling parameter contributes nearly 60% to the total variance in peak and average CMPS; contributes approximately 20%, whereas contributes less than 5%. The remaining contribution is from the 6 shearing components. Unlike peak and average CMPS, the VF-CMPS BIPV is associated with relatively evenly distributed Sobol indices across the 3 scaling parameters. Furthermore, the contribution of shearing components on the total variance in this case is negligible. Conclusions: Head shape has a considerable influence on the injury predictions of computational head injury models. Available “average”head injury models based on a 50th-percentile U.S. male are likely associated with considerable uncertainty. In general, larger head sizes correspond to greater BIPV magnitudes, which point to potentially a greater injury risk under rapid neck rotation for people with larger heads. © 2024 The Association of Military Surgeons of the United States. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Prediction of Functional Academic Outcomes by Fine Motor Skills in Individuals With Sickle Cell Disease
(2024) American Journal of Occupational Therapy, 78 (5), art. no. 7805205180, . 

Lakia, K.^a , Christina, D.^b , Catherine, H.^c , Jennifer, L.^d , Victoria, O.^e , Darcy, R.^f , Brian, P.^g , Guolian, K.^h , Jane, H.ⁱ , Clifford, T.^j , Andrew, H.^k

^a Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States
^c Department of Pediatrics and Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States
^e Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^f Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States
^g Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States
^h Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
ⁱ Global Hematology Program, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^j Clinical Hematology, Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^k Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
Importance: Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. Objective: To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. Design: Cross-sectional. Setting: St. Jude Children’s Research Hospital. Participants: Individuals with SCD (N 5 376; ages 8–24 yr). Outcomes and Measures: Fine motor outcomes included visual–motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. Results: Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual–motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. Conclusions and Relevance: Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills. © 2024 American Occupational Therapy Association, Inc. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Quantitative gradient recalled echo (qGRE) MRI enables in vivo measurement of pre-atrophic neurodegeneration in a mouse model of Alzheimer’s disease
(2024) NeuroImage, 298, art. no. 120794, . 

Tomaszewski, M.R.^a , Sukstanskii, A.L.^b , Haley, H.^a , Meng, X.^a , Miller, C.O.^a , Yablonskiy, D.A.^b

^a Translational Imaging Department, Merck & Co., Inc., Rahway, NJ, United States
^b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510. Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific R2* maps free of magnetic field inhomogeneity artifacts. Light-sheet microscopy of the brains stained with NeuN and MBP served to visualize neuronal nuclei and myelin content respectively. Significant decrease in NeuN staining between 3mo and 5mo was observed in the hippocampus of Tg4510, validating the mouse AD model. Longitudinal analysis showed clear decreases in R2* metric of qGRE signal in the Tg4510 mice hippocampus undergoing neurodegeneration between 3 and 5 months old. Histogram analysis revealed an upward trend in patterns of low R2* value (Dark Matter, DM), and broadening of R2* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R2* Standard Deviation (SD) in Tg4510 mice (p=0.004/p=0.016 DMVF/SD) but not in WT controls (p&gt;0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between the DMVF and myelin content (p=0.01, r=-0.76), suggesting sensitivity of the technique to the loss of myelinated axons. The presented qGRE technique, validated by histological measurements, can be readily applied as in vivo tool in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment. © 2024

Author Keywords
Alzheimer’s disease;  MRI;  Neurodegeneration;  Neuronal density;  QGRE;  Tg4510

Document Type: Article
Publication Stage: Final
Source: Scopus

Characterization of Ptau181 Among a Diverse Community-Based Cohort: A HABS-HD Study
(2024) Journal of Alzheimer’s Disease, 100 (s1), pp. S63-S73. 

Petersen, M.E.^a b , Zhang, F.^a b , Hall, J.R.^a b , Julovich, D.^a , Rissman, R.A.^c , Meeker, K.L.^a b , Phillips, N.^a , Large, S.^a , Ances, B.M.^d , O’bryant, S.E.^a b , HABS-HD Study Team^e

^a Institute for Translational Research, University of North Texas Health Science Center, Fort Worth, TX, United States
^b Deparment of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, United States
^c Keck School of Medicine of USC, Alzheimer’s Therapeutic Research Institute, San Diego, CA, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Examination of Alzheimer’s disease (AD) related biomarkers among diverse communities has remained limited. Objective: The aim of this study was to expand on prior work to provide a characterization of ptau181 among a diverse community sample. Consideration was taken regarding the impact of comorbidities on ptau181 levels including medical. Methods: 3,228 (n = 770 African American [AA], n = 1,231 Hispanic, and n = 1,227 non-Hispanic white [NHW]) Health and Aging Brain Study- Health Disparities (HABS-HD) participants were included in this study. ANCOVAs were conducted to examine differences in ptau181 levels across race and ethnic groups. Violin plots were also generated stratified by APOE ϵ4 carrier status, Amyloid PET positivity status, medical comorbidity (hypertension, dyslipidemia, chronic kidney disease [CKD], and diabetes) and by cognitive diagnosis. Results: Ptau181 levels were found to differ between Hispanics and NHW after covarying for age, sex, and APOE ϵ4 status. Amyloid PET positivity was associated with higher ptau181 levels across all groups. APOE ϵ4 positivity status was only significantly associated with ptau181 levels among AAs. Across all race and ethnic groups, those with a diagnosis of CKD had higher levels of ptau181. When stratified by cognitive diagnosis, cognitively unimpaired Hispanics had higher ptau181 if they also had a diagnosis of CKD or diabetes. p-values ≤0.01. Conclusions: Differences in ptau181 levels were shown in a diverse community sample. Medical comorbidities had a differing effect on ptau181 levels particularly among Hispanics even without cognitive impairment. Findings support the need for future work to consider comorbid conditions when examining the utility of ptau181. © 2024 – IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  biomarkers;  diverse;  plasma;  ptau181

Document Type: Article
Publication Stage: Final
Source: Scopus

Complexity organization of resting-state functional-MRI networks
(2024) Human Brain Mapping, 45 (12), art. no. e26809, . 

