White matter microstructure in school-age children with down syndrome
(2025) Developmental Cognitive Neuroscience, 73, art. no. 101540, .
Garic, D.a b , Al-Ali, K.W.c , Nasir, A.b , Azrak, O.b , Grzadzinski, R.L.a b , McKinstry, R.C.d , Wolff, J.J.e , Lee, C.M.f , Pandey, J.g , Schultz, R.T.g , St. John, T.h i , Dager, S.R.j , Estes, A.M.h i , Gerig, G.k , Zwaigenbaum, L.l , Marrus, N.m , Botteron, K.N.m , Piven, J.a b , Styner, M.b , Hazlett, H.C.a b , Shen, M.D.a b
a Carolina Institute for Developmental Disabilities, 101 Renee Lynne Ct, Carrboro, NC 27510, United States
b Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, 101 Manning Dr #1, Chapel HillNC 27514, United States
c Department of Psychiatry, Indiana University School of Medicine, N Senate Ave, Indianapolis, IN 46202, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kings Highway Blvd, St. Louis, MO 63110, United States
e Department of Educational Psychology, University of Minnesota Twin Cities College of Education and Human Development, 250 Education Sciences Bldg, 56 E River Rd, Minneapolis, MN 55455, United States
f Division of Clinical Behavioral Neuroscience, Department of Pediatrics, University of Minnesota Twin Cities Medical School, 2025 E. River Parkway 7962A, Minneapolis, MN 55414, United States
g Center for Autism Research, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, 2716 South St #5, Philadelphia, PA 19104, United States
h University of Washington Autism Center, University of Washington, 1701 NE Columbia Rd, Seattle, WA 98195, United States
i Department of Speech and Hearing Science, University of Washington, 1417 NE 42nd St, Seattle, WA 98105, United States
j Department of Radiology, University of Washington Medical Center, 1959 NE Pacific St, Seattle, WA 98195, United States
k Department of Computer Science and Engineering, New York University, 251 Mercer Street, Room 305, New York, NY 10012, United States
l Department of Pediatrics, University of Alberta, 11405-87 Avenue, Edmonton, AB, Canada
m Department of Psychiatry, Washington University School of Medicine in St. Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
Abstract
Down syndrome (DS) is the most common genetic cause of intellectual disability, but our understanding of white matter microstructure in children with DS remains limited. Previous studies have reported reductions in white matter integrity, but nearly all studies to date have been conducted in adults or relied solely on diffusion tensor imaging (DTI), which lacks the ability to disentangle underlying properties of white matter organization. This study examined white matter microstructural differences in 7- to 12-year-old children with DS (n = 23), autism (n = 27), and typical development (n = 50) using DTI as well as High Angular Resolution Diffusion Imaging, and Neurite Orientation and Dispersion Imaging. There was a spatially specific pattern of results that showed a dissociation between intra- and inter-hemispheric pathways. Intra-hemispheric pathways (e.g., inferior fronto-occipital fasciculus, superior longitudinal fasciculus) exhibited reduced organization and structural integrity. Inter-hemispheric pathways (e.g., corpus callosum projections) and motor pathways (e.g., corticospinal tract) showed denser neurite packing and lower neurite dispersion. The current findings provide early insight into white matter development in school-aged children with DS and have the potential to further elucidate microstructural differences and inform more targeted clinical trials than what has previously been observed through DTI models alone. © 2025
Author Keywords
Axonal density; Diffusion imaging; Down syndrome; Fiber pathways; Neurite dispersion; White matter development
Document Type: Article
Publication Stage: Final
Source: Scopus
Quantitative Magnetic Resonance Cerebrospinal Fluid Flow Properties and Neurocognitive Outcomes in Congenital Heart Disease
(2025) Journal of Pediatrics, 280, art. no. 114494, .
Lee, V.K.a b , Reynolds, W.T.b c , Hartog, R.R.d , Wallace, J.b , Beluk, N.b , Votava-Smith, J.K.e f , Badaly, D.g , Lo, C.W.h , Ceschin, R.a b c , Panigrahy, A.b
a Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Radiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
c Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
d Division of Cardiology, Department of Pediatrics, Washington University, St. Louis, MO, United States
e Division of Cardiology, Department of Pediatrics, Children’s Hospital Los Angeles, Los Angeles, CA, United States
f Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
g Learning and Development Center, Child Mind Institute, New York, NY, United States
h Developmental Biology, University of Pittsburgh, Pittsburgh, PA, United States
Abstract
Objectives: To determine whether there are differences in pulsatile cerebrospinal fluid (CSF) flow between children and adolescents with congenital heart disease (CHD) and healthy, age-matched peers, and to determine if abnormal CSF flow is associated with abnormal CSF volumes and whether it predicts executive function outcomes. Study design: CSF flow was measured across the lumen of the aqueduct of Sylvius using cardiac-gated phase-contrast MRI at 3.0 T on 60 children and adolescents (CHD = 22, healthy controls = 38). CSF flow modeled as standard pulsatility characteristics (anterograde and retrograde peak velocities, mean velocity, and velocity variance measurements) and dynamic pulsatility characteristics (each participant’s CSF flow deviation from study cohort’s consensus flow quantified using the root mean squared deviation) were measured. Participants underwent neurocognitive assessments for executive function, focused on inhibition, cognitive flexibility, and working memory domains. Results: Compared with controls, the CHD group demonstrated greater dynamic pulsatility over the entire cardiac cycle (higher overall flow root mean squared deviation: P = .0353 for the study cohort fitted; P = .0292 for the control only fitted), but no difference in standard pulsatility measures. However, a lower mean velocity (P = .0323) and lower dynamic CSF flow pulsatility (root mean squared deviation P = .0181 for the study cohort fitted; P = .0149 for the control only fitted) predicted poor inhibitory executive functional outcomes. Discussion: Although the whole CHD group exhibited higher dynamic CSF flow pulsatility compared with controls, the subset of patients with CHD with relatively reduced static and dynamic CSF flow pulsatility had the worst inhibitory domain executive functioning. These findings suggest that altered CSF flow pulsatility may be related to not only brain compensatory mechanisms, but also to cognitive impairment in CHD. © 2025 The Author(s)
Funding details
National Institute on AgingNIA
Additional VenturesAV
National Heart, Lung, and Blood InstituteNHLBIR01 HL152740-1, F31 HL165730-02, R01 HL128818-05 S1
National Heart, Lung, and Blood InstituteNHLBI
U.S. Department of DefenseDODW81XWH-16-1-0613
U.S. Department of DefenseDOD
U.S. National Library of MedicineNLM5T15LM007059-27
U.S. National Library of MedicineNLM
Document Type: Article
Publication Stage: Final
Source: Scopus
Synapsin Condensation is Governed by Sequence-Encoded Molecular Grammars
(2025) Journal of Molecular Biology, 437 (8), art. no. 168987, .
Hoffmann, C.a , Ruff, K.M.b , Edu, I.A.c , Shinn, M.K.b , Tromm, J.V.a , King, M.R.b , Pant, A.b , Ausserwöger, H.c , Morgan, J.R.d , Knowles, T.P.J.c e , Pappu, R.V.b , Milovanovic, D.a f g h
a Laboratory of Molecular Neuroscience Berlin, German Center for Neurodegenerative Diseases (DZNE), Berlin, 10117, Germany
b Department of Biomedical Engineering and Center for Biomolecular Condensates, James McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
c Centre for Misfolding Diseases, Yusuf Hamied, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, United Kingdom
d Eugene Bell Center for Regenerative Biology and Tissue Engineering, Marine Biological Laboratory, Woods HoleMA 02543, United States
e Cavendish Laboratory, Department of Physics, University of Cambridge, JJ Thomson Road, Cambridge, CB3 0HE, United Kingdom
f German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany
g Einstein Center for Neuroscience, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, 10117, Germany
h Whitman Center, Marine Biological Laboratory, 02543 Woods HoleMA, United States
Abstract
Multiple biomolecular condensates coexist at the pre- and post- synapse to enable vesicle dynamics and controlled neurotransmitter release in the brain. In pre-synapses, intrinsically disordered regions (IDRs) of synaptic proteins are drivers of condensation that enable clustering of synaptic vesicles (SVs). Using computational analysis, we show that the IDRs of SV proteins feature evolutionarily conserved non-random compositional biases and sequence patterns. Synapsin-1 is essential for condensation of SVs, and its C-terminal IDR has been shown to be a key driver of condensation. Focusing on this IDR, we dissected the contributions of two conserved features namely the segregation of polar and proline residues along the linear sequence, and the compositional preference for arginine over lysine. Scrambling the blocks of polar and proline residues weakens the driving forces for forming micron-scale condensates. However, the extent of clustering in subsaturated solutions remains equivalent to that of the wild-type synapsin-1. In contrast, substituting arginine with lysine significantly weakens both the driving forces for condensation and the extent of clustering in subsaturated solutions. Co-expression of the scrambled variant of synapsin-1 with synaptophysin results in a gain-of-function phenotype in cells, whereas arginine to lysine substitutions eliminate condensation in cells. We report an emergent consequence of synapsin-1 condensation, which is the generation of interphase pH gradients that is realized via differential partitioning of protons between coexisting phases. This pH gradient is likely to be directly relevant for vesicular ATPase functions and the loading of neurotransmitters. Our studies highlight how conserved IDR grammars serve as drivers of synapsin-1 condensation. © 2025 The Author(s)
Author Keywords
interphase pH gradient; microfluidics; phase separation; synapse; synapsin 1
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
National Institutes of HealthNIH
European Research CouncilERC101078172, 101001615
European Research CouncilERC
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Air Force Office of Scientific ResearchAFOSR
National Institute on AgingNIA2RF1 NS078165-12
National Institute on AgingNIA
Deutsche ForschungsgemeinschaftDFGSFB1286/B10, MI 2104
Deutsche ForschungsgemeinschaftDFG
National Science FoundationNSFMCB-2227268
National Science FoundationNSF
National Institute of Neurological Disorders and StrokeNINDSF32GM146418-01A1, R01NS121114, K99GM152778
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Loss of ATG7 in microglia impairs UPR, triggers ferroptosis, and weakens amyloid pathology control
(2025) The Journal of Experimental Medicine, 222 (4), .
