WashU weekly Neuroscience publications | Office of Neuroscience Research

"A machine learning approach for the factorization of psychometric data with application to the Delis Kaplan Executive Function System" (2021) Scientific Reports

A machine learning approach for the factorization of psychometric data with application to the Delis Kaplan Executive Function System
(2021) Scientific Reports, 11 (1), art. no. 16896, .

Camilleri, J.A.^a ^b , Eickhoff, S.B.^a ^b , Weis, S.^a ^b , Chen, J.^a ^b ^c , Amunts, J.^a ^b , Sotiras, A.^d , Genon, S.^a ^b

^a Institute of Neuroscience and Medicine (INM-7 Brain and Behaviour), Forschungszentrum Jülich, Jülich, Germany
^b Institute of Systems Neuroscience, Heinrich-Heine University, Düsseldorf, Germany
^c Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou, China
^d Mallinckrodt Institute of Radiology, Institute for Informatics, Washington University in Saint Louis, Saint Louis, United States

Abstract
While a replicability crisis has shaken psychological sciences, the replicability of multivariate approaches for psychometric data factorization has received little attention. In particular, Exploratory Factor Analysis (EFA) is frequently promoted as the gold standard in psychological sciences. However, the application of EFA to executive functioning, a core concept in psychology and cognitive neuroscience, has led to divergent conceptual models. This heterogeneity severely limits the generalizability and replicability of findings. To tackle this issue, in this study, we propose to capitalize on a machine learning approach, OPNMF (Orthonormal Projective Non-Negative Factorization), and leverage internal cross-validation to promote generalizability to an independent dataset. We examined its application on the scores of 334 adults at the Delis–Kaplan Executive Function System (D-KEFS), while comparing to standard EFA and Principal Component Analysis (PCA). We further evaluated the replicability of the derived factorization across specific gender and age subsamples. Overall, OPNMF and PCA both converge towards a two-factor model as the best data-fit model. The derived factorization suggests a division between low-level and high-level executive functioning measures, a model further supported in subsamples. In contrast, EFA, highlighted a five-factor model which reflects the segregation of the D-KEFS battery into its main tasks while still clustering higher-level tasks together. However, this model was poorly supported in the subsamples. Thus, the parsimonious two-factors model revealed by OPNMF encompasses the more complex factorization yielded by EFA while enjoying higher generalizability. Hence, OPNMF provides a conceptually meaningful, technically robust, and generalizable factorization for psychometric tools. © 2021, The Author(s).

Funding details
National Institute of Mental HealthNIMHR01-MH074457
National Institute on AgingNIAR01AG067103
Horizon 2020 Framework ProgrammeH2020785907, 826421, 945539
Deutsche ForschungsgemeinschaftDFGEI 816/16-1, EI 816/21-1, GE 2835/2–1

Document Type: Article
Publication Stage: Final
Source: Scopus

"Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project" (2021) Alzheimer's Research and Therapy

Developing methods to detect and diagnose chronic traumatic encephalopathy during life: rationale, design, and methodology for the DIAGNOSE CTE Research Project
(2021) Alzheimer’s Research and Therapy, 13 (1), art. no. 136, .

Alosco, M.L.^a , Mariani, M.L.^b , Adler, C.H.^c , Balcer, L.J.^d , Bernick, C.^e ^ac , Au, R.^f ^ad ^ae , Banks, S.J.^g , Barr, W.B.^h , Bouix, S.ⁱ , Cantu, R.C.^j , Coleman, M.J.^k , Dodick, D.W.^c , Farrer, L.A.^l , Geda, Y.E.^m , Katz, D.I.ⁿ ^af , Koerte, I.K.ⁱ ^ag , Kowall, N.W.^j ^ah , Lin, A.P.^o , Marcus, D.S.^p , Marek, K.L.^q , McClean, M.D.^r , McKee, A.C.^a ^ah , Mez, J.^s , Palmisano, J.N.^t , Peskind, E.R.^u , Tripodis, Y.^v , Turner, R.W., II^w , Wethe, J.V.^x , Cummings, J.L.^y , Reiman, E.M.^z , Shenton, M.E.^aa , Stern, R.A.^ab ^ai , Banks, S.^ai , Barr, W.^ai , Chen, K.^ai , Farrer, L.^ai , Fitzsimmons, J.^ai , Geda, Y.^ai , Goldberg, J.^ai , Helm, R.^ai , Johnson, K.A.^ai , Kirov, I.^ai , Kowall, N.^ai , Lui, Y.^ai , Mariani, M.^ai , Marmar, C.^ai , McClean, M.^ai , Miller, J.^ai , Pasternak, O.^ai , Protas, H.^ai , Reiman, E.^ai , Ritter, A.^ai , Stern, R.A.^ai , Su, Y.^ai , Turner, R.W.^ai , Weller, J.^ai , for the DIAGNOSE CTE Research Project Investigators^ai

^a Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^b Boston University CTE Center, Boston University School of Medicine, Boston, MA, United States
^c Department of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
^d Departments of Neurology, Population Health and Ophthalmology, NYU Grossman School of Medicine, New York, NY, United States
^e Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
^f Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Framingham Heart Study, and Slone Epidemiology Center, Boston, MA, United States
^g Departments of Neuroscience and Psychiatry, University of California, San Diego, CA, United States
^h Department of Neurology, NYU Grossman School of Medicine, New York, NY, United States
ⁱ Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^j Boston University Alzheimer’s Disease Research Center, Departments of Neurology and Neurosurgery, Boston University School of Medicine, Boston, MA, United States
^k Psychiatry Neuroimaging Laboratory, Brigham and Women’s Hospital, Boston, MA, United States
^l Departments of Medicine (Biomedical Genetics), Neurology, Ophthalmology, Epidemiology, and Biostatistics, BU Schools of Medicine and Public Health, Boston, MA, United States
^m Alzheimer’s Disease and Memory Disorders Program, Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
ⁿ Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^o Center for Clinical Spectroscopy, Department of Radiology, Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^p Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^q Institute for Neurodegenerative Disorders, Invicro, LLC, New Haven, CT, United States
^r Department of Environmental Health, Boston University School of Public Health, Boston, MA, United States
^s Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Framingham Heart Study, Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^t Biostatistics and Epidemiology Data Analytics Center (BEDAC), Boston University School of Public Health, Boston, MA, United States
^u VA Northwest Mental Illness Research, Education, and Clinical Center, VA Puget Sound Health Care System, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, United States
^v Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^w Department of Clinical Research & Leadership, The George Washington University School of Medicine & Health Sciences, Washington, DC, United States
^x Department of Psychiatry and Psychology, Mayo Clinic School of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, United States
^y Chambers-Grundy Center for Transformative Neuroscience, Department of Brain Health, School of Integrated Health Sciences, University of Nevada Las Vegas, Las Vegas, NV, United States
^z Banner Alzheimer’s Institute, University of Arizona, Arizona State University, Translational Genomics Research Institute, and Arizona Alzheimer’s Consortium, Phoenix, AZ, United States
^aa Psychiatry Neuroimaging Laboratory, Departments of Psychiatry and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^ab Boston University Alzheimer’s Disease Research Center, Boston University CTE Center, Departments of Neurology, Neurosurgery, and Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, United States
^ac Department of Neurology, University of Washington, Seattle, WA, United States
^ad Departments of Anatomy & Neurobiology and Neurology, Boston University School of Medicine, Boston, MA, United States
^ae Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
^af Encompass Health Braintree Rehabilitation Hospital, Braintree, MA, United States
^ag cBRAIN, Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwigs-Maximilians-Universität, Munich, Germany
^ah VA Boston Healthcare System, Boston, MA, United States

Abstract
Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the “Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project.” The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. Methods: The targeted sample and sample size was 240 male participants, ages 45–74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. Results: Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. Conclusions: Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. Trial registration: NCT02798185 © 2021, The Author(s).

Author Keywords
Biomarkers; Chronic traumatic encephalopathy; Cognitive function; College football; Concussion; Football; Head trauma; MRI; MRS; National Football League; Neurodegenerative disease; Neuroimaging; Positron emission tomography; Remote assessment; Repetitive head impacts; Subconcussion; Tau; Traumatic brain injury; Traumatic encephalopathy syndrome

Funding details
1UL1TR001430
National Institutes of HealthNIHK00NS113419, K01AG054762, K23NS102399, P30AG019610, P30AG13846, R01NS078337, R01NS100952
National Institute of Neurological Disorders and StrokeNINDSU01NS093334
National Center for Advancing Translational SciencesNCATS

Document Type: Article
Publication Stage: Final
Source: Scopus

"Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection" (2021) Experimental Neurology

Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection
(2021) Experimental Neurology, 345, art. no. 113842, .