Trevino, G.^a , Lee, J.J.^b , Shimony, J.S.^b , Luckett, P.H.^c d , Leuthardt, E.C.^a c d

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Neurotechnology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Entropy measures are increasingly being used to analyze the structure of neural activity observed by functional magnetic resonance imaging (fMRI), with resting-state networks (RSNs) being of interest for their reproducible descriptions of the brain’s functional architecture. Temporal correlations have shown a dichotomy among these networks: those that engage with the environment, known as extrinsic, which include the visual and sensorimotor networks; and those associated with executive control and self-referencing, known as intrinsic, which include the default mode network and the frontoparietal control network. While these inter-voxel temporal correlations enable the assessment of synchrony among the components of individual networks, entropic measures introduce an intra-voxel assessment that quantifies signal features encoded within each blood oxygen level-dependent (BOLD) time series. As a result, this framework offers insights into comprehending the representation and processing of information within fMRI signals. Multiscale entropy (MSE) has been proposed as a useful measure for characterizing the entropy of neural activity across different temporal scales. This measure of temporal entropy in BOLD data is dependent on the length of the time series; thus, high-quality data with fine-grained temporal resolution and a sufficient number of time frames is needed to improve entropy precision. We apply MSE to the Midnight Scan Club, a highly sampled and well-characterized publicly available dataset, to analyze the entropy distribution of RSNs and evaluate its ability to distinguish between different functional networks. Entropy profiles are compared across temporal scales and RSNs. Our results have shown that the spatial distribution of entropy at infra-slow frequencies (0.005–0.1 Hz) reproduces known parcellations of RSNs. We found a complexity hierarchy between intrinsic and extrinsic RSNs, with intrinsic networks robustly exhibiting higher entropy than extrinsic networks. Finally, we found new evidence that the topography of entropy in the posterior cerebellum exhibits high levels of entropy comparable to that of intrinsic RSNs. © 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
cerebellum;  entropy;  fMRI;  MSE;  multiscale entropy;  networks

Document Type: Article
Publication Stage: Final
Source: Scopus

Revisiting diabetes risk of olanzapine versus aripiprazole in serious mental illness care
(2024) BJPsych Open, 10 (5), art. no. e144, . 

Agniel, D.^a , Normand, S.-L.T.^b c , Newcomer, J.W.^d e , Zelevinsky, K.^b , Poulos, J.^b , Tsuei, J.^f , Horvitz-Lennon, M.^b d

^a RAND Corporation, Santa Monica, CA, United States
^b Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^c Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, United States
^d Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^e Thriving Mind South Florida, Miami, FL, United States
^f RAND Corporation, Boston, MA, United States

Abstract
Background Exposure to second-generation antipsychotics (SGAs) carries a risk of type 2 diabetes, but questions remain about the diabetogenic effects of SGAs. Aims To assess the diabetes risk associated with two frequently used SGAs. Method This was a retrospective cohort study of adults with schizophrenia, bipolar I disorder or severe major depressive disorder (MDD) exposed during 2008-2013 to continuous monotherapy with aripiprazole or olanzapine for up to 24 months, with no pre-period exposure to other antipsychotics. Newly diagnosed type 2 diabetes was quantified with targeted minimum loss-based estimation; risk was summarised as the restricted mean survival time (RMST), the average number of diabetes-free months. Sensitivity analyses were used to evaluate potential confounding by indication. Results Aripiprazole-Treated patients had fewer diabetes-free months compared with olanzapine-Treated patients. RMSTs were longer in olanzapine-Treated patients, by 0.25 months [95% CI: 0.14, 0.36], 0.16 months [0.02, 0.31] and 0.22 months [0.01, 0.44] among patients with schizophrenia, bipolar I disorder and severe MDD, respectively. Although some sensitivity analyses suggest a risk of unobserved confounding, E-values indicate that this risk is not severe. Conclusions Using robust methods and accounting for exposure duration effects, we found a slightly higher risk of type 2 diabetes associated with aripiprazole compared with olanzapine monotherapy regardless of diagnosis. If this result was subject to unmeasured selection despite our methods, it would suggest clinician success in identifying olanzapine candidates with low diabetes risk. Confirmatory research is needed, but this insight suggests a potentially larger role for olanzapine in the treatment of well-selected patients, particularly for those with schizophrenia, given the drug’s effectiveness advantage among them. © The Author(s), 2024.

Author Keywords
Antipsychotics;  causal inference;  machine learning methods

Document Type: Article
Publication Stage: Final
Source: Scopus

Cholesterol Accumulation Promotes Photoreceptor Senescence and Retinal Degeneration
(2024) Investigative Ophthalmology & Visual Science, 65 (10), p. 29. 

Terao, R.^a b , Sohn, B.S.^a , Yamamoto, T.^a c , Lee, T.J.^a , Colasanti, J.^a , Pfeifer, C.W.^a , Lin, J.B.^a , Santeford, A.^a , Yamaguchi, S.^a , Yoshida, M.^a d , Apte, R.S.^a e f

^a John F. Hardesty, MD, Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States
^b Department of Ophthalmology, Graduate School of Medicine, University of TokyoTokyo, Japan
^c Department of Ophthalmology, Faculty of Medicine and Graduate School of Medicine, Hokkaido UniversityHokkaido, Japan
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: Dysregulated cholesterol metabolism is critical in the pathogenesis of AMD. Cellular senescence contributes to the development of numerous age-associated diseases. In this study, we investigated the link between cholesterol burden and the cellular senescence of photoreceptors. Methods: Retinas from rod-specific ATP binding cassette subfamily A member 1 (Abca1) and G member 1 (Abcg1) (Abca1/g1-rod/-rod) knockout mice fed with a high-fat diet were analyzed for the signs of cellular senescence. Real-time quantitative PCR and immunofluorescence were used to characterize the senescence profile of the retina and cholesterol-treated photoreceptor cell line (661W). Inducible elimination of p16(Ink4a)-positive senescent cells (INK-ATTAC) mice or the administration of senolytic drugs (dasatinib and quercetin: D&Q) were used to examine the impact of senolytics on AMD-like phenotypes in Abca1/g1-rod/-rod retina. Results: Increased accumulation of senescent cells as measured by markers of cellular senescence was found in Abca1/g1-rod/-rod retina. Exogenous cholesterol also induced cellular senescence in 661W cells. Selective elimination of senescent cells in Abca1/g1-rod/-rod;INK-ATTAC mice or by administration of D&Q improved visual function, lipid accumulation in retinal pigment epithelium, and Bruch’s membrane thickening. Conclusions: Cholesterol accumulation promotes cellular senescence in photoreceptors. Eliminating senescent photoreceptors improves visual function in a model of retinal neurodegeneration, and senotherapy offers a novel therapeutic avenue for further investigation.