Cai, Z.a , Wang, S.a b , Cao, S.a , Chen, Y.a , Penati, S.a , Peng, V.a c , Yuede, C.M.d , Beatty, W.L.e , Lin, K.a , Zhu, Y.a , Zhou, Y.a f , Colonna, M.a
a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China
c Department of Medicine, University of California San Francisco, San Francisco, CA, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, United States
Abstract
Microglia impact brain development, homeostasis, and pathology. One important microglial function in Alzheimer’s disease (AD) is to contain proteotoxic amyloid-β (Aβ) plaques. Recent studies reported the involvement of autophagy-related (ATG) proteins in this process. Here, we found that microglia-specific deletion of Atg7 in an AD mouse model impaired microglia coverage of Aβ plaques, increasing plaque diffusion and neurotoxicity. Single-cell RNA sequencing, biochemical, and immunofluorescence analyses revealed that Atg7 deficiency reduces unfolded protein response (UPR) while increasing oxidative stress. Cellular assays demonstrated that these changes lead to lipoperoxidation and ferroptosis of microglia. In aged mice without Aβ buildup, UPR reduction and increased oxidative damage induced by Atg7 deletion did not impact microglia numbers. We conclude that reduced UPR and increased oxidative stress in Atg7-deficient microglia lead to ferroptosis when exposed to proteotoxic stress from Aβ plaques. However, these microglia can still manage misfolded protein accumulation and oxidative stress as they age. © 2025 Cai et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Statistical properties of functional connectivity MRI enrichment analysis in school-age autism research
(2025) Developmental Cognitive Neuroscience, 72, art. no. 101534, .
Ferguson, A.S.a , Nishino, T.a , Girault, J.B.b , Hazlett, H.C.b , Schultz, R.T.c , Marrus, N.a , Styner, M.d , Torres-Gomez, S.e , Gerig, G.f , Evans, A.e , Dager, S.R.g , Estes, A.M.h , Zwaigenbaum, L.i , Pandey, J.c , John, T.S.h , Piven, J.b , Pruett, J.R., Jr.a , Todorov, A.A.a , for the IBIS Networkj
a Department of Psychiatry; Washington University School of Medicine, 660 S. Euclid Ave, St Louis, MO 63110, United States
b The Carolina Institute for Developmental Disabilities; University of North Carolina at Chapel Hill, 101 Renee Lynn Court, Carrboro, NC 277599-3367, United States
c Children’s Hospital of Philadelphia, University of Pennsylvania, Civic Center Blvd, Philadelphia, PA 19104, United States
d Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, United States
e McGill Centre for Integrative Neuroscience, McGill University, Montreal, QC H3A 2B4, Canada
f Department of Computer Science and Engineering, Tandon School of Engineering, New York University, Brooklyn, NY 11201, United States
g Department of Radiology, University of Washington, 1410 NE Campus Parkway, Seattle, WA 98195, United States
h Department of Speech and Hearing Sciences, University of Washington, 1701 NE Columbia Rd., Seattle, WA 98195-7920, United States
i Department of Pediatrics, University of Alberta, Edmonton Clinic Health Academy, 11405-87 Avenue, Edmonton, AB T6G 1C9, Canada
Abstract
Mass univariate testing on functional connectivity MRI (fcMRI) data is limited by difficulties achieving experiment-wide significance. Recent work addressing this problem has used enrichment analysis, which aggregates univariate screening statistics for a set of variables into a single enrichment statistic. There have been promising results using this method to explore fcMRI-behavior associations. However, there has not yet been a rigorous examination of the statistical properties of enrichment analysis when applied to fcMRI data. Establishing power for fcMRI enrichment analysis will be important for future neuropsychiatric and cognitive neuroscience study designs that plan to include this method. Here, we use realistic simulation methods, which mimic the covariance structure of fcMRI data, to examine the false positive rate and statistical power of one technique for enrichment analysis, over-representation analysis. We find it can attain high power even for moderate effects and sample sizes, and it strongly outperforms univariate analysis. The false positive rate associated with permutation testing is robust. © 2025
Author Keywords
Asd; Brain Network; BWAS; Enrichment; Functional connectivity; Resting state fcMRI
Funding details
K01-MH122779, P50HD103573
P50 HD103525, R01 HD055741, T32 HD040127, R01 MH129426, R01 MH116961, R01 MH121462
Document Type: Article
Publication Stage: Final
Source: Scopus
Protocol to evaluate fasting metabolism and its relationship to the core circadian clock in mice
(2025) STAR Protocols, 6 (1), art. no. 103660, .
Sun, J.a b , DeBosch, B.J.b
a Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
b Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, United States
Abstract
To investigate the role of hepatocyte genes in fasting metabolism, it is essential to analyze their expression across the entire 24-h circadian cycle. Here, we present a protocol to evaluate fasting metabolism and its relationship to the core circadian clock in mice. We describe steps for time-course fasting/feeding experiment setup and performing staggered fasting and refeeding for 24 h. We then detail procedures for evaluating oxidative substrate selection and rescuing defective oxidative metabolism through FGF21 and CPI-613 injections. For complete details on the use and execution of this protocol, please refer to Sun et al.1 © 2025 The Author(s)
Author Keywords
genetics; metabolism; model organisms
Funding details
Longer Life FoundationLLF
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK1R01DK126622, 1R01DK131009
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
National Heart, Lung, and Blood InstituteNHLBI1R01HL147968-01A1
National Heart, Lung, and Blood InstituteNHLBI
Document Type: Article
Publication Stage: Final
Source: Scopus
Pathogenic de novo variants in PPP2R5C cause a neurodevelopmental disorder within the Houge-Janssens syndrome spectrum
(2025) American Journal of Human Genetics, 112 (3), pp. 554-571.
Verbinnen, I.a b , Douzgou Houge, S.c d , Hsieh, T.-C.e , Lesmann, H.f , Kirchhoff, A.e , Geneviève, D.g , Brimble, E.h , Lenaerts, L.a , Haesen, D.a , Levy, R.J.i , Thevenon, J.j , Faivre, L.k l , Marco, E.m , Chong, J.X.n , Bamshad, M.n o , Patterson, K.o , Mirzaa, G.M.n p , Foss, K.q , Dobyns, W.r , White, S.M.s t , Pais, L.u , O’Heir, E.u v , Itzikowitz, R.w , Donald, K.A.w , Van der Merwe, C.x y , Mussa, A.z , Cervini, R.aa , Giorgio, E.ab ac , Roscioli, T.ad ae af , Dias, K.-R.ad ag , Evans, C.-A.ad af , Brown, N.J.ah ai , Ruiz, A.aj , Trujillo Quintero, J.P.ak , Rabin, R.al , Pappas, J.al , Yuan, H.am , Lachlan, K.an , Thomas, S.ao ap , Devlin, A.aq ar , Wright, M.as , Martin, R.at , Karwowska, J.au , Posmyk, R.au , Chatron, N.av aw , Stark, Z.ah ax ay , Heath, O.ah , Delatycki, M.ah ay az , Buchert, R.ba , Korenke, G.-C.bb , Ramsey, K.bc , Narayanan, V.bc , Grange, D.K.bd , Weisenberg, J.L.be , Haack, T.B.ba bf , Karch, S.bg , Kipkemoi, P.bh , Mangi, M.bh , Bindels de Heus, K.G.C.B.bi bj , de Wit, M.-C.Y.bj bk , Barakat, T.S.bj bl bm , Lim, D.bn , Van Winckel, G.bo , Spillmann, R.C.bp , Shashi, V.bp , Jacob, M.bq , Stehr, A.M.bq , Krawitz, P.e , Douzgos Houge, G.c , Janssens, V.a b , The Undiagnosed Diseases Networkbr
a Laboratory of Protein Phosphorylation and Proteomics, KU Leuven Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium
b KU Leuven Institute for Rare Diseases (Leuven.IRD), Leuven, Belgium
c Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
d Department of Clinical Science, University of Bergen, Bergen, Norway
e Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
f Institute of Human Genetics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
g Montpellier University, INSERM U1183, Centre de Référence Anomalies du développement et syndromes malformatifs, ERN ITHACA, Génétique clinique, CHU Montpellier, Montpellier, France
h Invitae, San Francisco, CA, United States
i Department of Neurology and Neurological Sciences, Stanford Medicine, Stanford, CA, United States
j CNRS UMR 5309, INSERM U1209, Institute of Advanced Biosciences, Université Grenoble-Alpes, Service Génomique et Procréation, Centre Hospitalo-Universitaire Grenoble Alpes, Grenoble, Cedex, France
k Centre de génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Hôpital d’enfants, CHU Dijon Bourgogne, Dijon, France
l UMR1231 GAD, Inserm – Université Bourgogne-Franche Comté, Dijon, France
m Cortica Healthcare, San Rafael, CA, United States
n Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
o Department of Genome Sciences, University of Washington, Seattle, WA, United States
p Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, United States
q Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
r Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, United States
s Victorian Clinical Genetics Services (VCGS), Royal Children’s Hospital, Parkville, VIC, Australia
t Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
u Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
v Division of Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, United States
w Department of Paediatrics and Child Health, Red Cross War Memorial Children’s Hospital, and the Neuroscience Institute, University of Cape Town, Cape Town, South Africa
x Stanley Center for Psychiatric Research, The Broad Institute, Cambridge, MA, United States
y Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, United States
z Department of Public Health and Pediatric Sciences, University of Torino, Regina Margherita Children’s Hospital, Torino, Italy
aa Child Neuropsychiatry Department, Maria Vittoria Hospital, Torino, Italy
ab Department of Molecular Medicine, University of Pavia, Pavia, Italy
ac IRCCS Mondino Foundation, Neurogenetics Research Centre, Pavia, Italy
ad Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia
ae Centre for Clinical Genetics, Sydney Children’s Hospital, Sydney, NSW, Australia
af New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW 2031, Australia
ag Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW 2031, Australia
ah Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, University of Melbourne, Parkville, VIC, Australia
ai Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia
aj Genetics Laboratory, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, 08208, Spain
ak Unitat de Genètica Clínica, Servei de Medicina Pediàtrica, Parc Taulí Hospital Universitari, Institut d’Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, 08208, Spain
al Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, United States
am Department of Pediatrics, The First Affiliated Hospital, Guangxi Medical University, Guangxi, Nanning, China
an Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, SO16 5YA, United Kingdom
ao Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
ap Wessex Regional Genetics Laboratory, Salisbury NSF Foundation Trust, Salisbury District Hospital, Salisbury, United Kingdom
aq Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom
ar Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
as Newcastle Hospitals, Newcastle upon Tyne, United Kingdom
at The Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Genetic Medicine, Newcastle upon Tyne, United Kingdom
au Department of Clinical Genetics, Medical University in Bialystok, Bialystok, Poland
av Hospices Civils de Lyon, Groupe Hospitalier Est, Service de génétique, Bron, France
aw Université de Lyon, University Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, Lyon, France
ax Australian Genomics Health Alliance, Melbourne, VIC, Australia
ay Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC, Australia
az Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC, Australia
ba Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
bb Klinik für Neuropädiatrie und angeborene Stoffwechselerkrankungen, Klinikum Oldenburg, Oldenburg, Germany
bc Center for Rare Childhood Disorders, Translational Genomics Research Institute, Phoenix, AZ 85004, United States
bd Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, One Children’s Place, St. Louis, MO, United States
be Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
bf Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
bg Division of Pediatric Neurology and Metabolic Medicine, Department of Pediatrics I, Medical Faculty of Heidelberg, Heidelberg University, Heidelberg, Germany
bh Neuroscience Unit, KEMRI-Wellcome Trust, Center for Geographic Medicine Research Coast, Kilifi, Kenya
bi Department of Pediatrics, Erasmus MC University Medical Center, Rotterdam, Netherlands
bj ENCORE Expertise Center for Neurodevelopmental Disorders, Erasmus MC University Medical Center, Rotterdam, Netherlands
bk Department of Neurology and Pediatric Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands
bl Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
bm Discovery Unit, Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, Netherlands
bn Department of Clinical Genetics, Lavender House, Birmingham Women’s and Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom
bo Hospitaux Universitaires Genève, Geneva, Switzerland
bp Department of Pediatrics-Medical Genetics, Duke University School of Medicine, Durham, NC, United States
bq Institute of Human Genetics, Klinikum rechts der Isar, Technical University of Munich, School of Medicine and Health, Munich, Germany
Abstract
Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism. © 2025 American Society of Human Genetics
Author Keywords
autism; developmental delay; epilepsy; intellectual disability; macrocephaly; neurodevelopmental disorder; PP2A; PPP2R5C; PPP2R5D; protein phosphatase 2A
Funding details
Marguerite-Marie Delacroix foundation
State of CaliforniaA19-3376-S005, A19-3376-S002, A2853-S005
State of California
KU Leuven43066
KU Leuven
Document Type: Article
Publication Stage: Final
Source: Scopus
Mechanisms and correlates of incentivized response inhibition in schizophrenia and bipolar disorder
(2025) Journal of Psychiatric Research, 183, pp. 282-288.