Sasaki, Y.^a ^e , Zhu, J.^a ^e , Shi, Y.^b , Gu, W.^c , Kobe, B.^c , Ve, T.^b , DiAntonio, A.^d ^e ^e , Milbrandt, J.^a ^e ^e

^a Washington University School of Medicine in Saint Louis, Department of Genetics, St. Louis, MO, United States
^b Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia
^c School of Chemistry and Molecular Biosciences, Institute for Molecular Bioscience and Australian Infectious Diseases Research Centre, University of QueenslandQLD 4072, Australia
^d Washington University School of Medicine in Saint Louis, Department of Developmental Biology, St. Louis, MO, United States
^e Needleman Center for Neurometabolism and Axonal Therapeutics, United States

Abstract
SARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders. © 2021 Elsevier Inc.

Author Keywords
crystallography; mass spectrometer; NADase; NAMPT; Neuropathy; NMR; TIR; Traumatic brain injury; Vitamin; Wallerian degeneration; X-ray

Funding details
National Institutes of HealthNIHR01CA219866, RF1AG013730, RO1NS087632
Australian Research CouncilARCFL180100109, FT200100572
National Health and Medical Research CouncilNHMRC1071659, 1107804, 1160570, 1196590

Document Type: Article
Publication Stage: Final
Source: Scopus

"CACHD1-deficient mice exhibit hearing and balance deficits associated with a disruption of calcium homeostasis in the inner ear" (2021) Hearing Research

CACHD1-deficient mice exhibit hearing and balance deficits associated with a disruption of calcium homeostasis in the inner ear
(2021) Hearing Research, 409, art. no. 108327, .

Tian, C.^a ^c , Johnson, K.R.^a , Lett, J.M.^b , Voss, R.^b , Salt, A.N.^b , Hartsock, J.J.^b , Steyger, P.S.^c , Ohlemiller, K.K.^b

^a The Jackson Laboratory, Bar HarborME 04609, United States
^b Department of Otolaryngology, Central Institute for the Deaf, Fay and Carl Simons Center for Hearing and Deafness, Washington University School of Medicine, 660 S. Euclid, Saint Louis, MO 63110, United States
^c Department of Biomedical Sciences, School of Medicine, Creighton University, 2500 California Plaza, Omaha, NE 68178, United States

Abstract
CACHD1 recently was shown to be an α2δ-like subunit that can modulate the activity of some types of voltage-gated calcium channels, including the low-voltage activated, T-type CaV3 channels. CACHD1 is widely expressed in the central nervous system but its biological functions and relationship to disease states are unknown. Here, we report that mice with deleterious Cachd1 mutations are hearing impaired and have balance defects, demonstrating that CACHD1 is functionally important in the peripheral auditory and vestibular organs of the inner ear. The vestibular dysfunction of Cachd1 mutant mice, exhibited by leaning and head tilting behaviors, is related to a deficiency of calcium carbonate crystals (otoconia) in the saccule and utricle. The auditory dysfunction, shown by ABR threshold elevations and reduced DPOAEs, is associated with reduced endocochlear potentials and increased endolymph calcium concentrations. Paint-fills of mutant inner ears from prenatal and newborn mice revealed dilation of the membranous labyrinth caused by an enlarged volume of endolymph. These pathologies all can be related to a disturbance of calcium homeostasis in the endolymph of the inner ear, presumably caused by the loss of CACHD1 regulatory effects on voltage-gated calcium channel activity. Cachd1 expression in the cochlea appears stronger in late embryonic stages than in adults, suggesting an early role in establishing endolymph calcium concentrations. Our findings provide new insights into CACHD1 function and suggest the involvement of voltage-gated calcium channels in endolymph homeostasis, essential for normal auditory and vestibular function. © 2021 Elsevier B.V.

Author Keywords
Cochlea; Endocochlear potential; Endolymph; Macula; Mouse; Otolith

Funding details
National Institutes of HealthNIHP30-CA034196, R01-DC004301

Document Type: Article
Publication Stage: Final
Source: Scopus

"Primate Spatial Memory Cells Become Tuned Early and Lose Tuning at Cell-Specific Times" (2021) Cerebral Cortex

Primate Spatial Memory Cells Become Tuned Early and Lose Tuning at Cell-Specific Times
(2021) Cerebral Cortex, 31 (9), pp. 4206-4219.

Papadimitriou, C.^a , Holmes, C.D.^a ^b , Snyder, L.H.^a ^b

^a Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Working memory, the ability to maintain and transform information, is critical for cognition. Spatial working memory is particularly well studied. The premier model for spatial memory is the continuous attractor network, which posits that cells maintain constant activity over memory periods. Alternative models propose complex dynamics that result in a variety of cell activity time courses. We recorded from neurons in the frontal eye fields and dorsolateral prefrontal cortex of 2 macaques during long (5-15 s) memory periods. We found that memory cells turn on early after stimulus presentation, sustain activity for distinct and fixed lengths of time, then turn off and stay off for the remainder of the memory period. These dynamics are more complex than the dynamics of a canonical bump attractor network model (either decaying or nondecaying) but more constrained than the dynamics of fully heterogeneous memory models. We speculate that memory may be supported by multiple attractor networks working in parallel, with each network having its own characteristic mean turn-off time such that mnemonic resources are gradually freed up over time. © 2021 The Author(s). Published by Oxford University Press.

Author Keywords
frontal eye fields; macaque; prefrontal cortex; working memory

Document Type: Article
Publication Stage: Final
Source: Scopus

"Evoking highly focal percepts in the fingertips through targeted stimulation of sulcal regions of the brain for sensory restoration" (2021) Brain Stimulation

Evoking highly focal percepts in the fingertips through targeted stimulation of sulcal regions of the brain for sensory restoration
(2021) Brain Stimulation, 14 (5), pp. 1184-1196.

Chandrasekaran, S.^a , Bickel, S.^b ^c ^d , Herrero, J.L.^b ^c , Kim, J.-W.^e , Markowitz, N.^b , Espinal, E.^b , Bhagat, N.A.^a , Ramdeo, R.^a , Xu, J.^e , Glasser, M.F.^f , Bouton, C.E.^a ^g , Mehta, A.D.^b ^c

^a Neural Bypass and Brain Computer Interface Laboratory, Feinstein Institutes for Medical Research, Northwell Health, ManhassetNY, United States
^b The Human Brain Mapping Laboratory, Feinstein Institutes for Medical Research, Northwell Health, ManhassetNY, United States
^c Department of Neurosurgery, Northwell, ManhassetNY, United States
^d Department of Neurology, Donald and Barbara Zucker School of Medicine at Hofstra, Northwell, ManhassetNY, United States
^e Departments of Radiology and Psychiatry, Baylor College of Medicine, Houston, TX, United States
^f Departments of Radiology and Neuroscience, Washington University in St Louis, Saint Louis, MO, United States
^g Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, ManhassetNY, United States

Abstract
Background: Paralysis and neuropathy, affecting millions of people worldwide, can be accompanied by significant loss of somatosensation. With tactile sensation being central to achieving dexterous movement, brain-computer interface (BCI) researchers have used intracortical and cortical surface electrical stimulation to restore somatotopically-relevant sensation to the hand. However, these approaches are restricted to stimulating the gyral areas of the brain. Since representation of distal regions of the hand extends into the sulcal regions of human primary somatosensory cortex (S1), it has been challenging to evoke sensory percepts localized to the fingertips. Objective/hypothesis: Targeted stimulation of sulcal regions of S1, using stereoelectroencephalography (SEEG) depth electrodes, can evoke focal sensory percepts in the fingertips. Methods: Two participants with intractable epilepsy received cortical stimulation both at the gyri via high-density electrocorticography (HD-ECoG) grids and in the sulci via SEEG depth electrode leads. We characterized the evoked sensory percepts localized to the hand. Results: We show that highly focal percepts can be evoked in the fingertips of the hand through sulcal stimulation. fMRI, myelin content, and cortical thickness maps from the Human Connectome Project elucidated specific cortical areas and sub-regions within S1 that evoked these focal percepts. Within-participant comparisons showed that percepts evoked by sulcal stimulation via SEEG electrodes were significantly more focal (80% less area; p = 0.02) and localized to the fingertips more often, than by gyral stimulation via HD-ECoG electrodes. Finally, sulcal locations with consistent modulation of high-frequency neural activity during mechanical tactile stimulation of the fingertips showed the same somatotopic correspondence as cortical stimulation. Conclusions: Our findings indicate minimally invasive sulcal stimulation via SEEG electrodes could be a clinically viable approach to restoring sensation. © 2021

Author Keywords
Brain-computer interface; Fingertip representation; Sensory percepts; Sensory restoration; Stereoelectroencephalography depth electrodes

Funding details
National Institutes of HealthNIHR01MH060974

Document Type: Article
Publication Stage: Final
Source: Scopus

"ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids" (2021) Cell

ELAVL4, splicing, and glutamatergic dysfunction precede neuron loss in MAPT mutation cerebral organoids
(2021) Cell, 184 (17), pp. 4547-4563.e17. Cited 1 time.