Document Type: Article
Publication Stage: Final
Source: Scopus

Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH): Protocol for a prospective, triple-blinded, randomized controlled trial
(2024) PLoS ONE, 19 (8), art. no. e0301154, . 

Huguenard, A.^a , Tan, G.^b , Johnson, G.^a , Adamek, M.^c , Coxon, A.^a , Kummer, T.^d , Osbun, J.^a , Vellimana, A.^a , Limbrick, D., Jr^a , Zipfel, G.^a , Brunner, P.^a b , Leuthardt, E.^a b c

^a Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
^b Department Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background Inflammation has been implicated in driving the morbidity associated with subarachnoid hemorrhage (SAH). Despite understanding the important role of inflammation in morbidity following SAH, there is no current effective way to modulate this deleterious response. There is a critical need for a novel approach to immunomodulation that can be safely, rapidly, and effectively deployed in SAH patients. Vagus nerve stimulation (VNS) provides a non-pharmacologic approach to immunomodulation, with prior studies demonstrating VNS can reduce systemic inflammatory markers, and VNS has had early success treating inflammatory conditions such as arthritis, sepsis, and inflammatory bowel diseases. The aim of the Non-invasive Auricular Vagus nerve stimulation for Subarachnoid Hemorrhage (NAVSaH) trial is to translate the use of non-invasive transcutaneous auricular VNS (taVNS) to spontaneous SAH, with our central hypothesis being that implementing taVNS in the acute period following spontaneous SAH attenuates the expected inflammatory response to hemorrhage and curtails morbidity associated with inflammatory-mediated clinical endpoints. Materials and methods The overall objectives for the NAHSaH trial are to 1) Define the impact that taVNS has on SAH-induced inflammatory markers in the plasma and cerebrospinal fluid (CSF), 2) Determine whether taVNS following SAH reduces radiographic vasospasm, and 3) Determine whether taVNS following SAH reduces chronic hydrocephalus. Following presentation to a single enrollment site, enrolled SAH patients are randomly assigned twice daily treatment with either taVNS or sham stimulation for the duration of their intensive care unit stay. Blood and CSF are drawn before initiation of treatment sessions, and then every three days during a patient’s hospital stay. Primary endpoints include change in the inflammatory cytokine TNF-α in plasma and cerebrospinal fluid between day 1 and day 13, rate of radiographic vasospasm, and rate of requirement for long-term CSF diversion via a ventricular shunt. Secondary outcomes include exploratory analyses of a panel of additional cytokines, number and type of hospitalized acquired infections, duration of external ventricular drain in days, interventions required for vasospasm, continuous physiology data before, during, and after treatment sessions, hospital length of stay, intensive care unit length of stay, and modified Rankin Scale score (mRS) at admission, discharge, and each at follow-up appointment for up to two years following SAH. Discussion Inflammation plays a central role in morbidity following SAH. This NAVSaH trial is innovative because it diverges from the pharmacologic status quo by harnessing a novel non-invasive neuromodulatory approach and its known anti-inflammatory effects to alter the pathophysiology of SAH. The investigation of a new, effective, and rapidly deployable intervention in SAH offers a new route to improve outcomes following SAH. © 2024 Huguenard et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus

The Influence of Personality Traits on Driving Behaviors in Preclinical Alzheimer Disease
(2024) Alzheimer Disease and Associated Disorders, 38 (3), pp. 241-248. 

Aschenbrenner, A.J.^a , Carr, D.B.^a b , Benzinger, T.L.S.^c , Morris, J.C.^a , Babulal, G.M.^a d e f

^a Departments of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Departments of Medicine and Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Departments of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Institute of Public Health, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, DC, United States
^f Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa

Abstract
Introduction: Alzheimer disease (AD) has a long preclinical phase in which AD pathology is accumulating without detectable clinical symptoms. It is critical to identify participants in this preclinical phase as early as possible since treatment plans may be more effective in this stage. Monitoring for changes in driving behavior, as measured with GPS sensors, has been explored as a low-burden, easy-To-Administer method for detecting AD risk. However, driving is a complex, multifaceted process that is likely influenced by other factors, including personality traits, that may change in preclinical AD. Methods: We examine the moderating influence of neuroticism and conscientiousness on longitudinal changes in driving behavior in a sample of 203 clinically normal older adults who are at varying risk of developing AD. Results: Neuroticism moderated rates of change in the frequency of speeding as well as the number of trips taken at night. Conscientiousness moderated rates of change in typical driving space. Conclusions: Personality traits change in early AD and also influence driving behaviors. Studies that seek to utilize naturalistic driving behavior to establish AD risk need to accommodate interpersonal differences, of which personality traits are one of many possible factors. Future studies should explicitly establish how much benefit is provided by including personality traits in predictive models of AD progression. © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
Alzheimer disease;  naturalistic driving;  personality

Document Type: Article
Publication Stage: Final
Source: Scopus

Social Environment and Neurobehavioral Outcomes 1 Year after Severe Pediatric TBI in the Intensive Care Unit
(2024) Journal of Head Trauma Rehabilitation, .