Patel, P.K.a b , Green, M.F.a b , Barch, D.c d , Wynn, J.K.a b
a Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
b Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA, United States
c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
d Department of Psychological and Brain Sciences, Washington University in Saint Louis, St Louis, MO, United States
Abstract
When healthy individuals are incentivized on response inhibition tasks (e.g., Stroop), they recruit additional cognitive resources, enabling them to make faster, more accurate responses. Schizophrenia (SZ) and bipolar disorder (BP) are associated with poor response inhibition, but it is unknown whether SZ and BP show incentive-related improvements to the same degree as healthy controls (HC). To investigate this question, reaction time data from an incentivized Stroop-style task were analyzed from 37 SZ, 26 B P, and 33 H C. We examined: 1) group differences in mean reaction time, 2) group differences in response caution and in rate of processing task-relevant information derived from a computational approach (drift diffusion modeling), and 3) clinical and cognitive correlates of drift diffusion parameters in SZ and BP groups. When incentives were introduced, both HC and BP showed significantly faster response speed, but SZ did not show the same pattern of improvement as a function of incentives. Computational analyses indicated that groups did not significantly differ in response caution, but that both SZ and BP had a slower information processing rate compared to HC. In SZ, slow information processing rate was related to poor cognition; positive and negative symptoms were associated with impairments in information processing rate, but in opposite directions (i.e., increased information processing rate was associated with positive symptom severity; decreased information processing rate was associated with negative symptom severity). Our findings suggest impaired information processing rate may contribute to poor response inhibition in both SZ and BP, whereas response caution is intact in both disorders. However, SZ is distinguished from BP by a failure to enter an overall motivated state and decrease response speed when incentivized. © 2025
Author Keywords
Bipolar disorder; Computational modeling; Response inhibition; Reward processing; Schizophrenia
Funding details
Office of Academic Affiliations, Department of Veterans AffairsOAA, VA
Document Type: Article
Publication Stage: Final
Source: Scopus
How to be a realist about computational neuroscience
(2025) Synthese, 205 (3), art. no. 102, .
Williams, D.J.
Washington University in St. Louis, St. Louis, MO, United States
Abstract
Recently, a version of realism has been offered to address the simplification strategies used in computational neuroscience. According to this view, computational models provide us with knowledge about the brain, but they should not be taken literally in any sense, even rejecting the idea that the brain performs computations (computationalism). I acknowledge the need for considerations regarding simplification strategies in neuroscience and how they contribute to our interpretations of computational models; however, I argue that whether we should accept or reject computationalism about the brain is a separate issue that can be addressed independently by a philosophical theory of physical computation. This takes seriously the idea that the brain performs computations while also taking an analogical stance toward computational models in neuroscience. I call this version of realism “Analogical Computational Realism.” Analogical Computational Realism is a realist view in virtue of being committed to computationalism while taking certain computational models to pick out real patterns that provide a how-possibly explanation without also thinking that the model is literally implemented in the brain. © The Author(s), under exclusive licence to Springer Nature B.V. 2025.
Author Keywords
Computational modeling; Idealization; Neuroscience; Realism
Funding details
Washington University in St. LouisWUSTL
Document Type: Article
Publication Stage: Final
Source: Scopus
ATP-sensitive potassium channels alter glycolytic flux to modulate cortical activity and sleep
(2025) Proceedings of the National Academy of Sciences of the United States of America, 122 (8), pp. e2416578122.
Constantino, N.J.a b c , Carroll, C.M.d , Williams, H.C.a c , Vekaria, H.J.b e , Yuede, C.M.f g , Saito, K.b c , Sheehan, P.W.g , Snipes, J.A.a c , Raichle, M.E.g h i j k , Musiek, E.S.g , Sullivan, P.G.b e , Morganti, J.M.b c , Johnson, L.A.a c , Macauley, S.L.a b c
a Department of Physiology, University of Kentucky, Lexington, United States
b Department of Neuroscience, University of Kentucky, Lexington, United States
c Sanders Brown Center on Aging, University of Kentucky, Lexington, United States
d Department of Psychiatry, Wake Forest School of Medicine, Winston-Salem
e Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, United States
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
h Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
i Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
j Department of Psychology & Brain Sciences, Washington University, St. Louis, MO 63110, United States
k Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Metabolism plays a key role in the maintenance of sleep/wake states. Brain lactate fluctuations are a biomarker of sleep/wake transitions, where increased interstitial fluid (ISF) lactate levels are associated with wakefulness and decreased ISF lactate is required for sleep. ATP-sensitive potassium (KATP) channels couple glucose-lactate metabolism with excitability. Using mice lacking KATP channel activity (e.g., Kir6.2-/- mice), we explored how changes in glucose utilization affect cortical electroencephalography (EEG) activity and sleep/wake homeostasis. In the brain, Kir6.2-/- mice shunt glucose toward glycolysis, reducing neurotransmitter biosynthesis and dampening cortical EEG activity. Kir6.2-/- mice spent more time awake at the onset of the light period due to altered ISF lactate dynamics. Together, we show that Kir6.2-KATP channels act as metabolic sensors to gate arousal by maintaining the metabolic stability of sleep/wake states and providing the metabolic flexibility to transition between states.
Author Keywords
arousal; excitability; KATP channels; metabolism; sleep
Document Type: Article
Publication Stage: Final
Source: Scopus
Chromosomal and gonadal sex have differing effects on social motivation in mice
(2025) Biology of Sex Differences, 16 (1), p. 13.
Chaturvedi, S.M.a b , Sarafinovska, S.a b , Selmanovic, D.a b , McCullough, K.B.a b , Swift, R.G.a b , Maloney, S.E.b c , Dougherty, J.D.a b c
a Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63130, United States
Abstract
BACKGROUND: Sex differences in brain development are thought to lead to sex variation in social behavior. Sex differences are fundamentally driven by both gonadal hormones and sex chromosomes, yet little is known about the independent effects of each on social behavior. Further, mouse models of the genetic liability for the neurodevelopmental disorder MYT1L Syndrome have shown sex-specific deficits in social motivation. In this study, we aimed to determine if gonadal hormones or sex chromosomes primarily mediate the sex differences seen in mouse social behavior, both at baseline and in the context of Myt1l haploinsufficiency. METHODS: Four-core genotypes (FCG) mice, which uncouple gonadal and chromosomal sex, were crossed with MYT1L heterozygous mice to create eight different groups with unique combinations of sex factors and MYT1L genotype. A total of 131 mice from all eight groups were assayed for activity and social behavior via the open field and social operant paradigms. Measures of social seeking and orienting were analyzed for main effects of chromosome, gonads, and their interactions with Myt1l mutation. RESULTS: The FCGxMYT1L cross revealed independent effects of both gonadal and chromosomal sex on activity and social behavior. Specifically, the presence of ovarian hormones led to greater overall activity, social seeking, and social orienting regardless of MYT1L genotype. In contrast, sex chromosomes affected social behavior mainly in the MYT1L heterozygous group, with XX MYT1L mutant mice demonstrating elevated levels of social orienting and seeking compared to XY MYT1L mutant mice. CONCLUSIONS: Gonadal and chromosomal sex have independent mechanisms of driving greater social motivation in females. Additionally, genes on the sex chromosomes may interact with neurodevelopmental risk genes to influence sex variation in atypical social behavior. © 2025. The Author(s).