Bowles, K.R.^a , Silva, M.C.^b , Whitney, K.^a ^c , Bertucci, T.^d , Berlind, J.E.^e , Lai, J.D.^e ^f , Garza, J.C.^b , Boles, N.C.^d , Mahali, S.^g , Strang, K.H.^a ^c , Marsh, J.A.^g , Chen, C.^g , Pugh, D.A.^a , Liu, Y.^a , Gordon, R.E.^c , Goderie, S.K.^d , Chowdhury, R.^d , Lotz, S.^d , Lane, K.^d , Crary, J.F.^c , Haggarty, S.J.^b , Karch, C.M.^g , Ichida, J.K.^e , Goate, A.M.^a , Temple, S.^d

^a Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain Institute, Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY 10029, United States
^b Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology and Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
^c Department of Pathology, Neuropathology Brain Bank and Research Core, ISMMS, New York, NY 10029, United States
^d Neural Stem Cell Institute, Rensselaer, NY 12144, United States
^e Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
^f Amgen Research, One Amgen Center Dr., Thousand Oaks, CA 91320, United States
^g Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Frontotemporal dementia (FTD) because of MAPT mutation causes pathological accumulation of tau and glutamatergic cortical neuronal death by unknown mechanisms. We used human induced pluripotent stem cell (iPSC)-derived cerebral organoids expressing tau-V337M and isogenic corrected controls to discover early alterations because of the mutation that precede neurodegeneration. At 2 months, mutant organoids show upregulated expression of MAPT, glutamatergic signaling pathways, and regulators, including the RNA-binding protein ELAVL4, and increased stress granules. Over the following 4 months, mutant organoids accumulate splicing changes, disruption of autophagy function, and build-up of tau and P-tau-S396. By 6 months, tau-V337M organoids show specific loss of glutamatergic neurons as seen in individuals with FTD. Mutant neurons are susceptible to glutamate toxicity, which can be rescued pharmacologically by the PIKFYVE kinase inhibitor apilimod. Our results demonstrate a sequence of events that precede neurodegeneration, revealing molecular pathways associated with glutamate signaling as potential targets for therapeutic intervention in FTD. © 2021

Author Keywords
autophagy; ELAVL4; frontotemporal dementia; glutamatergic neurons; MAPT; organoids; splicing; synaptic signaling; tauopathy

Funding details
NS110890, R01AG054008, R01NS095252
National Institutes of HealthNIHAG046374
U.S. Department of DefenseDODW81XWH-20-1-0424, W81XWH-21-1-0131, W81XWH-21-1-0168
National Institute on AgingNIA2R01NS097850, R01 AG056293
National Institute of Neurological Disorders and StrokeNINDSF31NS117075, R35 NS097277
California Institute for Regenerative MedicineCIRM
ALS AssociationALSA
Alzheimer’s Drug Discovery FoundationADDF
New York Stem Cell FoundationNYSCF
Association for Frontotemporal DegenerationAFTD
Genentech
GlaxoSmithKlineGSK
Biogen
BrightFocus FoundationBFF
AbbVie
New York State Stem Cell ScienceNYSTEMC029158
Hope Center for Neurological Disorders
New York Genome CenterNYGCU01AG045390, U54NS092089
Rainwater Charitable FoundationRCF
Tau Consortium
Denali Therapeutics
Eisai
Sächsische AufbaubankSAB

Document Type: Article
Publication Stage: Final
Source: Scopus

"Induction of Ventral Spinal V0 Interneurons from Mouse Embryonic Stem Cells" (2021) Stem Cells and Development

Induction of Ventral Spinal V0 Interneurons from Mouse Embryonic Stem Cells
(2021) Stem Cells and Development, 30 (16), art. no. 0003, pp. 816-829.

Pardieck, J.^a ^b , Harb, M.^a , Sakiyama-Elbert, S.^a

^a Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The ventral spinal population of V0 interneurons (INs) contributes to the coordinated movements directed by spinal central pattern generators (CPGs), including respiratory circuits and left-right alternation in locomotion. One challenge in studying V0 INs has been the limited number of cells that can be isolated from primary sources for basic research or therapeutic use. However, derivation from a pluripotent source, such as has been done recently for other IN populations, could resolve this issue. However, there is currently no protocol to specifically derive V0 interneurons from pluripotent cell types. To generate an induction protocol, mouse embryonic stem cells (mESCs) were grown in suspension culture and then exposed to retinoic acid (RA) and collected at different time points to measure mRNA expression of the V0 progenitor transcription factor marker, Dbx1, and postmitotic transcription factor marker, Evx1. The cultures were also exposed to the sonic hedgehog signaling pathway agonist purmorphamine (purm) and the Notch signaling pathway inhibitor N-{N-(3,5-difluorophenacetyl-L-alanyl)}-(S)-phenylglycine-t-butyl-ester (DAPT) to determine if either of these pathways contribute to V0 IN induction, specifically the ventral (V0V) subpopulation. From the various parameters tested, the final protocol that generated the greatest percentage of cells expressing V0V IN markers was an 8-day protocol using 4 days of suspension culture to form embryoid bodies followed by addition of 1 μM RA from days 4 to 8, 100 nM purm from days 4 to 6, and 5 μM DAPT from days 6 to 8. This protocol will allow investigators to obtain V0 IN cultures for use in in vitro studies, such as those examining CPG microcircuits, electrophysiological characterization, or even for transplantation studies in injury or disease models. © Copyright 2021, Mary Ann Liebert, Inc., publishers 2021.

Author Keywords
central pattern generator; induction protocol; motor control; spinal cord injury; transcription factor; ventral patterning

Document Type: Article
Publication Stage: Final
Source: Scopus

"Influence of Mpv17 on Hair-Cell Mitochondrial Homeostasis, Synapse Integrity, and Vulnerability to Damage in the Zebrafish Lateral Line" (2021) Frontiers in Cellular Neuroscience

Influence of Mpv17 on Hair-Cell Mitochondrial Homeostasis, Synapse Integrity, and Vulnerability to Damage in the Zebrafish Lateral Line
(2021) Frontiers in Cellular Neuroscience, 15, art. no. 693375, .

Holmgren, M.^a , Sheets, L.^a ^b

^a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Noise exposure is particularly stressful to hair-cell mitochondria, which must produce enough energy to meet high metabolic demands as well as regulate local intracellular Ca2+ concentrations. Mitochondrial Inner Membrane Protein 17 (Mpv17) functions as a non-selective cation channel and plays a role in maintaining mitochondrial homeostasis. In zebrafish, hair cells in mpv17a9/a9 mutants displayed elevated levels of reactive oxygen species (ROS), elevated mitochondrial calcium, hyperpolarized transmembrane potential, and greater vulnerability to neomycin, indicating impaired mitochondrial function. Using a strong water current to overstimulate hair cells in the zebrafish lateral line, we observed mpv17a9/a9 mutant hair cells were more vulnerable to morphological disruption than wild type (WT) siblings simultaneously exposed to the same stimulus. To determine the role of mitochondrial homeostasis on hair-cell synapse integrity, we surveyed synapse number in mpv17a9/a9 mutants and WT siblings as well as the sizes of presynaptic dense bodies (ribbons) and postsynaptic densities immediately following stimulus exposure. We observed mechanically injured mpv17a9/a9 neuromasts were not more vulnerable to synapse loss; they lost a similar number of synapses per hair cell relative to WT. Additionally, we quantified the size of hair cell pre- and postsynaptic structures following stimulation and observed significantly enlarged WT postsynaptic densities, yet relatively little change in the size of mpv17a9/a9 postsynaptic densities following stimulation. These results suggest chronically impaired hair-cell mitochondrial activity influences postsynaptic size under homeostatic conditions but does not exacerbate synapse loss following mechanical injury. © Copyright © 2021 Holmgren and Sheets.