 Miley, A.E.^a , Patronick, J.^b e , Zhang, N.^c f , Bode, R.L.^g , Fabio, A.^h , Treble-Barna, A.ⁱ , Chima, R.S.^d f , Adlam, A.-L.R.^j , Bell, M.J.^k , Wisniewski, S.R.^h , Beers, S.R.^l , Wade, S.L.^b e f , Kurowski, B.G.^b f g , Adlam, A.^m , Agbeko, R.ⁿ , Au, A.^o , Beers, S.^p , Bell, M.J.^q , Butt, W.^r , Chima, R.S.^s , Clark, R.^p , Deep, A.^t , Edwards, R.^u , Fabio, A.^p , Ferrazzano, P.^v , Figaji, A.^w , Kirkwood, M.^x , Kong, M.^y , LaRovere, K.^z , MacIntosh, I.^aa , Mahoney, S.^ab , Martin, L.J.^s , McNally, K.^ac , Miles, D.^ad , Morris, K.^ae , O’Brien, N.^ac , Pilipenko, V.^s , Ramirez, J.B.^af , Robertson, C.^ag , Sarnaik, A.^ah , Schober, M.^ai , Soto, J.P.^aj ak , Telling, A.^m , Thangarajah, H.^al , Thomas, N.J.^am , Treble-Barna, A.^p , Walson, K.^an , West, A.N.^ao , Willyerd, A.^ap , Wisniewski, S.R.^p , Zimmerman, J.^aq , TBI Genetics and Environment Study Team^ar

^a Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^b Division of Pediatric Rehabilitation Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^c Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^d Division of Critical Care Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^e Department of Psychology, University of Cincinnati, Cincinnati, OH, United States
^f Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
^g Department of Neurology and Rehabilitation Medicine, University of Cincinnati, College of Medicine, Cincinnati, OH, United States
^h Department of Epidemiology, Epidemiology Data Center, University of Pittsburgh, Pittsburgh, PA, United States
ⁱ Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States
^j School of Psychology, Faculty of Health and Life Sciences, University of Exeter, Exeter, United Kingdom
^k Department of Critical Care Medicine, Children’s National Hospital, Washington, DC, United States
^l Department of Psychiatry and Neurological Surgery, University of Pittsburgh, School of Medicine, Pittsburgh, PA, United States
^m University of Exeter, Exeter, United Kingdom
ⁿ Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom
^o Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, PA, United States
^p University of Pittsburgh, Pittsburgh, PA, United States
^q Children’s National Hospital, Washington, DC, United States
^r Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia
^s Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^t King’s College Hospital, London, United Kingdom
^u Bristol Royal Children’s Hospital for Children, Bristol, United Kingdom
^v University of Wisconsin, Madison, WI, United States
^w University of Cape Town, Rondebosch, South Africa
^x Children’s Hospital Colorado, University of Colorado, School of Medicine, Aurora, CO, United States
^y Children’s of Alabama, University of Alabama at Birmingham, Birmingham, AL, United States
^z Boston Children’s Hospital, Boston, MA, United States
^aa Southampton Children’s Hospital, Southampton General Hospital, Southampton, United Kingdom
^ab Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom
^ac Nationwide Children’s Hospital, Columbus, OH, United States
^ad Children’s Medical Center of Dallas, Dallas, TX, United States
^ae Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom
^af Hospital Vall d’Hebron, Barcelona, Spain
^ag John Hopkins University, Baltimore, MD, United States
^ah Children’s Hospital of Michigan, Detroit, MI, United States
^ai University of Utah Health, Salt Lake City, UT, United States
^aj Washington University, St Louis, MO, United States
^ak Children’s Hospital of Los Angeles, Los Angeles, CA, United States
^al Rady Children’s Hospital, San Diego, CA, United States
^am Penn State Hershey Children’s Hospital, Hershey, PA, United States
^an Children’s Healthcare of Atlanta, Atlanta, GA, United States
^ao University of Tennessee Health Science Center, Memphis, TN, United States
^ap Phoenix Children’s Hospital, Phoenix, AZ, United States
^aq Seattle Children’s Hospital, University of Washington, School of Medicine, Seattle, WA, United States

Abstract
Objective: To examine the association of home and neighborhood environment with neurobehavioral outcomes after severe pediatric traumatic brain injury (TBI). Setting: Domestic and international children’s medical centers. Participants: Participants enrolled in the study were 18 years or younger at the time of their severe TBI (Glasgow Coma Scale [GCS] ≤ 8), admitted to the intensive care unit, and underwent placement of an intracranial pressure (ICP) monitor. Exclusionary criteria included less severe injury (GCS > 8), pregnancy, and/or ICP monitor placement occurred at a non-participating hospital. Design: A multicenter, observational cohort study. Main Measures: Outcomes assessed at 12 months post-injury included measures of global functioning, intellectual ability, caregiver-report measures of family functioning, executive functioning behaviors, behavior problems, and health-related quality of life. We examined mortality risk (assessed acutely after injury), family functioning (assessed at 12 months post-injury) and parenting practices, social environment, and neighborhood stressors (all assessed > 12 months post-injury), as correlates and moderators of the 12-month post-injury outcomes. Results: Home and neighborhood factors were associated with neurobehavioral outcomes (ie, intellectual ability, executive functioning, behavioral adjustment, and health-related quality of life) but not with global functioning outcomes. A negative association between a more vulnerable home and neighborhood environment and neurobehavioral outcomes was more consistent in older children compared with younger children, based on age of injury. The influence of mortality risk on neurobehavioral outcomes was variable. Conclusion: Parenting practices and quality of social and neighborhood environment are associated with neurobehavioral outcomes 12 months after severe pediatric TBI. More research is needed to better understand the relationship between home/neighborhood stressors and TBI recovery to develop and implement strategies for patients and families to optimize outcomes. Future intervention development should focus on addressing parenting practices and social environment in a developmentally sensitive way for children who have sustained a severe TBI. Copyright © 2024 Wolters Kluwer Health, Inc.

Author Keywords
home environment;  neighborhood characteristics;  neurobehavioral outcomes;  pediatrics;  post-injury;  severe;  traumatic brain injuries

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

Alzheimer’s Disease-Related Analytes Amyloid-β and Tau in Perilymph: Correlation With Patient Age and Cognitive Score
(2024) Otolaryngology – Head and Neck Surgery (United States), .