As our brain develops, many factors influence how we behave later in life. The brain forms differently in males and females, potentially leading to sex variation seen in many behaviors including sociability. In addition, conditions defined by differences in social behaviors, such as autism, are diagnosed more in males than females. However, researchers don’t know exactly how distinct sex factors, such as gonadal hormones and sex chromosome genes, lead to different behaviors in males and females. In this study, we used mouse models and tests of mouse behavior to explore these differences. Results show that gonadal hormones primarily contributed to differences in social motivation between sexes. Yet, when we repeated these same assays in a mouse model of genetic liability for a human neurodevelopmental syndrome, we found that sex chromosome genes rather than gonadal hormones played a larger role in the behavioral consequences of impaired neurodevelopment. These insights can inform future research on the biological mechanisms of social behavior in the context of genetic liability for neurodevelopmental disorders.
Author Keywords
Gonadal hormones; Mouse models; MYT1L syndrome; Neurodevelopmental disorders; Sex chromosomes; Sex differences; Social behavior
Document Type: Article
Publication Stage: Final
Source: Scopus
Impulsivity facets and substance use involvement: insights from genomic structural equation modeling
(2025) Psychological Medicine, 55, p. e51.
Vilar-Ribó, L.a , Hatoum, A.S.b , Grotzinger, A.D.c d , Mallard, T.T.e , Elson, S.f , Fontanillas, P.f , Palmer, A.A.a g , Gustavson, D.E.c d , Sanchez-Roige, S.a g h , 23andMe Research Teami
a Department of Psychiatry, University of California San Diego, La JollaCA, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
d Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, United States
e Psychiatric and Neurodevelopmental Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
f 23andMe, Sunnyvale, CA, United States
g Institute for Genomic Medicine, University of California San Diego, La JollaCA, United States
h Division of Genetic Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, United States
Abstract
BACKGROUND: Impulsivity is a multidimensional trait associated with substance use disorders (SUDs), but the relationship between distinct impulsivity facets and stages of substance use involvement remains unclear. METHODS: We used genomic structural equation modeling and genome-wide association studies (N = 79,729-903,147) to examine the latent genetic architecture of nine impulsivity traits and seven substance use (SU) and SUD traits. RESULTS: We found that the SU and SUD factors were strongly genetically inter-correlated (rG=0.77) but their associations with impulsivity facets differed. Lack of premeditation, negative and positive urgency were equally positively genetically correlated with both the SU (rG=.0.30-0.50) and SUD (rG=0.38-0.46) factors; sensation seeking was more strongly genetically correlated with the SU factor (rG=0.27 versus rG=0.10); delay discounting was more strongly genetically correlated with the SUD factor (rG=0.31 versus rG=0.21); and lack of perseverance was only weakly genetically correlated with the SU factor (rG=0.10). After controlling for the genetic correlation between SU/SUD, we found that lack of premeditation was independently genetically associated with both the SU (β=0.42) and SUD factors (β=0.21); sensation seeking and positive urgency were independently genetically associated with the SU factor (β=0.48, β=0.33, respectively); and negative urgency and delay discounting were independently genetically associated with the SUD factor (β=0.33, β=0.36, respectively). CONCLUSIONS: Our findings show that specific impulsivity facets confer risk for distinct stages of substance use involvement, with potential implications for SUDs prevention and treatment.
Author Keywords
addiction; genomic structural equation modeling; GWAS; impulsivity; substance use
Document Type: Article
Publication Stage: Final
Source: Scopus
Efficacy and Safety of Zilucoplan in Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial
(2025) JAMA Network Open, 8 (2), p. e2459058.
Paganoni, S.a b , Fournier, C.N.c , Macklin, E.A.a d , Chibnik, L.B.a d e , Quintana, M.f , Saville, B.R.f , Detry, M.A.f , Vestrucci, M.f , Marion, J.f , McGlothlin, A.f , Ajroud-Driss, S.g , Chase, M.a , Pothier, L.a , Harkey, B.A.a , Yu, H.a , Sherman, A.V.a , Shefner, J.M.h , Hall, M.h , Kittle, G.h , Berry, J.D.a , Babu, S.a , Andrews, J.i , Dagostino, D.a , Tustison, E.a , Giacomelli, E.a , Scirocco, E.a , Alameda, G.j , Locatelli, E.j k , Ho, D.a , Quick, A.l , Katz, J.m , Heitzman, D.n , Appel, S.H.o , Shroff, S.o , Felice, K.p , Maragakis, N.J.q , Simmons, Z.r , Miller, T.M.s , Olney, N.t , Weiss, M.D.u , Goutman, S.A.v , Fernandes, J.A.w , Jawdat, O.x , Owegi, M.A.y , Foster, L.A.z , Vu, T.aa , Ilieva, H.ab , Newman, D.S.ac , Arcila-Londono, X.ac , Jackson, C.E.ad , Ladha, S.h , Heiman-Patterson, T.ae , Caress, J.B.af , Swenson, A.ag , Peltier, A.ah , Lewis, R.ai , Fee, D.aj , Elliott, M.ak , Bedlack, R.al , Kasarskis, E.J.am , Elman, L.an , Rosenfeld, J.ao , Walk, D.ap , McIlduff, C.aq , Twydell, P.ar , Young, E.as , Johnson, K.at , Rezania, K.au , Goyal, N.A.av , Cohen, J.A.aw , Benatar, M.ax , Jones, V.ay , Glass, J.c , Shah, J.az , Beydoun, S.R.ba , Wymer, J.P.bb , Zilliox, L.bc , Nayar, S.bd , Pattee, G.L.be , Martinez-Thompson, J.bf , Harvey, B.bg , Patel, S.bg , Mahoney, P.bh , Duda, P.W.bg , Cudkowicz, M.E.a , HEALEY ALS Platform Trial Study Groupbi
a Sean M. Healey & AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School, Boston, United States
b Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, United States
c Department of Neurology, Emory University, Atlanta, Georgia
d Biostatistics Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, United States
e Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
f Berry Consultants LLC, Austin, TX, United States
g Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
h Barrow Neurological Institute, Phoenix, AZ, United States
i Department of Neurology, Columbia UniversityNY, United States
j Phil Smith Neuroscience Institute, Holy Cross Hospital, Silver SpringMD, Liberia
k Department of Neurology, Nova Southeastern University, Fort Lauderdale, FL, Puerto Rico
l Department of Neurology, Ohio State University, Columbus, United States
m California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco, Mexico
n Texas Neurology, Dallas, United States
o Methodist Neurological Institute, Houston, TX, United States
p Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, CT, United States
q Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, Liberia
r Department of Neurology, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
s Department of Neurology, Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, United States
t Providence ALS Clinic, Portland, Oregon
u Department of Neurology, University of Washington Medical Center, Seattle, United States
v Department of Neurology, University of Michigan, Ann Arbor, United States
w Department of Neurology, University of Nebraska Medical Center, Omaha, United States
x Departmennt of Neurology, University of Kansas Medical Center, Kansas City, United States
y Department of Neurology, University of Massachusetts Medical School, Worcester, United Kingdom
z Department of Neurology, University of Colorado School of Medicine, Aurora, United States
aa Department of Neurology, University of South Florida, Tampa, Romania
ab Jefferson Weinberg ALS Center, Philadelphia, PA, United States
ac Henry Ford Health System Department of Neurology, Detroit, MI, United States
ad Department of Neurology, University of Texas Health, San Antonio, Mexico
ae Department of Neurology, Temple Health, Philadelphia, PA, United States
af Department of Neurology, Wake Forest University School of Medicine, Winston-SalemNC, United States
ag Department of Neurology, University of Iowa, Iowa City, United States
ah Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
ai Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
aj Department of Neurology, Medical College of Wisconsin, Milwaukee, United States
ak Department of Neurology, University of Virginia, Arlington, United Kingdom
al Department of Neurology, Duke University, Durham, NC, United States
am Department of Neurology, University of Kentucky, Lexington, United States
an Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, United States
ao Department of Neurology, Loma Linda University School of Medicine, Loma Linda, CA, United States
ap Department of Neurology, University of Minnesota/Twin Cities ALS Research Consortium, Minneapolis and St Paul
aq Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
ar Department of Neurology, Spectrum Health Medical Group, Grand RapidsMI, United States
as Department of Neurology, SUNY (State University of New York) Upstate, Syracuse, United States
at Department of Neurology, Ochsner Health System, New Orleans, LA, United States
au Department of Neurology, University of Chicago, Chicago, IL, United States
av Department of Neurology, University of California, Medical Center, Irvine, United Kingdom
aw Department of Neurology, Dartmouth-Hitchcock Medical CenterNH, Lebanon
ax Department of Neurology, University of Miami, Miami, FL, Puerto Rico
ay Department of Physical Medicine and Rehabilitation, School of Medicine, University of Missouri, Columbia, United States
az Department of Neurology, Mayo Clinic, Jacksonville, FL, Puerto Rico
ba Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, Mexico
bb Department of Neurology, University of Florida, Gainesville, United States
bc Department of Neurology, University of Maryland School of Medicine, Baltimore, United States
bd Department of Neurology, Georgetown UniversityWA, United States
be Neurology Associates, Lincoln, NE, United States
bf Department of Neurology, Mayo Clinic, Rochester, MN, United States
bg UCB Pharma, Cambridge, MA, United States
bh UCB, Slough, United Kingdom
Abstract
Importance: The etiology of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease, is unknown. However, neuroinflammation and complement activation may play a role in disease progression. Objective: To determine the effects of zilucoplan, an inhibitor of complement C5, in individuals with ALS. Design, Setting, and Participants: Zilucoplan was tested as regimen A of the HEALEY ALS Platform Trial, a phase 2 to 3 multicenter, randomized, double-blind, placebo-controlled perpetual platform clinical trial with sharing of trial infrastructure and placebo data across multiple regimens. Regimen A was conducted from August 17, 2020, to May 4, 2022. A total of 162 participants were randomized to receive zilucoplan (122 [75.3%]) or regimen-specific placebo (40 [24.7%]). An additional 124 concurrently randomized participants were randomized to receive placebo in other regimens. Interventions: Eligible participants were randomized in a 3:1 ratio to receive zilucoplan or matching placebo within strata of edaravone and/or riluzole use for a planned duration of 24 weeks. Active drug (zilucoplan, 0.3 mg/kg) and placebo were provided for daily subcutaneous dosing. Main Outcomes and Measures: The primary end point was change in disease severity from baseline through 24 weeks as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) total score and survival, analyzed using a bayesian shared-parameter model and reported as disease rate ratio (DRR; <1 indicating treatment benefit). The study included prespecified rules for early stopping for futility. Outcome analyses were performed in the full analysis set comparing the zilucoplan group with the total shared placebo group (n = 164). Results: Among the 162 participants who were randomized (mean [SD] age, 59.6 [11.3]; 99 [61.1%] male), 115 (71.0%) completed the trial. The estimated DRR common to ALSFRS-R and survival was 1.08 (95% credible interval, 0.87-1.31; posterior probability of superiority, 0.24). The trial was stopped early for futility. No unexpected treatment-related risks were identified. Conclusions and Relevance: In this randomized clinical trial of zilucoplan in ALS, treatment did not alter disease progression. The adaptive platform design of the HEALEY ALS Platform Trial made it possible to test a new investigational product with efficient use of time and resources. Trial Registration: ClinicalTrials.gov Identifier: NCT04297683.