Author Keywords
damage; hair cell; mitochondrial homeostasis; Mpv17; neuromast

Funding details
National Institute on Deafness and Other Communication DisordersNIDCDR01DC016066

Document Type: Article
Publication Stage: Final
Source: Scopus

"The influence of childhood adversities on mid to late cognitive function: From the perspective of life course" (2021) PLoS ONE

The influence of childhood adversities on mid to late cognitive function: From the perspective of life course
(2021) PLoS ONE, 16 (8 August), art. no. e0256297, .

Ma, J.^a , Yang, Y.^b , Wan, Y.^c , Shen, C.^b , Qiu, P.^c

^a Office of Cancer Prevention and Treatment, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
^b The Brown School, Washington University in Saint Louis, Saint Louis, MO, United States
^c West China School of Public Health, West China Fourth Hospital, Sichuan University, Chengdu, China

Abstract
Background The effects of childhood adversities on cognitive function in later life are well reported. However, few studies have examined the cumulative mechanism, especially in Chinese population. This study aims to explore this cumulative effects of childhood adversities on mid to late cognitive decline in China. Methods Data were drawn from the second and third wave of the China Health and Retirement Longitudinal Study (CHARLS). We included 9,942 respondents aged 45 and above and retrospectively collected information on childhood adversities. Cognitive function was measured in three dimensions: orientation and calculation, immediate memory, and delayed memory. A structural equation model was employed for analysis. Results Age (β = -0.155, P<0.001) and mid to late depressive symptoms (β = -0.041, P<0.001) showed direct effects on cognitive decline. Low mid to late life socioeconomic status (SES) showed a direct effect on mid-late cognitive impairment (β = 0.603, P<0.001) and an indirect effect through depression (β = 0.007, P<0.001). Low childhood SES (β = 0.310, P<0.001), lack of friends (β = 0.208, P<0.001), parental mental health problems (β = 0.008, P<0.001), and poor relationship with parents (β = 0.001, P<0.001) had an indirect effect on cognitive impairment. Conclusions Childhood adversities had negative effects on cognitive function among middle aged and elderly population in China. The findings suggest that early counter measures on childhood adversities may lead to an effective reduction of cognitive impairment. Copyright: © 2021 Ma et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus

"Does ventromedial prefrontal cortex damage really increase impulsiveness? Delay and probability discounting in patients with focal lesions" (2021) Journal of Cognitive Neuroscience

Does ventromedial prefrontal cortex damage really increase impulsiveness? Delay and probability discounting in patients with focal lesions
(2021) Journal of Cognitive Neuroscience, 33 (9), pp. 1909-1927. Cited 1 time.

Mok, J.N.Y.^a , Green, L.^b , Myerson, J.^b , Kwan, D.^a , Kurczek, J.^c , Ciaramelli, E.^d , Craver, C.F.^b , Rosenbaum, R.S.^a ^e

^a York University, Toronto, ON, Canada
^b Washington University, St. Louis, MO, United States
^c Loras College, Dubuque, IA, United States
^d Università di Bologna, Italy
^e Rotman Research Institute, Toronto, ON, Canada

Abstract
If the tendency to discount rewards reflects individuals’ general level of impulsiveness, then the discounting of delayed and probabilistic rewards should be negatively correlated: The less a person is able to wait for delayed rewards, the more they should take chances on receiving probabilistic rewards. It has been suggested that damage to the ventromedial prefrontal cortex (vmPFC) increases individuals’ impulsiveness, but both intertemporal choice and risky choice have only recently been assayed in the same patients with vmPFC damage. Here, we assess both delay and probability discounting in individuals with vmPFC damage (n = 8) or with medial temporal lobe (MTL) damage (n = 10), and in age-and education-matched controls (n = 30). On average, MTL-lesioned individuals discounted delayed rewards at normal rates but discounted probabilistic rewards more shallowly than controls. In contrast, vmPFC-lesioned individuals discounted delayed rewards more steeply but probabilistic rewards more shallowly than controls. These results suggest that vmPFC lesions affect the weighting of reward amount relative to delay and certainty in opposite ways. Moreover, whereas MTL-lesioned individuals and controls showed typical, nonsig-nificant correlations between the discounting of delayed and probabilistic rewards, vmPFC-lesioned individuals showed a significant negative correlation, as would be expected if vmPFC damage increases impulsiveness more in some patients than in others. Although these results are consistent with the hypothesis that vmPFC plays a role in impulsiveness, it is unclear how they could be explained by a single mechanism governing valuation of both delayed and probabilistic rewards. © 2020 Massachusetts Institute of Technology.

Funding details
National Institute on AgingNIA13039/100000049, R01AG058885
Natural Sciences and Engineering Research Council of CanadaNSERCRGPIN-04238-2015

Document Type: Article
Publication Stage: Final
Source: Scopus

"Parental educational attainment, the superior temporal cortical surface area, and reading ability among american children: A test of marginalization-related diminished returns" (2021) Children

Parental educational attainment, the superior temporal cortical surface area, and reading ability among american children: A test of marginalization-related diminished returns
(2021) Children, 8 (5), art. no. 412, .

Assari, S.^a ^b ^c , Boyce, S.^a ^d , Bazargan, M.^a ^c ^e , Thomas, A.^f , Cobb, R.J.^g , Hudson, D.^h , Curry, T.J.ⁱ , Nicholson, H.L., Jr.^j , Cuevas, A.G.^k ^l , Mistry, R.^m , Chavous, T.M.ⁿ ^o ^p , Caldwell, C.H.^m ^q , Zimmerman, M.A.^m ^r

^a Minorities’ Diminished Returns (MDRs) Center, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, United States
^b Department of Urban Public Health, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, United States
^c Department of Family Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, United States
^d Department of Pediatrics, Charles R. Drew University of Medicine and Science, Los Angeles, CA 90059, United States
^e Department of Family Medicine, University of California-Los Angeles (UCLA), Los Angeles, CA 90095, United States
^f Human Development and Family Studies Department, School of Human Ecology, University of Wisconsin-Madison, Madison, WI 53706, United States
^g Department of Sociology, University of Georgia, Athens, GA 30602, United States
^h Brown School, Washington University, St. Louis, MO 63130, United States
ⁱ Department of Philosophy, School of Philosophy, Psychology and Language Sciences, University of Edinburgh, Edinburgh, EH8 9JS, United Kingdom
^j Department of Sociology and Criminology & Law, University of Florida, Gainesville, FL 32611-7330, United States
^k Psychosocial Determinants of Health (PSDH) Lab, Tufts University, Boston, MA 02155, United States
^l Department of Community Health, Tufts University, Boston, MA 02155, United States
^m Department of Health Behavior and Health Education, University of Michigan School of Public Health, Ann Arbor, MI 48109-2029, United States
ⁿ School of Education, University of Michigan, Ann Arbor, MI 48109-2029, United States
^o National Center for Institutional Diversity, University of Michigan, Ann Arbor, MI 48109-2029, United States
^p Department of Psychology, University of Michigan, Ann Arbor, MI 48109-2029, United States
^q Center for Research on Ethnicity, Culture, and Health (CRECH), University of Michigan, School of Public Health, Ann Arbor, MI 48109-2029, United States
^r Prevention Research Center, University of Michigan School of Public Health, Ann Arbor, MI 48109-2029, United States