Walia, A.^a , Shew, M.A.^a , Durakovic, N.^a , Herzog, J.A.^a , Cirrito, J.R.^b , Yuede, C.M.^b , Wick, C.C.^a , Manis, M.^b , Holtzman, D.M.^b c , Buchman, C.A.^a , Rutherford, M.A.^a

 ^a Department of Otolaryngology–Head and Neck Surgery, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^c Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: To describe the collection methods for perilymph fluid biopsy during cochlear implantation, detect levels of amyloid β 42 and 40 (Aβ42 and Aβ40), and total tau (tTau) analytes with a high-precision assay, to compare these levels with patient age and Montreal Cognitive Assessment (MoCA) scores, and explore potential mechanisms and relationships with otic pathology. Study Design: Prospective study. Setting: Tertiary referral center. Methods: Perilymph was collected from 25 patients using polyimide tubing to avoid amyloid adherence to glass, and analyzed with a single-molecule array advanced digital enzyme-linked immunosorbent assay platform for Aβ40, Aβ42, and tTau. Cognition was assessed by MoCA. Results: Perilymph volumes ranged from ∼1 to 13 µL, with analyte concentrations spanning 2.67 to 1088.26 pg/mL. All samples had detectable levels of tTau, Aβ40, and Aβ42, with a significant positive correlation between Aβ42 and Aβ40 levels. Levels of Aβ42, Aβ40, and tTau were positively correlated with age, while MoCA scores were inversely correlated with age. tTau and Aβ42/Aβ40-ratios were significantly correlated with MoCA scores. Conclusion: Alzheimer’s disease-associated peptides Aβ42, Aβ40, and tau analytes are detectable in human perilymph at levels approximately 10-fold lower than those found in cerebrospinal fluid (CSF). These species increase with age and correlate with cognitive impairment indicators, suggesting their potential utility as biomarkers for cognitive impairment in patients undergoing cochlear implantation. Future research should investigate the origin of these analytes in the perilymph and their potential links to inner ear pathologies and hearing loss, as well as their relationships to CSF and plasma levels in individuals. © 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.

Author Keywords
Alzheimer’s disease;  amyloid;  Aβ40;  Aβ42;  cochlear implantation;  cognition;  MoCA;  perilymph;  tau

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

Neural populations in the language network differ in the size of their temporal receptive windows
(2024) Nature Human Behaviour, . 

Regev, T.I.^a b , Casto, C.^a b c d , Hosseini, E.A.^a b , Adamek, M.^e f , Ritaccio, A.L.^g , Willie, J.T.^e f , Brunner, P.^e f h , Fedorenko, E.^a b c

^a Brain and Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, MA, United States
^b McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, MA, United States
^c Program in Speech and Hearing Bioscience and Technology (SHBT), Harvard University, Boston, MA, United States
^d Kempner Institute for the Study of Natural and Artificial Intelligence, Harvard University, Allston, MA, United States
^e National Center for Adaptive Neurotechnologies, Albany, NY, United States
^f Department of Neurosurgery, Washington University School of Medicine, St Louis, MO, United States
^g Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^h Department of Neurology, Albany Medical College, Albany, NY, United States

Abstract
Despite long knowing what brain areas support language comprehension, our knowledge of the neural computations that these frontal and temporal regions implement remains limited. One important unresolved question concerns functional differences among the neural populations that comprise the language network. Here we leveraged the high spatiotemporal resolution of human intracranial recordings (n = 22) to examine responses to sentences and linguistically degraded conditions. We discovered three response profiles that differ in their temporal dynamics. These profiles appear to reflect different temporal receptive windows, with average windows of about 1, 4 and 6 words, respectively. Neural populations exhibiting these profiles are interleaved across the language network, which suggests that all language regions have direct access to distinct, multiscale representations of linguistic input—a property that may be critical for the efficiency and robustness of language processing. © The Author(s), under exclusive licence to Springer Nature Limited 2024.

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

Validating an Evoked Potential Platform for Electrocochleography During Cochlear Implantation
(2024) Laryngoscope, . 

Varghese, J.J., Shew, M.A., Walia, A., Lefler, S.M., Durakovic, N., Wick, C.C., Ortmann, A.J., Herzog, J.A., Buchman, C.A.

Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: To validate electrocochleography (ECochG) between an auditory evoked potential (AEP) machine and an established cochlear implant (CI) manufacturer ECochG system. Methods: Intraoperative validation study at a tertiary referral center. Patients included adults and children undergoing cochlear implantation. Intraoperative ECochG was measured with both the Intelligent Hearing Systems (IHS) Duet AEP machine and Cochlear Corporation (CC) ECochG platform. Recording electrodes captured extracochlear measurements through a standard facial recess. Tone-bursts were presented from 250 Hz to 2 kHz (~110 dB SPL). A fast Fourier transform (FFT) of ECochG waveforms at key frequencies was summed into a total response (ECochG-TR). Pearson’s correlation was utilized to evaluate the relationship between IHS-ECochG-TR and CC-ECochG-TR after confirming normality. Results: Thirty patients were enrolled with an average age of 67 years (SD 18.8). In the ear that was implanted, mean preoperative pure-tone average (PTA; 0.5, 1, 2, and 4 kHz) was 87.4 dB HL (SD 19.3) and mean preoperative word-recognition scores (WRS) was 17.0% correct (SD 19.1). There was strong correlation (r = 0.905, 95% confidence interval: 0.809 to 0.954) between IHS-ECochG-TR (median 2.30 μV, range 0.1–148.26) and CC-ECochG-TR (median 3.00 μV, range 0.1–239.63). Four patients underwent transtympanic ECochG with the IHS system for feasibility evaluation and achieved similar responses. Conclusion: Extracochlear ECochG has been predictive of CI speech perception performance. The IHS duet system is a valid measure of extracochlear ECochG for the CI population. Future work will utilize this system for measuring transtympanic ECochG to improve preoperative estimation of CI performance. Level of Evidence: 3 Laryngoscope, 2024. © 2024 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
cochlear implantation;  cochlear implants;  ECochG;  extracochlear electrocochleography;  intraoperative electrocochleography

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

The association between maternal sleep and circadian rhythms during pregnancy and infant sleep and socioemotional outcomes
(2024) European Child and Adolescent Psychiatry, . 