Document Type: Article
Publication Stage: Final
Source: Scopus
Ecological Trait Differences Are Associated with Gene Expression in the Primary Visual Cortex of Primates
(2025) Genes, 16 (2), art. no. 117, .
Zintel, T.M.a , Ely, J.J.b , Raghanti, M.A.c , Hopkins, W.D.d , Hof, P.R.e f , Sherwood, C.C.g , Kamilar, J.M.h i , Bauernfeind, A.L.j k , Babbitt, C.C.a
a Department of Biology, University of Massachusetts Amherst, Amherst, MA 01003, United States
b MAEBIOS, Alamogordo, NM 88310, United States
c Department of Anthropology, Kent State University, Kent, OH 44242, United States
d Keeling Center for Comparative Medicine and Research, The University of Texas, MD Anderson Cancer Center, Bastrop, TX 78602, United States
e Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
f New York Consortium in Evolutionary Primatology, New York, NY 10065, United States
g Department of Anthropology and Center for the Advanced Study of Human Paleobiology, The George Washington University, Washington, DC 20052, United States
h Department of Anthropology, University of Massachusetts Amherst, Amherst, MA 01003, United States
i Organismic and Evolutionary Biology Graduate Program, University of Massachusetts Amherst, Amherst, MA 01003, United States
j Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
k Department of Anthropology, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Primate species differ drastically from most other mammals in how they visually perceive their environments, which is particularly important for foraging, predator avoidance, and detection of social cues. Background/Objectives: Although it is well established that primates display diversity in color vision and various ecological specializations, it is not understood how visual system characteristics and ecological adaptations may be associated with gene expression levels within the primary visual cortex (V1). Methods: We performed RNA-Seq on V1 tissue samples from 28 individuals, representing 13 species of primates, including hominoids, cercopithecoids, and platyrrhines. We explored trait-dependent differential expression (DE) by contrasting species with differing visual system phenotypes and ecological traits. Results: Between 4–25% of genes were determined to be differentially expressed in primates that varied in type of color vision (trichromatic or polymorphic di/trichromatic), habitat use (arboreal or terrestrial), group size (large or small), and primary diet (frugivorous, folivorous, or omnivorous). Conclusions: Interestingly, our DE analyses revealed that humans and chimpanzees showed the most marked differences between any two species, even though they are only separated by 6–8 million years of independent evolution. These results show a combination of species-specific and trait-dependent differences in the evolution of gene expression in the primate visual cortex. © 2025 by the authors.
Author Keywords
brain; evolution; genomics; metabolic; phenotype
Funding details
National Science FoundationNSFBCS-1750377
James S. McDonnell FoundationJSMF220020293
National Institutes of HealthNIHNS092988
Document Type: Article
Publication Stage: Final
Source: Scopus
Dissociable spatial topography of cortical atrophy in early-onset and late-onset Alzheimer’s disease: A head-to-head comparison of the LEADS and ADNI cohorts
(2025) Alzheimer’s and Dementia, .
Katsumi, Y.a , Touroutoglou, A.a , Brickhouse, M.a , Eloyan, A.b , Eckbo, R.a , Zaitsev, A.a , La Joie, R.c , Lagarde, J.c , Schonhaut, D.c , Thangarajah, M.b , Taurone, A.b , Vemuri, P.d , Jack, C.R., Jr.d , Dage, J.L.e f , Nudelman, K.N.H.f , Foroud, T.f , Hammers, D.B.e , Ghetti, B.f , Murray, M.E.g , Newell, K.L.f , Polsinelli, A.J.e , Aisen, P.h , Reman, R.h , Beckett, L.i , Kramer, J.H.c , Atri, A.j , Day, G.S.k , Duara, R.l , Graff-Radford, N.R.k , Grant, I.M.m , Honig, L.S.n , Johnson, E.C.B.o , Jones, D.T.d , Masdeu, J.C.p , Mendez, M.F.q , Musiek, E.r , Onyike, C.U.s , Riddle, M.t , Rogalski, E.u , Salloway, S.b , Sha, S.v , Turner, R.S.w , Wingo, T.S.x , Wolk, D.A.y , Womack, K.r , Carrillo, M.C.z , Rabinovici, G.D.c , Apostolova, L.G.e f aa , Dickerson, B.C.a , the LEADS Consortium for the Alzheimer’s Disease Neuroimaging Initiativeab
a Frontotemporal Disorders Unit and Massachusetts Alzheimer’s Disease Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
c Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
d Department of Radiology, Mayo Clinic, Rochester, MN, United States
e Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
f Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
g Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
h Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, United States
i Department of Public Health Sciences, University of California – Davis, Davis, CA, United States
j Banner Sun Health Research Institute, Sun City, AZ, United States
k Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
l Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
m Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
n Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
o Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
p Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
q Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
r Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
s Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
t Department of Neurology, Alpert Medical School, Brown University, Providence, RI, United States
u Department of Neurology, University of Chicago, Chicago, IL, United States
v Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
w Department of Neurology, Georgetown University, Washington, DC, United States
x Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
y Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
z Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
aa Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
Abstract
INTRODUCTION: Early-onset and late-onset Alzheimer’s disease (EOAD and LOAD, respectively) have distinct clinical manifestations, with prior work based on small samples suggesting unique patterns of neurodegeneration. The current study performed a head-to-head comparison of cortical atrophy in EOAD and LOAD, using two large and well-characterized cohorts (LEADS and ADNI). METHODS: We analyzed brain structural magnetic resonance imaging (MRI) data acquired from 377 sporadic EOAD patients and 317 sporadicLOAD patients who were amyloid positive and had mild cognitive impairment (MCI) or mild dementia (i.e., early-stage AD), along with cognitively unimpaired participants. RESULTS: After controlling for the level of cognitive impairment, we found a double dissociation between AD clinical phenotype and localization/magnitude of atrophy, characterized by predominant neocortical involvement in EOAD and more focal anterior medial temporal involvement in LOAD. DISCUSSION: Our findings point to the clinical utility of MRI-based biomarkers of atrophy in differentiating between EOAD and LOAD, which may be useful for diagnosis, prognostication, and treatment. Highlights: Early-onset Alzheimer’s disease (EOAD) and late-onset AD (LOAD) patients showed distinct and overlapping cortical atrophy patterns. EOAD patients showed prominent atrophy in widespread neocortical regions. LOAD patients showed prominent atrophy in the anterior medial temporal lobe. Regional atrophy was correlated with the severity of global cognitive impairment. Results were comparable when the sample was stratified for mild cognitive impairment (MCI) and dementia. © 2025 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amnestic; atypical Alzheimer’s disease; disease signature; magnetic resonance imaging (MRI); neurodegeneration; non-amnestic
Funding details
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Biogen
Alzheimer’s Drug Discovery FoundationADDF
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
U.S. Department of DefenseDOD
National Institutes of HealthNIHS10RR021110, S10 RR023401, S10 RR023043
National Institutes of HealthNIH
P41 EB015896
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Alzheimer’s Disease Neuroimaging InitiativeADNI
Alzheimer’s AssociationAAAA LDRFP‐21‐824473, AA LDRFP‐21‐828356
Alzheimer’s AssociationAA
National Institute on AgingNIAU24 AG072122
National Institute on AgingNIA
Fondation pour la Recherche sur AlzheimerU24 AG021886, R56 AG057195, U01 AG6057195
Fondation pour la Recherche sur Alzheimer
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Treatment efficacy for infantile epileptic spasms syndrome in children with trisomy 21
(2025) Frontiers in Pediatrics, 13, art. no. 1498425, .