Abstract
Background: Recent studies have shown that parental educational attainment is associated with a larger superior temporal cortical surface area associated with higher reading ability in children. Simultaneously, the marginalization-related diminished returns (MDRs) framework suggests that, due to structural racism and social stratification, returns of parental education are smaller for black and other racial/ethnic minority children compared to their white counterparts. Purpose: This study used a large national sample of 9–10-year-old American children to investigate associations between parental educational attainment, the right and left superior temporal cortical surface area, and reading ability across diverse racial/ethnic groups. Methods: This was a cross-sectional analysis that included 10,817 9–10-year-old children from the Adolescent Brain Cognitive Development (ABCD) study. Parental educational attainment was treated as a five-level categorical variable. Children’s right and left superior temporal cortical surface area and reading ability were continuous variables. Race/ethnicity was the moderator. To adjust for the nested nature of the ABCD data, mixed-effects regression models were used to test the associations between parental education, superior temporal cortical surface area, and reading ability overall and by race/ethnicity. Results: Overall, high parental educational attainment was associated with greater superior temporal cortical surface area and reading ability in children. In the pooled sample, we found statistically significant interactions between race/ethnicity and parental educational attainment on children’s right and left superior temporal cortical surface area, suggesting that high parental educational attainment has a smaller boosting effect on children’s superior temporal cortical surface area for black than white children. We also found a significant interaction between race and the left superior temporal surface area on reading ability, indicating weaker associations for Alaskan Natives, Native Hawaiians, and Pacific Islanders (AIAN/NHPI) than white children. We also found interactions between race and parental educational attainment on reading ability, indicating more potent effects for black children than white children. Conclusion: While parental educational attainment may improve children’s superior temporal cortical surface area, promoting reading ability, this effect may be unequal across racial/ethnic groups. To minimize the racial/ethnic gap in children’s brain development and school achievement, we need to address societal barriers that diminish parental educational attainment’s marginal returns for middle-class minority families. Social and public policies need to go beyond equal access and address structural and societal barriers that hinder middle-class families of color and their children. Future research should test how racism, social stratification, segregation, and discrimination, which shape the daily lives of non-white individuals, take a toll on children’s brains and academic development. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Adolescents; Brain development; Child; Cortical surface; Magnetic resonance imaging; Population groups; Reading; School perfor-mance; Socioeconomic factors

Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U24DA041123, U24DA041147
Centers for Disease Control and PreventionCDC5S21MD000103, CA201415 02, D084526-03, DA035811-05, U54CA229974, U54MD007598, U54MD008149
University of California, San DiegoUCSD

Document Type: Article
Publication Stage: Final
Source: Scopus

"Genetic differential susceptibility to the parent–child relationship quality and the life span development of compassion" (2021) Developmental Psychobiology

Genetic differential susceptibility to the parent–child relationship quality and the life span development of compassion
(2021) Developmental Psychobiology, .

Dobewall, H.^a ^b ^c , Keltikangas-Järvinen, L.^b , Saarinen, A.^b , Lyytikäinen, L.-P.^c ^d , Zwir, I.^e ^f , Cloninger, R.^e , Raitakari, O.T.^g ^h ⁱ , Lehtimäki, T.^c ^d , Hintsanen, M.^a

^a Division of Psychology, Faculty of Education, University of Oulu, Oulu, Finland
^b Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
^c Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center – Tampere, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^d Finnish Cardiovascular Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Computer Science, University of Granada, Granada, Spain
^g Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
^h Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
ⁱ Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland

Abstract
The development of compassion for others might be influenced by the social experiences made during childhood and has a genetic component. No research has yet investigated whether the parent–child relationship quality interacts with genetic variation in the oxytocin and dopamine systems in predicting compassion over the life span. In the prospective Young Finns Study (N = 2099, 43.9% men), we examined the interaction between mother-reported emotional warmth and intolerance toward their child assessed in 1980 (age of participants, 3–18 years) and two established genetic risk scores for oxytocin levels and dopamine signaling activity. Dispositional compassion for others was measured with the Temperament and Character Inventory 1997, 2001, and 2012 (age of participants, 20–50 years). We found a gene–environment interaction (p =.031) that remained marginally significant after adjustment for multiple testing. In line with the differential susceptibility hypothesis, only participants who carry alleles associated with low dopamine signaling activity had higher levels of compassion when growing up with emotionally warm parents, whereas they had lower levels of compassion when their parents were emotionally cold. Children’s genetic variability in the dopamine system might result in plasticity to early environmental influences that have a long-lasting effect on the development of compassion. However, our findings need replication. © 2021 Wiley Periodicals LLC

Author Keywords
compassion; dopamine and oxytocin signaling pathways; gene–environment interaction; parenting; personality development

Funding details
Yrjö Jahnssonin Säätiö
European Research CouncilERC742927
Academy of FinlandAKA117787, 121584, 124282, 126925, 129378, 134309, 286284, 308676, 322098, 41071
Suomen KulttuurirahastoSKR
Juho Vainion Säätiö
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Tampereen Tuberkuloosisäätiö
Horizon 2020755320, 848146
Paavo Nurmen Säätiö
Turun Yliopistollinen KeskussairaalaAUCSX51001

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

"Links between socioeconomic disadvantage, neural function, and working memory in early childhood" (2021) Developmental Psychobiology

Links between socioeconomic disadvantage, neural function, and working memory in early childhood
(2021) Developmental Psychobiology, .

Li, X.^a , Lipschutz, R.^a , Hernandez, S.M.^b , Biekman, B.^a , Shen, S.^a , Montgomery, D.A.^a , Perlman, S.B.^c , Pollonini, L.^b , Bick, J.^a

^a Department of Psychology, University of Houston, Houston, TX, United States
^b Department of Engineering Technology, University of Houston, Houston, TX, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Children reared in socioeconomically disadvantaged environments are at risk for academic, cognitive, and behavioral problems. Mounting evidence suggests that childhood adversities, encountered at disproportionate rates in contexts of socioeconomic risk, shape the developing brain in ways that explain disparities. Circuitries that subserve neurocognitive functions related to memory, attention, and cognitive control are especially affected. However, most work showing altered neural function has focused on middle childhood and adolescence. Understanding alterations in brain development during foundational points in early childhood is a key next step. To address this gap, we examined functional near-infrared-spectroscopy-based neural activation during a working memory (WM) task in young children aged 4–7 years (N = 30) who varied in socioeconomic risk exposure. Children who experienced greater disadvantage (lower income to needs ratio and lower Hollingshead index) exhibited lower activation in the lateral prefrontal cortex than children who experienced less to no disadvantage. Variability in prefrontal cortex activation, but not behavioral performance on the WM task, was associated with worse executive functioning in children as reported by parents. These findings add to existing evidence that exposure to early adversity, such as socioeconomic risk, may lead to foundational changes in the developing brain, which increases risk for disparities in functioning across multiple cognitive and social domains. © 2021 Wiley Periodicals LLC

Author Keywords
functional near-infrared-spectroscopy (fNIRS); prefrontal cortex; preschoolers; socioeconomic risk; working memory

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

"Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients" (2021) Journal of Diabetes Investigation

Utility of using electrocardiogram measures of heart rate variability as a measure of cardiovascular autonomic neuropathy in type 1 diabetes patients
(2021) Journal of Diabetes Investigation, .

Pop-Busui, R.^a , Backlund, J.-Y.C.^b , Bebu, I.^b , Braffett, B.H.^b , Lorenzi, G.^c , White, N.H.^d , Lachin, J.M.^b , Soliman, E.Z.^e ^f ^g , DCCT/EDIC Research Group^h

^a Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI, United States
^b Biostatistics Center, The George Washington University, Rockville, MD, United States
^c University of California San Diego, La Jolla, CA, United States
^d Washington University, St. Louis, MO, United States
^e Epidemiological Cardiology Research Center (EPICARE), Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, NC, United States
^f Department of Medicine, Section on Cardiology, Wake Forest School of Medicine, Winston-Salem, NC, United States
^g Institute of Global Health and Human Ecology, School of Science and Engineering, American University in Cairo, Cairo, Egypt

Abstract
Aims/Introduction: Cardiovascular autonomic neuropathy (CAN) is a predictor of cardiovascular disease and mortality. Cardiovascular reflex tests (CARTs) are the gold standard for the diagnosis of CAN, but might not be feasible in large research cohorts or in clinical care. We investigated whether measures of heart rate variability obtained from standard electrocardiogram (ECG) recordings provide a reliable measure of CAN. Materials and Methods: Standardized CARTs (R-R response to paced breathing, Valsalva, postural changes) and digitized 12-lead resting ECGs were obtained concomitantly in Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications participants (n = 311). Standard deviation of normally conducted R-R intervals (SDNN) and the root mean square of successive differences between normal-to-normal R-R intervals (rMSSD) were measured from ECG. Sensitivity, specificity, probability of correct classification and Kappa statistics evaluated the agreement between ECG-derived CAN and CARTs-defined CAN. Results: Participants with CARTs-defined CAN had significantly lower SDNN and rMSSD compared with those without CAN (P < 0.001). The optimal cut-off points of ECG-derived CAN were <17.13 and <24.94 ms for SDNN and rMSSD, respectively. SDNN plays a dominant role in defining CAN, with an area under the curve of 0.73, indicating fair test performance. The Kappa statistic for SDNN was 0.41 (95% confidence interval 0.30–0.51) for the optimal cut-off point, showing fair agreement with CARTs-defined CAN. Combining SDNN and rMSSD optimal cut-off points does not provide additional predictive power for CAN. Conclusions: These analyses are the first to show the agreement between indices of heart rate variability derived from ECGs and the gold standard CARTs, thus supporting potential use as a measure of CAN in clinical research and clinical care. © 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Author Keywords
Cardiovascular autonomic neuropathy; Cardiovascular reflex tests; Heart rate variability

Funding details
National Eye InstituteNEI
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKU01 DK094157, U01 DK094176
National Institute of Neurological Disorders and StrokeNINDS1993‐2007, 2006

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

"Common and unique structural plasticity after left and right hemisphere stroke" (2021) Journal of Cerebral Blood Flow and Metabolism

Common and unique structural plasticity after left and right hemisphere stroke
(2021) Journal of Cerebral Blood Flow and Metabolism, .