Hoyniak, C.P.^a , Donohue, M.R.^a , Luby, J.L.^a , Barch, D.M.^a b c d , Zhao, P.^e , Smyser, C.D.^d f g , Warner, B.^g , Rogers, C.E.^a g , Herzog, E.D.^h , England, S.K.^e

^a Department of Psychiatry, Washington University School of Medicine in St. Louis, 4444 Forest Park Ave, Suite 2100, St. Louis, MO 63108, United States
^b The Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e Department of Obstetrics and Gynecology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^f Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^h Department of Biology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Studies have established that maternal sleep and circadian rhythm disturbances during pregnancy are associated with poor prenatal and perinatal outcomes for mothers and offspring. However, little work has explored its effects on infant sleep or socioemotional outcomes. The current study examined the relationship between maternal sleep and circadian rhythm disturbances during pregnancy and infant sleep and socioemotional outcomes in a diverse sample of N = 193 mothers and their infants (51% White; 52% Female; Mage = 11.95 months). Maternal sleep and circadian rhythms during pregnancy were assessed using self-reports and actigraphy. Mothers reported on infants’ sleep and socioemotional outcomes when infants were one year old. When controlling for infant sex, age, gestational age at birth, family income-to-needs ratios, and maternal depression, mothers who reported more sleep problems during pregnancy had infants with more sleep disturbances when they were one year old. Moreover, mothers who had later sleep timing (i.e., went to bed and woke up later, measured via actigraphy) during pregnancy had infants with more dysregulation (e.g., increased feeding difficulties, sensory sensitivities) and externalizing problems, and mothers with increased intra-daily variability in rest-activity rhythms (as measured via actigraphy) had infants with more externalizing problems. Findings suggest that maternal sleep and circadian rhythm disturbances during pregnancy may be a risk factor for infant sleep problems and socioemotional difficulties. © Springer-Verlag GmbH Germany, part of Springer Nature 2024.

Author Keywords
Infant sleep disturbance;  Infant socioemotional outcomes;  Maternal circadian rhythms;  Maternal sleep;  Pregnancy

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

Multi-peptide characterization of plasma neurofilament light chain in preclinical and mild Alzheimer’s disease
(2024) Brain Communications, 6 (4), art. no. fcae247, . 

Coulton, J.B.^a b , He, Y.^a b , Barthélemy, N.R.^a b , Jiang, H.^a c d , Holtzman, D.M.^a c d , Bateman, R.J.^a b c d

^a Department of Neurology, Washington University, School of Medicine, St. Louis, MO 63110, United States
^b Tracy Family SILQ Center, Washington University, School of Medicine, St. Louis, MO 63110, United States
^c Knight Alzheimer’s Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63108, United States
^d Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Although neurofilament light chain is a well-known marker of neuronal damage, its characterization at the proteoform level is underdeveloped. Here, we describe a new method to profile and quantify neurofilament light chain in plasma at the peptide level, using three in-house monoclonal antibodies targeting distinct protein domains and nano-liquid chromatography coupled to high-resolution tandem mass spectrometry. This study profiled and compared plasma neurofilament light chain to CSF in 102 older individuals (73.9 ± 6.3 years old), 37 of which had a clinical dementia rating greater than 0. We observed elevated neurofilament light chain in preclinical Alzheimer’s disease plasma for two measures (NfL101 and NfL324) and CSF for seven measures (NfL92, NfL101, NfL117, NfL137, NfL148, NfL165 and NfL530). We found five plasma peptides (NfL92, NfL101, NfL117, NfL324 and NfL530) significantly associated with age and two (NfL148 and NfL324) with body mass index. © The Author(s) 2024.

Author Keywords
biomarkers;  immunoprecipitation;  mass spectrometry;  neurodegeneration;  neurofilament

Document Type: Article
Publication Stage: Final
Source: Scopus

Recurrent p.H119Y variant in MAP2K1 expands the phenotypic spectrum of MAP2K1-related RASopathy
(2024) American Journal of Medical Genetics, Part A, . 

Grange, D.K.^a , Wegner, D.J.^a , Wambach, J.A.^a , Sisco, K.A.^a , Stone, S.I.^a , Sheehan, J.H.^b , Ramsey, K.M.^c , Narayanan, V.^c , Rauen, K.A.^d , Cole, F.S.^a , the Undiagnosed Diseases Network^e

^a Edward Mallinckrodt Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^c Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ, United States
^d Department of Pediatrics, University of California Davis, Sacramento, CA, United States

Abstract
We report three unrelated individuals with atypical clinical findings for cardio-facio-cutaneous (CFC) syndrome, all of whom have the same novel, heterozygous de novo p.H119Y (c.355 C>T) transition variant in MAP2K1, identified by exome sequencing. MAP2K1 encodes MEK1, dual specificity mitogen-activated protein kinase kinase 1, and is one of four genes in the canonical RAS/MAPK signal transduction pathway associated with CFC syndrome. The p.H119Y variant is a non-conservative amino acid substitution that is predicted to impact the tertiary protein structure, and it occurs at a position in the protein kinase domain of MAP2K1 that is highly conserved across species. The clinical findings in these three individuals include facial features that are nonclassical for CFC syndrome, extremely poor weight gain, absence of congenital cardiac defects or cardiomyopathy, normal cognition or only mild intellectual disabilities, normal hair, mild skin abnormalities, and consistent behavioral features of anxiety, photophobia, and sensory hypersensitivities. These individuals expand the phenotypic spectrum of MAP2K1-related RASopathy. © 2024 Wiley Periodicals LLC.

Author Keywords
cardio-facio-cutaneous (CFC) syndrome;  MAP2K1;  RASopathy

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

Ultra-Widefield and Early Treatment Diabetic Retinopathy Study 7-Field Grading of Diabetic Retinopathy
(2024) JAMA Ophthalmology, . Cited 1 time.