Chen, H.a b , Numis, A.L.a b , Shellhaas, R.A.c , Mytinger, J.R.d , Samanta, D.e , Singh, R.K.f g , Hussain, S.A.h , Takacs, D.i , Knupp, K.G.j , Shao, L.-R.k , Stafstrom, C.E.k
a Department of Neurology and Weill Institute for Neuroscience, University of California San Francisco, San Francisco, CA, United States
b Department of Pediatrics, UCSF Benioff Children’s Hospital, University of California San Francisco, San Francisco, CA, United States
c Department of Neurology, Washington University at St. Louis, St. Louis, MO, United States
d Division of Pediatric Neurology, Department of Pediatrics, Nationwide Children’s Hospital, The Ohio State University, Columbus, OH, United States
e Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States
f Department of Pediatrics, Atrium Health-Levine Children’s Hospital, Charlotte, NC, United States
g Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, NC, United States
h Division of Pediatric Neurology, Department of Pediatrics, University of California, Los Angeles, CA, United States
i Department of Pediatric Neurology and Developmental Neuroscience, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
j Departments of Pediatrics and Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
k Division of Pediatric Neurology, Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
Abstract
Background: Infantile Epileptic Spasms Syndrome (IESS) is the most common epilepsy syndrome in children with trisomy 21. First-line standard treatments for IESS include adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin. Among children with trisomy 21 and IESS, treatment with ACTH or oral corticosteroids may yield higher response rates compared with vigabatrin. However, supporting data are largely from single-center, retrospective cohort studies. Methods: Leveraging the multi-center, prospective National Infantile Spasms Consortium (NISC) database, we evaluated the efficacy of first-line (standard) treatments for IESS in children with trisomy 21. We assessed clinical spasms remission at two weeks, clinical spasms remission at three months, and improvement of EEG (resolution of hypsarrhythmia) three months after initiation of treatment. Results: Thirty four of 644 (5.3%) children with IESS were diagnosed with trisomy 21. In all children with trisomy 21, epileptic spasms was their presenting seizure type. Twenty of 34 (59%) children were initially treated with ACTH, nine (26%) with oral corticosteroids, and five (15%) with vigabatrin. Baseline demographics did not vary among treatment groups. The overall clinical remission rate after two weeks of treatment was 53% including 13 of 20 (65%) receiving ACTH, three of nine (33%) receiving oral corticosteroids, and two of five (40%) receiving vigabatrin (p = 0.24). The continued clinical response rate at three months was 32% including 8 of 20 (40%) receiving ACTH, two of nine (22%) receiving oral corticosteroids, and one of five (20%) receiving vigabatrin. Thirty of the 34 (88%) children presented with hypsarrhythmia (88%). EEG improvement at three months was better for children treated with ACTH (74%) or oral corticosteroids (83%) than vigabatrin (20%; p = 0.048). Adjustment for time from epileptic spasms onset to treatment did not alter results. Conclusions: In our cohort, epileptic spasms were the first presenting seizure type in all children with trisomy 21. Among first-line standard treatment options, ACTH may have superior efficacy for clinical and electrographic outcomes for IESS in children with trisomy 21. 2025 Chen, Numis, Shellhaas, Mytinger, Samanta, Singh, Hussain, Takacs, Knupp, Shao and Stafstrom.
Author Keywords
anti-seizure medications; Down syndrome; hypsarrhythmia; infantile epileptic spasms syndrome; infantile spasms; trisomy 21
Funding details
Pediatric Epilepsy Research FoundationPERF
American Epilepsy SocietyAES
Document Type: Article
Publication Stage: Final
Source: Scopus
Sleep variability and time to achieving pregnancy: findings from a pilot cohort study of women desiring pregnancy
(2025) Fertility and Sterility, .
Zhao, P.a , Jungheim, E.S.b , Bedrick, B.S.c , Wan, L.a , Jimenez, P.T.a , McCarthy, R.a , Chubiz, J.a , Fay, J.C.d , Herzog, E.D.e , Sutcliffe, S.f , England, S.K.a
a Department of Obstetrics and Gynecology, School of Medicine, Washington University, St. Louis, Missouri, United States
b Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
c Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
d Department of Biology, University of Rochester, Rochester, New York, United States
e Department of Biology, School of Arts and Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
f Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, Missouri, United States
Abstract
Objective: To determine whether chronodisruption is associated with achieving pregnancy. Design: Pilot prospective cohort study. Setting: Academic Medical Center. Patient(s): One hundred eighty-three women desiring pregnancy were recruited from the local community of an academic medical center located in the Midwest and provided sleep information between February 1, 2015, and November 30, 2017. Intervention: Sleep and activity data were obtained via actigraphy watches worn continuously for 2 weeks to assess measures of chronodisruption, including sleep period onset, offset, midtime, and duration; as well as variability in each of these measures. Main Outcome Measures: Time to becoming pregnant over 1-year of follow-up. Results: Of the 183 eligible women, 82 became pregnant over a median of 2.8 months of follow-up. Greater interdaily variability in time of sleep onset and variability in sleep duration were associated with a longer time to achieving pregnancy after adjusting for age, body mass index, race, education, income, and smoking status (adjusted hazard ratio [aHR], 0.60; 95% confidence interval [CI], 0.36–0.999 comparing participants with a standard deviation of >1.8 hours to <1.8 hours in daily time of sleep onset; and aHR, 0.58; 95% CI, 0.36–0.98 comparing participants with a standard deviation of >2.3 hours to <2.3 hours in daily sleep duration). In adjusted analyses, no statistically significant associations were observed for average time of sleep onset and offset, midsleep time, and sleep duration, or for variability in time of sleep offset and midtime. Conclusions: Higher day-to-day variability in time of sleep onset and sleep duration—two measures of chronodisruption—were associated with a longer time to achieving pregnancy over 1 year of follow-up in women desiring pregnancy. If replicated in additional studies, these findings could point to lifestyle interventions to help women achieve a desired pregnancy. © 2025 The Authors
Author Keywords
chronodisruption; lifestyle modification; pregnancy success; sleep
Funding details
March of Dimes FoundationMDF
University of WashingtonUW
Department of Obstetrics and Gynecology, Baylor College of Medicine
National Institutes of HealthNIHR01 HD037831
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
From Serendipity to Scalability in Rare Disease Patient Collaborations
(2025) Missouri Medicine, 122 (1), pp. 53-59.
Grens, K.a , Weisenberg, J.L.b , Ryther, R.C.b , Gabel, H.W.c
a Vice President of the Tatton Brown Rahman Syndrome Community, StanfordvilleNY, United States
b Washington University School of Medicine Division of Pediatric Neurology, Department of Neurology, St. Louis, MO, United States
c Washington University School of Medicine, Department of Neuroscience, St. Louis, MO, United States
Abstract
As the rate of diagnosis for rare disease increases, so does the need to develop scalable solutions to address patient community needs. Drawing upon our experiences in rare intellectual and developmental disability research, advocacy, and treatment, we present two examples of how collaboration between patient groups, clinicians, and investigators at Washington University in St. Louis have generated invaluable resources to accelerate toward treatments. These successful partnerships serve as models for building research and clinical infrastructure for rare diseases. Copyright 2025 by the Missouri State Medical Association.
Document Type: Article
Publication Stage: Final
Source: Scopus
Inhibition of SARM1 Reduces Neuropathic Pain in a Spared Nerve Injury Rodent Model
(2025) Muscle and Nerve, .
Herbosa, C.G., Perez, R., Jaeger, A., Dy, C.J., Brogan, D.M.
Department of Orthopedic Surgery, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Introduction/Aims: The function of the sterile alpha and toll/interleukin receptor motif-containing protein 1 (SARM1) in neuropathic pain development has not yet been established. This protein has a central role in regulating axon degeneration and its depletion delays this process. This study aims to demonstrate the effects of SARM1 deletion on the development of neuropathic pain. Methods: Thirty-two wild-type (WT) or SARM1 knockout (KO) rats underwent spared nerve injury (SNI) or sham surgery. Mechanical allodynia was assessed by electronic Von Frey and cold hyperalgesia by the acetone test. Nociception was evaluated at the baseline, Day-1, Day-2, Week-1, Week-2, Week-3, and Week-4 time points. Nerve sections were examined by immunohistochemistry (IHC). Results: WT Injury rats were more sensitive to pain than WT Sham at all postoperative time points, validating the pain model. Injured SARM1 KO rats only demonstrated a difference in mechanical or cold nociception from KO Sham at Week 3. Injured KO rats demonstrated a clear trend of decreased sensitivity compared to WT Injury nociception, reaching significance at Week 4 (p = 0.044). Injured KO rats showed attenuated sensitivity to cold allodynia relative to WT at Week 2 (p = 0.019). IHC revealed decreased macrophages in spared sural nerves of injured KO animals at 2 and 4 weeks, and the proximal portion of tibial/peroneal nerves at Week 2. Discussion: This study demonstrates that SARM1 KO rats are less sensitive to mechanical and cold nociception than WT rats in an SNI model with decreased inflammatory response. Given these results, inhibition of SARM1 should be further investigated in the treatment of neuropathic pain. © 2025 Wiley Periodicals LLC.
Author Keywords
inflammation; macrophages; nerve injury; neuropathic pain; SARM1
Funding details
National Institutes of HealthNIH
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSK08AR080260‐01
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Retinal microstructure and microvasculature in association with brain amyloid burden
(2025) Brain Communications, 7 (1), art. no. fcaf013, .
Egle, M.a , Hamedani, A.G.b c d , Deal, J.A.e , Ramulu, P.Y.f , Walker, K.A.g , Wong, D.F.h , Sharett, A.R.e , Abraham, A.G.i j , Gottesman, R.F.a
a National Institute of Neurological Disorders and Stroke Intramural Research Program, National Institutes of Health, Bethesda, MD 20814, United States
b Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
d Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
e Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, United States
f Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
g Laboratory of Behavioral Neuroscience, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, United States
h Department of Radiology, Washington University School of Medicine in St Louis, St. Louis, MI 63110, United States
i Department of Epidemiology, University of Colorado, Colorado School of Public Health, Aurora, CO 80045, United States
j Department of Ophthalmology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, United States
Abstract
Cortical amyloid burden is associated with neuronal and vascular abnormalities. The retina shares significant structural and physiological similarities with the brain. This study assessed the association of retinal microstructural and microvascular signs with cortical amyloid burden in the prospective Atherosclerosis Risk in Communities-Positron Emission Tomography study. One hundred and twenty-four participants without a diagnosis of dementia underwent florbetapir PET (2011–13) and optical coherence tomography and optical coherence tomography angiography imaging (2017–19). Retinal nerve fibre thickness, total macular thickness and the ganglion cell-inner plexiform layer thickness were derived from the optical coherence tomography scan. Vessel density and the foveal avascular zone were measured on the 3 × 3 mm2 optical coherence tomography angiography scan. Amyloid burden, defined by global cortical standardized uptake value ratio, was treated as a dichotomous (standardized uptake value ratio > 1.2) and continuous outcome measure in logistic and robust linear regression models, respectively. Only lower intermediate capillary plexus vessel density [β (95% confidence interval) = −0.05 (−0.12, −0.01)] was significantly associated with increased continuous amyloid standardized uptake value ratio but not elevated dichotomous amyloid burden independently of demographic, genetic and vascular risk factors. No other retinal measure showed a significant association. Microvascular signs may accompany greater amyloid burden in late life in individuals without dementia. © 2025 Oxford University Press. All rights reserved.