Chen, Y.^a , Jiang, Y.^a , Kong, X.^a , Zhao, C.^a , Zhong, S.^a , Yang, L.^a , Feng, T.^a ^b , Peng, S.^a , Bi, Y.^a ^c , Corbetta, M.^d ^e ^f ^g , Gong, G.^a ^c

^a State Key Laboratory of Cognitive Neuroscience and Learning IDG, McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
^b Department of Rehabilitation, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
^c Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China
^d Department of Neuroscience, Neurology Clinic, University of Padua, Padua, Italy
^e Padova Neuroscience Center, University of Padua, Padua, Italy
^f Venetian Institute of Molecular Medicine, Padova, Italy
^g Department of Neurology, Radiology, and Neuroscience, Washington University in St. Louis, St. Louis, United States

Abstract
Strokes to the left and right hemisphere lead to distinctive behavioral profiles. Are left and right hemisphere strokes (LHS and RHS) associated with distinct or common poststroke neuroplasticity patterns? Understanding this issue would reveal hemispheric neuroplasticity mechanisms in response to brain damage. To this end, we investigated poststroke structural changes (2 weeks to 3 months post-onset) using longitudinal MRI data from 69 LHS and 55 RHS patients and 31 demographic-matched healthy control participants. Both LHS and RHS groups showed statistically common plasticity independent of the lesioned hemisphere, including 1) gray matter (GM) expansion in the ipsilesional and contralesional precuneus, and contralesional superior frontal gyrus; 2) GM shrinkage in the ipsilesional medial orbital frontal gyrus and middle cingulate cortex. On the other hand, only RHS patients had significant GM expansion in the ipsilesional medial superior and orbital frontal cortex. Importantly, these common and unique GM changes post-stroke largely overlapped with highly-connected cortical hub regions in healthy individuals. Moreover, they correlated with behavioral recovery, indicating that post-stroke GM volumetric changes in cortical hubs reflect compensatory rather than maladaptive mechanisms. These results highlight the importance of structural neuroplasticity in hub regions of the cortex, along with the hemispheric specificity, for stroke recovery. © The Author(s) 2021.

Author Keywords
gray matter volume; Left hemisphere stroke; poststroke plasticity; right hemisphere stroke; voxel-based morphometry

Funding details
National Institutes of HealthNIHR01 NS095741
National Natural Science Foundation of ChinaNSFC82021004, 91732101
Ministero dell’Istruzione, dell’Università e della RicercaMIUR

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

"Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy" (2021) Epilepsia

Final results from a Phase 3, long-term, open-label, repeat-dose safety study of diazepam nasal spray for seizure clusters in patients with epilepsy
(2021) Epilepsia, .

Wheless, J.W.^a , Miller, I.^b , Hogan, R.E.^c , Dlugos, D.^d , Biton, V.^e , Cascino, G.D.^f , Sperling, M.R.^g , Liow, K.^h , Vazquez, B.ⁱ , Segal, E.B.^j , Tarquinio, D.^k , Mauney, W.^l , Desai, J.^m , Rabinowicz, A.L.ⁿ , Carrazana, E.ⁿ , for the DIAZ.001.05 Study Group^o

^a Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Memphis, TN, United States
^b Formerly Nicklaus Children’s Hospital, Miami, FL, United States
^c Washington University in St. Louis, St. Louis, MO, United States
^d Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^e Arkansas Epilepsy Program, Little Rock, AR, United States
^f Mayo Clinic, Rochester, MN, United States
^g Thomas Jefferson University, Philadelphia, PA, United States
^h Hawaii Pacific Neuroscience, Honolulu, HI, United States
ⁱ New York University, Comprehensive Epilepsy Center, New York, NY, United States
^j Hackensack University Medical Center and Northeast Regional Epilepsy Group, Hackensack, NJ, United States
^k Center for Rare Neurological Diseases, Atlanta, GA, United States
^l Northwest Florida Clinical Research Group, Gulf Breeze, FL, United States
^m Children’s Hospital of Los Angeles, Los Angeles, CA, United States
ⁿ Neurelis, San Diego, CA, United States

Abstract
Objective: A Phase 3 open-label safety study (NCT02721069) evaluated long-term safety of diazepam nasal spray (Valtoco) in patients with epilepsy and frequent seizure clusters. Methods: Patients were 6–65 years old with diagnosed epilepsy and seizure clusters despite stable antiseizure medications. The treatment period was 12 months, with study visits at Day 30 and every 60 days thereafter, after which patients could elect to continue. Doses were based on age and weight. Seizure and treatment information was recorded in diaries. Treatment-emergent adverse events (TEAEs), nasal irritation, and olfactory changes were recorded. Results: Of 163 patients in the safety population, 117 (71.8%) completed the study. Duration of exposure was ≥12 months for 81.6% of patients. There was one death (sudden unexpected death in epilepsy) and one withdrawal owing to a TEAE (major depression), both considered unlikely to be related to treatment. Diazepam nasal spray was administered 4390 times for 3853 seizure clusters, with 485 clusters treated with a second dose within 24 h; 53.4% of patients had monthly average usage of one to two doses, 41.7% two to five doses, and 4.9% more than five doses. No serious TEAEs were considered to be treatment related. TEAEs possibly or probably related to treatment (n = 30) were most commonly nasal discomfort (6.1%); headache (2.5%); and dysgeusia, epistaxis, and somnolence (1.8% each). Only 13 patients (7.9%) showed nasal irritation, and there were no relevant olfactory changes. The safety profile of diazepam nasal spray was generally similar across subgroups based on age, monthly usage, concomitant benzodiazepine therapy, or seasonal allergy/rhinitis. Significance: In this large open-label safety study, the safety profile of diazepam nasal spray was consistent with the established profile of rectal diazepam, and the high retention rate supports effectiveness in this population. A second dose was used in only 12.6% of seizure clusters. Epilepsia© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Author Keywords
acute repetitive seizure; diazepam; intranasal; rescue; stereotypic episodes of frequent seizure activity

Funding details
National Institutes of HealthNIH
American Epilepsy SocietyAES
Pfizer
Genentech
American Academy of NeurologyAAN
Pediatric Epilepsy Research FoundationPERF
School of Public Health, University of California BerkeleyUCB
Zogenix
ACADIA PharmaceuticalsACADIA
Ministerio de Sanidad, Consumo y Bienestar SocialMISAN
Seoul National UniversitySNU

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

"Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia" (2021) Experimental Biology and Medicine

Progression of central nervous system disease from pediatric to young adulthood in sickle cell anemia
(2021) Experimental Biology and Medicine, .