Aiello, L.P.^a b , Blodi, B.^c , Gao, X.^d , Sun, J.K.^a b , Gubitosi-Klug, R.A.^e , White, N.H.^f , Hainsworth, D.^g , Lorenzi, G.M.^h , Bebu, I.ⁱ , Adkins, T.^j , Agarwal, A.^j , Aiello, L.P.^j , Albers, J.W.^j , Arends, V.^j , Arrigg, P.^j , Averkiou, X.^j , Avery, R.B.^j , Azevedo, R.^j , Backlund, J.-Y.^j , Bakshi, N.^j , Bancroft, A.P.^j , Bantle, A.^j , Bantle, J.^j , Barkmeier, A.^j , Barnie, A.^j , ABarr, M.^j , Bartholomew, R.^j , Beaser, R.^j , Bebu, I.^j , Bergenstal, R.^j , Bhan, A.^j , Blodi, B.^j , Bott, M.^j , Bourne, P.A.^j , Braffett, B.H.^j , Brent, M.^j , Brown, A.^j , Brucker, A.J.^j , Burge, M.R.^j , Bylsma, J.^j , Campbell, C.^j , Carlson, A.^j , Cavallerano, J.^j , Cavicchi, R.^j , Chan, R.^j , Chapin, J.E.^j , Chu, K.^j , Coonrod, B.A.^j , Costacou, T.^j , Dagogo-Jack, S.^j , Danis, R.^j , Das, A.^j , Devenyi, R.^j , Diminick, L.^j , Driscoll, M.^j , Dunnigan, S.^j , Edwards, P.^j , El Muayed, M.^j , El ghormli, L.^j , Farrell, K.^j , Feldman, E.^j , Fernandes, J.^j , Ganda, O.^j , Gao, X.^j , Gatcomb, P.M.^j , Gill, M.^j , Goldbaum, M.^j , Golden, E.^j , Greanoff, G.^j , Gregory, N.S.^j , Gubitosi-Klug, R.A.^j , Hainsworth, D.^j , Hamdy, O.^j , Hanna, R.^j , Hartmuller, M.^j , He, Y.-G.^j , Heier, J.^j , Hensley, S.^j , Herman, W.^j , Hermayer, K.L.^j , Hirsch, I.^j , Hitt, S.^j , Ho, S.^j , Hoffman, E.^j , Hu, J.^j , Huddleston, S.^j , Jacobson, A.M.^j , Jarvis, A.^j , Johnson, M.L.^j , Johnsonbaugh, S.^j , Jones, J.K.^j , Jordan, L.F.^j , Joseph, A.^j , Karanchi, H.^j , Karger, A.^j , Keasler, L.^j , Kenny, D.^j , Ketai, L.H.^j , Kiss, S.^j , Klumpp, K.^j , Kolterman, O.^j , Koozekanani, D.^j , Koushan, K.^j , Kruger, D.F.^j , Lachin, J.^j , Larkin, M.^j , Lawrence, J.^j , Lee, K.^j , Lee, P.G.^j , Leong, A.^j , Leschek, E.^j , Li, Y.^j , Lin, M.-H.^j , Lorenz, G.^j , Lovell, C.K.^j , Lyon, A.T.^j , Lyons, T.J.^j , Malone, J.I.^j , Mandelcorn, M.^j , Marksbury, T.^j , Martin, C.^j , May, M.^j , Mayer, L.^j , McDonald, C.^j , Mendelson, E.^j , Miller, D.^j , Miller, R.^j , Mirza, R.G.^j , Montezuma, S.R.^j , Morrison, A.^j , Mudaliar, S.^j , Mukhashen, S.^j , Murtha, T.J.^j , Nathan, D.M.^j , Novak, M.^j , Nutaitis, M.J.^j , Olegario, D.^j , de Koo, L.O.^j , Orchard, T.^j , Orlin, A.^j , O’Brian, J.^j , Pavan, P.R.^j , Pendegast, S.^j , Perdikaris, F.^j , Perkins, B.A.^j , Pop-Busui, R.^j , Raskin, P.^j , Rath, S.^j , Rhodes, M.^j , Rodriguez, H.^j , Rubin, M.^j , Ryan, C.^j , Saporito, D.^j , Saporito, M.^j , Schade, D.S.^j , Schlossman, D.K.^j , Schutta, M.H.^j , Seegmiller, J.^j , Shah, R.^j , Shao, B.^j , Sharuk, G.S.^j , Sheidow, T.^j , Sherr, J.^j , Silva, P.A.^j , Silver, P.^j , Singerman, L.J.^j , Sivitz, W.^j , Soliman, E.Z.^j , Spillers, L.^j , Steffes, M.^j , Stockman, M.E.^j , Stoessel, K.^j , Sun, J.^j , Tamborlane, W.^j , Taylor, T.^j , Terry, J.^j , Thangthaeng, N.^j , Thomas, L.A.^j , Toledo, F.^j , Trapani, V.^j , Ufret-Vincenty, R.L.^j , Vella, A.^j , Vittetoe, B.^j , Wabers, H.^j , Wallia, A.^j , Weimann, E.^j , Weiss, D.^j , White, N.^j , Wilson, R.^j , Wood, J.^j , Zegarra, H.^j , Zhang, Z.-M.^j , Zipse, A.^j , de Boer, I.H.^j , the DCCT/EDIC Research Group^j

^a Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
^b Beetham Eye Institute, Joslin Diabetes Center, Boston, MA, United States
^c Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, United States
^d The Biostatistics Center, The George Washington University, Washington, DC, United States
^e Rainbow Babies and Children’s Hospital, Cleveland, OH, United States
^f Washington University in St Louis, St Louis, MO, United States
^g Department of Ophthalmology, University of Missouri, Columbia, United States
^h Department of Medicine, Division of Metabolism, Endocrinology and Diabetes, University of California, San Diego, United States
ⁱ Department of Biostatistics and Bioinformatics, Biostatistics Center, The George Washington University, Washington, DC, United States