Author Keywords
amyloid burden; retinal microstructure; retinal microvasculature
Funding details
National Institute of Neurological Disorders and StrokeNINDS
National Institutes of HealthNIH
National Institute on AgingNIA
National Heart, Lung, and Blood InstituteNHLBIU01HL096917, 75N92022D00005, U01HL096814, U01HL096902, 75N92022D00003, 75N92022D00001, 75N92022D00004, 75N92022D00002, U01HL096899, U01HL096812
National Heart, Lung, and Blood InstituteNHLBI
National Eye InstituteNEIK23 EY033438-02, K01AG054693
National Eye InstituteNEI
National Institute on Deafness and Other Communication DisordersNIDCD1R01AG052412, R01AG040282
National Institute on Deafness and Other Communication DisordersNIDCD
Document Type: Article
Publication Stage: Final
Source: Scopus
Does “Item-Specific” Cognitive Control Operate at the Item Level?
(2025) Journal of Experimental Psychology: Learning Memory and Cognition, .
Ileri-Tayar, M.a , Colvett, J.S.a b , Dey, A.a , Bugg, J.M.a
a Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
b Department of Psychology, Berry College, United States
Abstract
People learn and retrieve cognitive control settings (e.g., attentional focus) associated with stimulus and contextual features. It has been theorized that control adjustments occur at the item level (e.g., for a specific picture) and the category level (i.e., for the overarching category represented by the picture), but evidence is lacking for the former. We aimed to determine whether control can truly operate at the item level. In Experiments 1–3, we manipulated item-specific proportion congruencies in a picture–word Stroop task while holding category-specific proportion congruencies constant at 50% congruent. One item in each animal category (e.g., Dog 1, Fish 1) was mostly congruent (MC) and one item (e.g., Dog 2, Fish 2) was mostly incongruent (MI). Item-level control (i.e., larger Stroop effect for MC items compared to MI items) was observed in Experiment 1, but neither Experiment 2 nor 3 replicated this finding. Experiments 4a and 4b used MC and MI categories, with each comprising both MC and MI items, allowing us to potentially index both levels of control. However, the findings indicated that control operated only at the category level and not the item level. Using novel stimuli, Experiment 5 showed Stroop effects differed between items that shared a response but were visually/conceptually dissimilar. This finding suggests that applying item-level control may be difficult when items within a category are visually/conceptually similar (as in Experiments 1–4). Collectively, our findings provided little evidence for item-level control; instead, the findings suggest control primarily operates at the category level in the picture–word Stroop task. © 2025 American Psychological Association
Author Keywords
category learning; item-specific control; learning-guided control; picture–word Stroop task; proportion congruence
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neural pathway activation in the subthalamic region depends on stimulation polarity
(2025) Brain Communications, 7 (1), art. no. fcaf006, .
Borgheai, S.B.a , Opri, E.b , Isbaine, F.c , Cole, E.R.d , Jafari Deligani, R.a , Laxpati, N.G.c , Risk, B.B.e , Willie, J.T.f , Gross, R.E.c g , AuYong, N.c d h , McIntyre, C.C.i , Miocinovic, S.a d
a Department of Neurology, Emory University, Atlanta, GA 30322, United States
b Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, United States
c Department of Neurosurgery, Emory University, Atlanta, GA 30322, United States
d Department of Biomedical Engineering, Emory University, Georgia Institute of Technology, Atlanta, GA 30332, United States
e Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, United States
f Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO 63110, United States
g Department of Neurosurgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 08901, United States
h Department of Cell Biology, Emory University, Atlanta, GA 30322, United States
i Department of Biomedical Engineering, Duke University, Durham, NC 27708, United States
Abstract
Deep brain stimulation (DBS) is an effective treatment for Parkinson’s disease; however, there is limited understanding of which subthalamic pathways are recruited in response to stimulation. Here, by focusing on the polarity of the stimulus waveform (cathodic versus anodic), our goal was to elucidate biophysical mechanisms that underlie electrical stimulation in the human brain. In clinical studies, cathodic stimulation more easily triggers behavioural responses, but anodic DBS broadens the therapeutic window. This suggests that neural pathways involved respond preferentially depending on stimulus polarity. To experimentally compare the activation of therapeutically relevant pathways during cathodic and anodic subthalamic nucleus (STN) DBS, pathway activation was quantified by measuring evoked potentials resulting from antidromic or orthodromic activation in 15 Parkinson’s disease patients undergoing DBS implantation. Cortical evoked potentials (cEPs) were recorded using subdural electrocorticography, DBS local evoked potentials (DLEPs) were recorded from non-stimulating contacts, and electromyography activity was recorded from arm and face muscles. We measured (i) the amplitude of short-latency cEP, previously demonstrated to reflect activation of the cortico-STN hyperdirect pathway, (ii) DLEP amplitude thought to reflect activation of STN-globus pallidus (GP) pathway and (iii) amplitudes of very short-latency cEPs and motor evoked potentials for activation of corticospinal/bulbar tract (CSBT). We constructed recruitment and strength–duration curves for each EP/pathway to compare the excitability for different stimulation polarities. We compared experimental data with the most advanced DBS computational models. Our results provide experimental evidence that subcortical cathodic and anodic stimulation activate the same pathways in the STN region and that cathodic stimulation is in general more efficient. However, relative efficiency varies for different pathways so that anodic stimulation is the least efficient in activating CSBT, more efficient in activating the hyperdirect pathway and as efficient as cathodic in activating STN-GP pathway. Our experiments confirm biophysical model predictions regarding neural activations in the central nervous system and provide evidence that stimulus polarity has differential effects on passing axons, terminal synapses, and local neurons. Comparison of experimental results with clinical DBS studies provides further evidence that the hyperdirect pathway may be involved in the therapeutic mechanisms of DBS. © The Author(s) 2025. Published by Oxford University Press on behalf of the Guarantors of Brain.
Author Keywords
anodic; chronaxie; electrocorticography; evoked resonant neural activity; hyperdirect pathway
Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR01 NS125143, K23 NS097576
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
The Sleep Train Program: Efficacy of a Behavioral Sleep Intervention for Children with Externalizing Problems
(2025) Behavioral Sleep Medicine, .
Honaker, S.M.a , Hoyniak, C.b , McQuillan, M.E.a , Bates, J.c
a School of Medicine, Indiana University, Indianapolis, United States
b School of Medicine, Washington University, St. Louis, United States
c Department of Psychological and Brain Sciences, Indiana University, Indianapolis, United States
Abstract
Objectives: The study objective was to examine the impact of a brief behavioral sleep intervention (The Sleep Train Program) on sleep and behavior in children with externalizing behavior problems. Method: Children (3–8 years) presenting to a behavioral health clinic for externalizing problems were randomized to receive a behavioral sleep intervention or a mealtime intervention (active control). Families then completed parent management training followed by the cross-over intervention. Outcomes included parent-reported child sleep and behavior and actigraphic sleep, and were examined in the full sample and in a subsample of children with comorbid sleep difficulties. Results: In a subsample of children with both externalizing and sleep difficulties, children randomized to behavioral sleep intervention showed reduced externalizing problems (t = –2.75, p <.05), reduced night wakings (t = –2.21, p <.05), and improved parent-child interactions (t = 2.99, p =.01) and child behavior (t = –2.42, p <.05) at bedtime, compared to active control. In the full sample, in which some children did not present with sleep difficulties, behavioral sleep intervention, compared to active control, did not yield significant improvements in most sleep and behavior outcomes. Comparing sleep and behavior before and after behavioral sleep intervention across groups, children had fewer externalizing behaviors (t = 4.98, p <.001), improved sleep habits (t = –3.24, p <.05) and improved parent-child bedtime interaction (t = –3.24, p <.01), but no changes in sleep patterns. Conclusion: A brief behavioral sleep intervention was efficacious in improving both sleep and behavior outcomes for children with comorbid sleep and externalizing difficulties, but not for children with only externalizing difficulties. © 2025 Taylor & Francis Group, LLC.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Adult brain cancer incidence patterns: A comparative study between Japan and Japanese Americans
(2025) International Journal of Cancer, .
Sigel, B.a , Withrow, D.R.b , Veiga, L.H.S.c , Saito, E.d , Matsuda, T.e , Katanoda, K.e
a Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom
c Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States
d Sustainable Society Design Center, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan
e National Cancer Center Institute for Cancer Control, Tokyo, Japan
Abstract
Adult primary brain and central nervous system (CNS) cancers, though comprising only about 4% of new cancer diagnoses, significantly impact morbidity and mortality due to their low survival rates. Globally, brain and CNS tumor incidence varies considerably, with the United States exhibiting one of the highest rates and Japan among the lowest worldwide. In the United States, incidence rates differ by race, with higher rates in non-Hispanic whites (NHW) and lower rates in Asian Americans and Pacific Islanders (AAPI). This study examines the incidence of malignant CNS tumors in Japan and Japanese Americans, comparing these groups to NHW and AAPI populations in the United States. We estimated age-standardized incidence rates (ASR) of brain and CNS tumors among adults using data from the Monitoring of Cancer Incidence in Japan (MCIJ) and the U.S. Surveillance, Epidemiology, and End Results (SEER)-9 registries from 2007 to 2014. Incidence rates were stratified by age, sex, and specific CNS tumor subtypes. Incidence rates of CNS tumors among Japanese (ASR: 3.66, 95% CI: 3.56–3.76) and Japanese Americans (ASR: 2.5, 95% CI: 2.13–3.05) were lower than among NHW (9.43, 95% CI, 9.31–9.56) and AAPI populations (ASR: 4.13, 95% CI: 3.94–4.33) in the United States. The same pattern was observed for CNS tumor subtypes and across age groups and sex. This study supports a genetic component in the risk of brain and CNS tumors, a cancer type with largely unknown etiology. By comparing incidence rates across populations, it contributes to understanding the balance of genetic and environmental risk factors in the development of these cancers. © 2025 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Author Keywords
brain and central nervous system tumors; incidence rates; Japanese ancestry; migrant study; non-Hispanic Whites
Funding details
Ministry of Health, Labour and WelfareMHLW20EA1026, 20EA1017, 23EA1009
Ministry of Health, Labour and WelfareMHLW
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors” (2025) Nature Neuroscience
PTEN mutations impair CSF dynamics and cortical networks by dysregulating periventricular neural progenitors
(2025) Nature Neuroscience, art. no. 596027, .