Champlin, G.^a , Hwang, S.N.^b , Heitzer, A.^c , Ding, J.^d , Jacola, L.^c , Estepp, J.H.^e ^f , Wang, W.^e , Ataga, K.I.^g ^h , Owens, C.L.^h , Newman, J.ⁱ , King, A.A.^j , Davis, R.^k , Kang, G.^d , Hankins, J.S.^e

^a Department of Clinical Education and Training, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^b Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^c Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^d Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^e Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^f Global Medicine, St. Jude Children’s Research Hospital, Memphis, TN 38105, United States
^g University of Tennessee Health Science Center (UTHSC), Center for Sickle Cell Disease, Memphis, TN 38163, United States
^h Methodist University Comprehensive Sickle Cell Center, Memphis, TN 38104, United States
ⁱ Memphis Radiological Professional Corporation, Memphis, TN 38138, United States
^j Washington University School of Medicine, St. LouisMO 63130, United States
^k Center in Biomedical Informatics at UTHSC, Memphis, TN 38163, United States

Abstract
Silent cerebral infarcts and arteriopathy are common and progressive in individuals with sickle cell anemia. However, most data describing brain lesions in sickle cell anemia are cross-sectional or derive from pediatric cohorts with short follow-up. We investigated the progression of silent cerebral infarct and cerebral vessel stenosis on brain MRI and MRA, respectively, by describing the incidence of new or worsening lesions over a period of up to 25 years among young adults with sickle cell anemia and explored risk factors for progression. Forty-four adults with sickle cell anemia (HbSS or HbSβ0thalassemia), exposed to chronic transfusions (n = 12) or hydroxyurea (n = 32), median age 19.2 years (range 18.0–31.5), received a screening brain MRI/MRA and their results were compared with a clinical exam performed during childhood and adolescence. We used exact log-rank test to compare MRI and MRA progression among any two groups. The hazard ratio (HR) and 95% confidence interval (CI) were calculated from Cox regression analyses. Progression of MRI and MRA occurred in 12 (27%) and 4 (9%) young adults, respectively, relative to their pediatric exams. MRI progression risk was high among participants with abnormal pediatric exams (HR: 11.6, 95% CI: 2.5–54.7) and conditional or abnormal transcranial Doppler ultrasound velocities (HR: 3.9, 95% CI: 1.0–15.1). Among individuals treated with hydroxyurea, high fetal hemoglobin measured in childhood was associated with lower hazard of MRI progression (HR: 0.86, 95% CI: 0.76–0.98). MRA progression occurred more frequently among those with prior stroke (HR: 8.6, 95% CI: 1.2–64), abnormal pediatric exam (P = 0.00084), and elevated transcranial Doppler ultrasound velocities (P = 0.004). Brain MRI/MRA imaging in pediatrics can identify high-risk patients for CNS disease progression in young adulthood, prompting consideration for early aggressive treatments. © 2021 by the Society for Experimental Biology and Medicine.

Author Keywords
disease-modifying therapy; sickle cell anemia; silent cerebral infarct; Stroke; vasculopathy; young adult

Funding details
1K24 HL148305, 5U01HL133994
U01HL133996
U.S. Food and Drug AdministrationFDA
Eli Lilly and Company
Pfizer
American Lebanese Syrian Associated CharitiesALSAC

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

"Sleep apnea and respiratory anomaly detection from a wearable band and oxygen saturation" (2021) Sleep and Breathing

Sleep apnea and respiratory anomaly detection from a wearable band and oxygen saturation
(2021) Sleep and Breathing, .

Ganglberger, W.^a ^b , Bucklin, A.A.^a , Tesh, R.A.^a , Da Silva Cardoso, M.^a , Sun, H.^a , Leone, M.J.^a , Paixao, L.^a ^c , Panneerselvam, E.^a , Ye, E.M.^a , Thompson, B.T.^d , Akeju, O.^e , Kuller, D.^f , Thomas, R.J.^g , Westover, M.B.^a

^a Department of Neurology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States
^b Sleep & Health Zurich, University of Zurich, Zurich, Switzerland
^c Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^d Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States
^e Department of Anesthesiology, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States
^f MyAir Inc., Boston, MA, United States
^g Division of Pulmonary, Critical Care & Sleep, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

Abstract
Objective: Sleep-related respiratory abnormalities are typically detected using polysomnography. There is a need in general medicine and critical care for a more convenient method to detect sleep apnea automatically from a simple, easy-to-wear device. The objective was to detect abnormal respiration and estimate the Apnea–Hypopnea Index (AHI) automatically with a wearable respiratory device with and without SpO2 signals using a large (n = 412) dataset serving as ground truth. Design: Simultaneously recorded polysomnography (PSG) and wearable respiratory effort data were used to train and evaluate models in a cross-validation fashion. Time domain and complexity features were extracted, important features were identified, and a random forest model was employed to detect events and predict AHI. Four models were trained: one each using the respiratory features only, a feature from the SpO2 (%)-signal only, and two additional models that use the respiratory features and the SpO2 (%) feature, one allowing a time lag of 30 s between the two signals. Results: Event-based classification resulted in areas under the receiver operating characteristic curves of 0.94, 0.86, and 0.82, and areas under the precision-recall curves of 0.48, 0.32, and 0.51 for the models using respiration and SpO2, respiration-only, and SpO2-only, respectively. Correlation between expert-labelled and predicted AHI was 0.96, 0.78, and 0.93, respectively. Conclusions: A wearable respiratory effort signal with or without SpO2 signal predicted AHI accurately, and best performance was achieved with using both signals. © 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.

Author Keywords
Apnea; Machine learning; Respiration disorders; Wearable

Funding details
National Institutes of HealthNIH1R01NS102190, 1R01NS102574, 1R01NS107291, 1RF1AG064312
U.S. Department of DefenseDOD
Harvard University
American Academy of Sleep MedicineAASM
American Academy of Sleep Medicine FoundationAASMF

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

"Accelerating Prediction of Malignant Cerebral Edema After Ischemic Stroke with Automated Image Analysis and Explainable Neural Networks" (2021) Neurocritical Care

Accelerating Prediction of Malignant Cerebral Edema After Ischemic Stroke with Automated Image Analysis and Explainable Neural Networks
(2021) Neurocritical Care, .

Foroushani, H.M.^a , Hamzehloo, A.^b , Kumar, A.^b , Chen, Y.^b , Heitsch, L.^c , Slowik, A.^d , Strbian, D.^e , Lee, J.-M.^b , Marcus, D.S.^f , Dhar, R.^b

^a Department of Electrical and Systems Engineering, Washington University in St. Louis McKelvey School of Engineering, 1 Brookings Drive, 63130-4899, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis School of Medicine, 660 S Euclid Avenue, Campus, Box 8111, St. Louis, MO 63110, United States
^c Department of Emergency Medicine, Washington University in St. Louis School of Medicine, 660 S. Euclid Ave, Campus, Box 8072, St. Louis, MO 63110, United States
^d Department of Neurology, Jagiellonian University Medical College, Kraków, Poland
^e Department of Neurology, Helsinki University Hospital, Helsinki, Finland
^f Department of Radiology, Washington University in St. Louis School of Medicine, 525 Scott Ave, Campus, Box 8225, St. Louis, MO 63110, United States

Abstract
Background: Malignant cerebral edema is a devastating complication of stroke, resulting in deterioration and death if hemicraniectomy is not performed prior to herniation. Current approaches for predicting this relatively rare complication often require advanced imaging and still suffer from suboptimal performance. We performed a pilot study to evaluate whether neural networks incorporating data extracted from routine computed tomography (CT) imaging could enhance prediction of edema in a large diverse stroke cohort. Methods: An automated imaging pipeline retrospectively extracted volumetric data, including cerebrospinal fluid (CSF) volumes and the hemispheric CSF volume ratio, from baseline and 24 h CT scans performed in participants of an international stroke cohort study. Fully connected and long short-term memory (LSTM) neural networks were trained using serial clinical and imaging data to predict those who would require hemicraniectomy or die with midline shift. The performance of these models was tested, in comparison with regression models and the Enhanced Detection of Edema in Malignant Anterior Circulation Stroke (EDEMA) score, using cross-validation to construct precision-recall curves. Results: Twenty of 598 patients developed malignant edema (12 required surgery, 8 died). The regression model provided 95% recall but only 32% precision (area under the precision-recall curve [AUPRC] 0.74), similar to the EDEMA score (precision 28%, AUPRC 0.66). The fully connected network did not perform better (precision 33%, AUPRC 0.71), but the LSTM model provided 100% recall and 87% precision (AUPRC 0.97) in the overall cohort and the subgroup with a National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 (p = 0.0001 vs. regression and fully connected models). Features providing the most predictive importance were the hemispheric CSF ratio and NIHSS score measured at 24 h. Conclusions: An LSTM neural network incorporating volumetric data extracted from routine CT scans identified all cases of malignant cerebral edema by 24 h after stroke, with significantly fewer false positives than a fully connected neural network, regression model, and the validated EDEMA score. This preliminary work requires prospective validation but provides proof of principle that a deep learning framework could assist in selecting patients for surgery prior to deterioration. © 2021, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.

Author Keywords
Brain computed tomography scan; Brain edema; Cerebral infarction; Deep learning; Early diagnosis

Funding details
National Institutes of HealthNIHK23NS099440, K23NS099487, P30NS098577, R01NS085419
Biogen

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

"Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA" (2021) Molecular Genetics and Metabolism

Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA
(2021) Molecular Genetics and Metabolism, .