Abstract
IMPORTANCE High concordance in diabetic retinopathy (DR) outcomes between 7-field (7F) and ultra-widefield (UWF) images would allow for combining longitudinal assessments based on the 2 modalities both in clinical studies and clinical care. OBJECTIVE To compare 7F and UWF imaging with regard to DR severity and the associations of DR severity with risk factors, such as hemoglobin A1c, age, diabetes duration, and sex. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study describes the outcomes of the randomized clinical Diabetes Control and Complications Trial (DCCT) and its subsequent observational study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Of the 1441 participants with type 1 diabetes in the DCCT, 1375 were enrolled in the EDIC study. Of the 1171 participants who were active between March 2019 and December 2021, 200° UWF color imaging and 7F fundus photographs were obtained for 785 participants once at the same visit. Central graders assessed 7F-UWF with a 7F template masking the retinal periphery and the full UWF image (UWF-global). Data were analyzed from January 2022 to March 2023. EXPOSURES Hemoglobin A1c was assessed quarterly during the DCCT and annually during the EDIC study using high-performance liquid chromatography. MAIN OUTCOMES AND MEASURES Retinopathywas determined independently for all imaging as mild, moderate, or severe nonproliferative DR (SNPDR) using the Early Treatment Diabetic Retinopathy Study (ETDRS) grading scale for the 7F images and the global ETDRS grading scale for the UWF images. Panretinal and focal photocoagulation were self-reported or based on scarring location and pattern observed during grading. Proliferative DR (PDR) was defined by observed neovascularization or evidence of panretinal photocoagulation. RESULTS Among the 785 participants included in this study, 420 (53%) were male and 365 (47%) were female. The mean (SD) age was 61 (7) years. DR grading between UWF-7F and 7F imaging was correlated for all outcomes, including for severe outcomes, such as SNPDR (κ, 0.73; concordance, 96%), PDR (κ, 0.74; concordance, 97%), scatter photocoagulation (κ, 0.97; concordance, 99%), and focal photocoagulation (κ, 0.71; concordance, 98%). Most DR severity scores were within 1 step (1410 of 1529 [92%]), and 3%(51 of 1529) were more than 2 steps apart (κ, 0.45; 95%CI, 0.42-0.49; weighted κ, 0.63; 95%CI, 0.60-0.67) on the ETDRS severity scale. DR severity assessed within the UWF-global area was higher compared to 7F (median [IQR] UWF-global score, 3 [2-3] vs median 7F level score, 2.0 [1-3]; P < .001), although the 2 modalities were correlated (1225 of 1508 [81%] 1-step agreement; weighted κ, 0.41). CONCLUSIONS AND RELEVANCE Standard ETDRS 7F and UWF evaluations of DR were comparable for ETDRS severity levels as previously reported by Diabetic Retinopathy Clinical Research Retina Network reports. In addition, these evaluations of DR were comparable for DCCT/EDIT study outcomes and major study conclusions, suggesting that use of UWF imaging is not likely to introduce relevant measurement biases in future longitudinal studies. © 2024 American Medical Association. All rights reserved.

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

Combination of or Transition between Deep Brain Stimulation and Responsive Neurostimulation for the Treatment of Drug-Resistant Epilepsy
(2024) Stereotactic and Functional Neurosurgery, . 

Yang, J.C.^a b , Skelton, H.^b , Isbaine, F.^b , Bullinger, K.L.^c , Alwaki, A.^c , Cabaniss, B.T.^c , Willie, J.T.^d , Gross, R.E.^b c

^a Department of Neurological Surgery, The Ohio State University College of Medicine, Columbus, OH, United States
^b Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States
^c Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^d Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Neuromodulation is an important treatment modality for patients with drug-resistant epilepsy who are not candidates for resective or ablative procedures. However, randomized controlled trials and real-world studies reveal that a subset of patients will experience minimal reduction or even an increase in seizure frequency after neuromodulation. We describe our experience with patients who undergo a second intracranial neuromodulation procedure after unsatisfactory initial response to intracranial neuromodulation. Methods: We performed a retrospective chart review to identify all patients who had undergone deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) or responsive neurostimulation (RNS), followed by additional intracranial neuromodulatory procedures, with at least 12 months of follow-up. Demographic and clinical data, including seizure frequencies, were collected. Results: All patients had temporal lobe epilepsy. Six patients were treated with concurrent ANT DBS and temporal lobe RNS, and 3 patients transitioned between neuromodulation systems. Of the patients treated concurrently with ANT DBS and temporal lobe RNS, 5 of the 6 patients experienced additional reduction in seizure frequency after adding a second neuromodulation system. Of the patients who switched between neuromodulation modalities, all patients experienced further reduction in seizure frequency. Conclusions: For patients who do not experience adequate benefit from initial therapy with ANT DBS or temporal lobe RNS, the addition of a neuromodulation system or switching to a different form of neuromodulation may allow for additional reduction in seizure frequency. Larger studies will need to be performed to understand whether the use of multiple systems concurrently leads to improved clinical results in patients who are initially treatment resistant to neuromodulation. © 2024 S. Karger AG, Basel.

Author Keywords
Deep brain stimulation;  Epilepsy;  Neuromodulation;  Responsive neurostimulation

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

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer’s disease
(2024) Alzheimer’s and Dementia, . 

Norambuena, A.^a , Sagar, V.K.^a b , Wang, Z.^c , Raut, P.^a , Feng, Z.^c , Wallrabe, H.^a b , Pardo, E.^a , Kim, T.^a , Alam, S.R.^a b , Hu, S.^c , Periasamy, A.^a b , Bloom, G.S.^a d e

^a Department of Biology, University of Virginia, Charlottesville, VA, United States
^b W.M. Keck Center for Cellular Imaging, University of Virginia, Charlottesville, VA, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Cell Biology, University of Virginia, Charlottesville, VA, United States
^e Department of Neuroscience, University of Virginia, Charlottesville, VA, United States

Abstract
INTRODUCTION: Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer’s disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. METHODS: Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. RESULTS: NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. DISCUSSION: NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Highlights: Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer’s disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
amino acids;  brain metabolism;  insulin;  mammalian target of rapamycin;  tau

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

On the relationship between word reading ability and spelling ability
(2024) Reading and Writing, . 

Treiman, R.^a , Hulslander, J.^b , Willcutt, E.G.^b , Pennington, B.F.^c , Olson, R.K.^b

^a Washington University in St. Louis, 1125-0249-02, 1 Brookings Dr, St. Louis, MO 63130, United States
^b University of Colorado, Boulder, United States
^c University of Denver, Denver, United States

Abstract
The goal of the present study was to test theories about the extent to which individual differences in word reading align with those in spelling and the extent to which other cognitive and linguistic skills play different roles in word reading and spelling. Using data from 1,116 children ranging from 8 to 17 years, we modeled word reading and spelling as latent traits with two measures of each skill to reduce measurement error. The models also included five skills that have been theorized to relate differentially to reading and spelling: phonemic awareness, working memory, rapid automatized naming, arithmetic, and vocabulary. The latent-trait correlation for reading and spelling was very high, 0.96, although significantly less than perfect. Vocabulary correlated more strongly with reading (0.64) than spelling (0.56), but the correlations of the other skills with reading and spelling did not differ significantly. Breaking down the sample by age, we found a significantly higher latent-trait correlation between reading and spelling in the younger half (r =.98) than in the older half (r =.94). This difference may reflect the fact that the words on reading and spelling tests are more different from one another at older ages. Our results suggest that word reading and spelling are one and the same, almost, but that spoken vocabulary knowledge is more closely related to reading than to spelling. © The Author(s) 2024.

Author Keywords
Individual differences;  Spelling;  Vocabulary;  Word reading

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