DeSpenza, T., Jr.a b c d , Kiziltug, E.c e , Allington, G.f g h , Barson, D.G.a b , McGee, S.i , O’Connor, D.j , Robert, S.M.c , Mekbib, K.Y.c g , Nanda, P.g , Greenberg, A.B.W.c , Singh, A.c , Duy, P.Q.a b c , Mandino, F.j , Zhao, S.k , Lynn, A.b , Reeves, B.C.c , Marlier, A.c , Getz, S.A.l , Nelson-Williams, C.c , Shimelis, H.m , Walsh, L.K.m , Zhang, J.c , Wang, W.l , Prina, M.L.l n , OuYang, A.l , Abdulkareem, A.F.l n , Smith, H.c , Shohfi, J.c , Mehta, N.H.g , Dennis, E.g , Reduron, L.R.l , Hong, J.l , Butler, W.g , Carter, B.S.g , Deniz, E.o , Lake, E.M.R.j , Constable, R.T.j , Sahin, M.p , Srivastava, S.p , Winden, K.p , Hoffman, E.J.q r , Carlson, M.a q r , Gunel, M.c , Lifton, R.P.s , Alper, S.L.t u , Jin, S.C.k , Crair, M.C.a , Moreno-De-Luca, A.m u , Luikart, B.W.l n , Kahle, K.T.c g v w
a Interdepartmental Neuroscience Program, Yale School of Medicine, Yale University, New Haven, CT, United States
b Medical Scientist Training Program, Yale School of Medicine, Yale University, New Haven, CT, United States
c Department of Neurosurgery, Yale School of Medicine, Yale University, New Haven, CT, United States
d Department of Neurosurgery, Duke University Medical Center, Durham, NC, United States
e Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
f Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, United States
g Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
h Department of Neurology, Columbia University Vagelos College of Physicians and Surgeons and New York Presbyterian Hospital, New York, NY, United States
i GeneDx, Gaithersburg, MD, United States
j Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States
k Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
l Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
m Autism & Developmental Medicine Institute, Geisinger, Lewisburg, PA, United States
n Department of Neurobiology, UAB Heersink School of Medicine, Birmingham, AL, United States
o Department of Pediatrics, Yale University School of Medicine, New Haven, CT, United States
p Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
q Child Study Center, Yale School of Medicine, New Haven, CT, United States
r Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
s Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
t Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, MA, United States
u Department of Radiology, Diagnostic Medicine Institute, Geisinger, Danville, PA, United States
v Broad Institute of Harvard and MIT, Cambridge, MA, United States
w Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
Abstract
Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (ventriculomegaly) is a defining feature of congenital hydrocephalus (CH) and an under-recognized concomitant of autism. Here, we show that de novo mutations in the autism risk gene PTEN are among the most frequent monogenic causes of CH and primary ventriculomegaly. Mouse Pten-mutant ventriculomegaly results from aqueductal stenosis due to hyperproliferation of periventricular Nkx2.1+ neural progenitor cells (NPCs) and increased CSF production from hyperplastic choroid plexus. Pten-mutant ventriculomegalic cortices exhibit network dysfunction from increased activity of Nkx2.1+ NPC-derived inhibitory interneurons. Raptor deletion or postnatal everolimus treatment corrects ventriculomegaly, rescues cortical deficits and increases survival by antagonizing mTORC1-dependent Nkx2.1+ NPC pathology. Thus, PTEN mutations concurrently alter CSF dynamics and cortical networks by dysregulating Nkx2.1+ NPCs. These results implicate a nonsurgical treatment for CH, demonstrate a genetic association of ventriculomegaly and ASD, and help explain neurodevelopmental phenotypes refractory to CSF shunting in select individuals with CH. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2025.
Funding details
Hydrocephalus AssociationHA
March of Dimes FoundationMDF
Simons FoundationSF
National Institute of Neurological Disorders and StrokeNINDSF31NS115519
National Institute of Neurological Disorders and StrokeNINDS
National Institute of Mental HealthNIMHT32GM007205, 1R01MH097949
National Institute of Mental HealthNIMH
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD104938, R01NS127879
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institutes of HealthNIH1R01NS111029-01A1, 1R01NS109358-01
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Attention-mediated genetic influences on psychotic symptomatology in adolescence
(2024) Nature Mental Health, 2 (12), art. no. 80, pp. 1518-1531.
Chang, S.E.a , Hughes, D.E.b , Zhu, J.c , Hyat, M.c , Salone, S.D.a , Goodman, Z.T.d , Roffman, J.L.e , Karcher, N.R.f , Hernandez, L.M.a , Forsyth, J.K.c , Bearden, C.E.a b
a Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, United States
b Department of Psychology, University of California, Los Angeles, Los Angeles, CA, United States
c Department of Psychology, University of Washington, Seattle, WA, United States
d Department of Psychology, University of Miami, Miami, FL, United States
e Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
f Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
Abstract
Attention problems are among the earliest precursors of schizophrenia. In this longitudinal cohort study, we examine relationships between cognitive and neuropsychiatric polygenic scores (PGSs), psychosis-spectrum symptoms and attention-related phenotypes in adolescence (ABCD; n = 11,855; mean baseline age 9.93 ± 0.6). Across three biennial visits, greater attentional variability and altered functional connectivity were associated with severity of psychotic-like experiences (PLEs). In European-ancestry youth, neuropsychiatric and cognitive PGSs were associated with greater PLE severity (R2 = 0.026–0.035) and greater attentional variability (R2 = 0.100–0.109). Notably, the effect of broad neurodevelopmental PGS on PLEs weakened over time, whereas schizophrenia PGS did not. Attentional variability partially mediated relationships between multiple PGSs and PLEs, explaining 4–16% of these associations. Finally, PGSs parsed by developmental coexpression modules were significantly associated with PLE severity, though effect sizes were larger for genome-wide PGSs. Findings implicate broad neurodevelopmental liability in the pathophysiology of psychosis-spectrum symptomatology in adolescence; attentional variability may link risk variants to symptoms. © The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.
Funding details
National Institutes of HealthNIHU01DA051016, U01DA041022, U01DA041117, U01DA051037, U01DA050987, U01DA051038, U01DA041134, U24DA041147, U01DA041148, U01DA041120, U01DA041028, U01DA051039, U24DA041123, U01DA041174, U01DA041089, U01DA041048, U01DA041106, U01DA050989, U01DA041156, U01DA050988, U01DA041025, U01DA041093, U01DA051018
National Institutes of HealthNIH
R01MH124694, R01MH129858, K08MH118577
National Institute of Mental HealthNIMHK01 1K01MH135289-01, K23 MH121792-01
National Institute of Mental HealthNIMH
Document Type: Article
Publication Stage: Final
Source: Scopus
Chronic urinary tract infections cause persistent microglial changes in a humanized ɑ-synuclein mouse model
(2024) Journal of Parkinson’s Disease, 14 (8), pp. 1559-1574.
Mercado, G.a b , Clabout, A.-C.c , Howland, V.a , Arkin, E.c , Janer, A.B.d , Plessers, D.c , Steiner, J.A.a , Smith, W.W.b , Hannan, T.e , Brundin, P.a f , Peelaerts, W.a c
a Parkinson’s Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand RapidsMI, United States
b Division of Neurobiology, Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States
c Laboratory for Virology and Gene Therapy, Department of Pharmacy and Pharmaceutical Sciences, KU Leuven, Leuven, Belgium
d Laboratory for Neurobiology and Gene Therapy, Department of Pharmacy and Pharmaceutical Sciences, KU Leuven, Leuven, Belgium
e Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
f Pharma Research and Early Development (pRED), F. Hoffman-La Roche, Basel, Switzerland
Abstract
BACKGROUND: Urinary tract infections (UTIs) have recently been linked to the onset of multiple synucleinopathies including Parkinson’s disease (PD) and multiple system atrophy (MSA). UTIs are more common in people with PD or MSA, than in the general population and within these patient groups the incidence of UTIs is evenly distributed between men and women. UTIs are especially common during disease, but also in the years before clinical diagnosis. OBJECTIVE: The mechanisms by which UTIs may contribute to the development and progression of PD or MSA are not well understood. In this work, we evaluate the neuroinflammatory effects of recurrent UTIs on the brain. METHODS: In a humanized mouse model of ɑ-synuclein, we find that repeated administration of uropathogenic E. coli result in sustained UTIs, or a non-resolving chronic UTI phenotype with persistent bacteriuria. Using this model, we investigate the effects of repeated chronic UTIs on neuroinflammation and synucleinopathy in the brain. RESULTS: Recurrent UTIs lead to behavioral motor changes and are accompanied by persistent neuroinflammatory changes in multiple brain areas. Affected regions with microglial changes involve multiple lower brainstem areas responsible for sickness behavior, including the dorsal vagal complex, and the cingulate cortex. CONCLUSIONS: These results suggests that recurrent UTIs can have lasting impact on the brain, and it warrants further investigation of the potential role of UTIs in the disease progression of synucleinopathies and related neurological disorders.
This study explores how repeated urinary tract infections (UTIs) might influence the brain and contribute to the development of diseases like Parkinson’s disease (PD) and multiple system atrophy (MSA). UTIs are common, especially in older adults and people with these neurodegenerative diseases, and they can worsen symptoms.A novel mouse model is established by repeatedly infecting mice with a type of bacteria known to cause UTIs in humans. We find that repeated infections lead to persistent UTIs and, more importantly, causes long-term inflammation in the brain. The areas of the brain affected by this inflammation are known to be involved in movement, pain regulation and sickness behavior.The findings suggest that chronic UTIs may not only be a symptom of PD and MSA but that they could also contribute to the progression of these diseases by causing ongoing brain inflammation. This inflammation might make the brain more vulnerable to further damage. Better understanding of these mechanisms could lead to new strategies for preventing or slowing the progression of these neurodegenerative diseases. The study highlights the need for more research to determine how managing UTIs could potentially protect the brain and improve outcomes for people at risk of or living with PD and MSA.
Author Keywords
multiple system atrophy; neuroinflammation; Parkinson’s disease; synuclein; synucleinopathies; urinary tract infections
Document Type: Article
Publication Stage: Final
Source: Scopus