Boulin, T.^a , Itani, O.^e ^f , El Mouridi, S.^a , Leclercq-Blondel, A.^a , Gendrel, M.^a ^b , Macnamara, E.^c , Soldatos, A.^c , Murphy, J.L.^c , Gorman, M.P.^d , Lindsey, A.^e ^f , Shimada, S.^c , Turner, D.^e ^f , Silverman, G.A.^f , Baldridge, D.^f , Malicdan, M.C.^c , Schedl, T.^e ^g , Pak, S.C.^e ^f , Undiagnosed Diseases Network^h

^a Institut NeuroMyoGène, Univ Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Lyon, 69008, France
^b Institut de Biologie de l’Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, Université Paris Sciences et Lettres Research University, Paris, 75005, France
^c Undiagnosed Diseases Program Translational Laboratory, NHGRI, National Institutes of Health, Bethesda, MD 20892, United States
^d Department of Neurology, Neuroimmunology Program, Boston Children’s Hospital, Harvard Medical School, Boston, MA 02115, United States
^e C. elegans Model Organism Screening Center, Washington University in St Louis School of Medicine, St Louis, MO 63110, United States
^f Department of Pediatrics, Washington University in St Louis School of Medicine, St Louis, MO 63110, United States
^g Department of Genetics, Washington University in St Louis School of Medicine, St Louis, MO 63110, United States

Abstract
Neurobeachin (NBEA) was initially identified as a candidate gene for autism. Recently, variants in NBEA have been associated with neurodevelopmental delay and childhood epilepsy. Here, we report on a novel NBEA missense variant (c.5899G > A, p.Gly1967Arg) in the Domain of Unknown Function 1088 (DUF1088) identified in a child enrolled in the Undiagnosed Diseases Network (UDN), who presented with neurodevelopmental delay and seizures. Modeling of this variant in the Caenorhabditis elegans NBEA ortholog, sel-2, indicated that the variant was damaging to in vivo function as evidenced by altered cell fate determination and trafficking of potassium channels in neurons. The variant effect was indistinguishable from that of the reference null mutation suggesting that the variant is a strong hypomorph or a complete loss-of-function. Our experimental data provide strong support for the molecular diagnosis and pathogenicity of the NBEA p.Gly1967Arg variant and the importance of the DUF1088 for NBEA function. © 2021

Author Keywords
C. elegans; Epilepsy; Neurobeachin; Neurodevelopmental delay; SEL-2

Funding details
P40 OD010440
National Institutes of HealthNIHU54 NS108251
National Human Genome Research InstituteNHGRI
Children’s Discovery InstituteCDI
European Research CouncilERC

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

"Subgroup and subtype-specific outcomes in adult medulloblastoma" (2021) Acta Neuropathologica

Subgroup and subtype-specific outcomes in adult medulloblastoma
(2021) Acta Neuropathologica, .

Coltin, H.^a ^b , Sundaresan, L.^b , Smith, K.S.^c , Skowron, P.^b , Massimi, L.^d , Eberhart, C.G.^e , Schreck, K.C.^f , Gupta, N.^g , Weiss, W.A.^h , Tirapelli, D.ⁱ , Carlotti, C.ⁱ , Li, K.K.W.^j , Ryzhova, M.^k , Golanov, A.^k , Zheludkova, O.^k , Absalyamova, O.^k , Okonechnikov, K.^l , Stichel, D.^m , von Deimling, A.^m , Giannini, C.ⁿ , Raskin, S.^o , Van Meir, E.G.^p , Chan, J.A.^q , Fults, D.^r , Chambless, L.B.^s , Kim, S.-K.^t , Vasiljevic, A.^u ^v , Faure-Conter, C.^w , Vibhakar, R.^x , Jung, S.^y , Leary, S.^z , Mora, J.^aa , McLendon, R.E.^ab , Pollack, I.F.^ac , Hauser, P.^ad , Grajkowska, W.A.^ae , Rubin, J.B.^af , van Veelen, M.-L.C.^ag , French, P.J.^ah , Kros, J.M.^ai , Liau, L.M.^aj , Pfister, S.M.^l ^ak , Kool, M.^l ^al , Kijima, N.^am , Taylor, M.D.^b , Packer, R.J.^o , Northcott, P.A.^c , Korshunov, A.^m , Ramaswamy, V.^a ^b ^an

^a Division of Haematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, Canada
^b Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada
^c Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, MS 325, Room D2058, 262 Danny Thomas Place, Memphis, TN 38105-3678, United States
^d Department of Neurosurgery, Fondazione Policlinico A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy
^e Department of Neuropathology and Ophthalmic Pathology, Johns Hopkins University, Baltimore, MD, United States
^f Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^g Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, CA, United States
^h Departments of Neurology, Neurological Surgery, and Pediatrics, University of California, San Francisco, CA, United States
ⁱ Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil
^j Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
^k NN Burdenko Neurosurgical Research Centre, Moscow, Russian Federation
^l Hopp Children’s Cancer Center Heidelberg (KiTZ) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
^m Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ) and Department of Neuropathology, University of Heidelberg, University Hospital Heidelberg, Im Neuenheimer Feld 224, Heidelberg, 69120, Germany
ⁿ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^o Center for Cancer and Blood Disorders, Children’s National Medical Center, Washington, DC, United States
^p Department of Neurosurgery, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham (UAB), Birmingham, AL, United States
^q Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
^r Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
^s Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, United States
^t Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea
^u Centre de Pathologie et Neuropathologie Est, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France
^v ONCOFLAM, Neuro-Oncologie Et Neuro-Inflammation Centre de Recherche en Neurosciences de Lyon, Lyon, France
^w Department of Pediatrics, Institut d’Hemato-Oncologie Pediatrique, Lyon, France
^x Department of Pediatrics, University of Colorado Denver, Aurora, CO, United States
^y Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea
^z Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, United States
^aa Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
^ab Department of Pathology, Duke University, Durham, NC, United States
^ac Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^ad 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
^ae Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland
^af Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, MO, United States
^ag Department of Neurosurgery, Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands
^ah Department of Neurology, Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, Netherlands
^ai Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands
^aj Department of Neurosurgery, David Geffen School of Medicine at University of California at Los Angeles, University of California Los Angeles, Los Angeles, CA 90095, United States
^ak Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
^al Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
^am Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan
^an Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

Abstract
Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0–86.5), 61.9% (51.6–74.2), 80.0% (95% CI 51.6–100.0), and 44.9% (95% CI 28.6–70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1–7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3–9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1–4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1–6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1–0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Adult; DNA methylation profiling; Medulloblastoma; Molecular groups; Risk stratification

Funding details
National Institutes of HealthNIH5R01CA159859-08, R01CA235162, R01NS096236, R01NS106155-01
Pediatric Brain Tumor FoundationPBTF
Stand Up To CancerSU2CSU2C-AACR-DT1113
Princess Margaret Cancer FoundationPMCF
Government of Ontario
Canadian Cancer Society Research InstituteCCSRI
Canadian Institutes of Health ResearchCIHR
Ontario Ministry of Research, Innovation and ScienceMRIS
Garron Family Cancer CentreGFCC

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

"Pupillometry reveals cognitive demands of lexical competition during spoken word recognition in young and older adults" (2021) Psychonomic Bulletin and Review

Pupillometry reveals cognitive demands of lexical competition during spoken word recognition in young and older adults
(2021) Psychonomic Bulletin and Review, .

McLaughlin, D.J.^a , Zink, M.E.^b , Gaunt, L.^a , Brent Spehar^b , Van Engen, K.J.^a , Sommers, M.S.^a , Peelle, J.E.^b

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, One Brookings Dr, St. Louis, MO 63130, United States
^b Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In most contemporary activation-competition frameworks for spoken word recognition, candidate words compete against phonological “neighbors” with similar acoustic properties (e.g., “cap” vs. “cat”). Thus, recognizing words with more competitors should come at a greater cognitive cost relative to recognizing words with fewer competitors, due to increased demands for selecting the correct item and inhibiting incorrect candidates. Importantly, these processes should operate even in the absence of differences in accuracy. In the present study, we tested this proposal by examining differences in processing costs associated with neighborhood density for highly intelligible items presented in quiet. A second goal was to examine whether the cognitive demands associated with increased neighborhood density were greater for older adults compared with young adults. Using pupillometry as an index of cognitive processing load, we compared the cognitive demands associated with spoken word recognition for words with many or fewer neighbors, presented in quiet, for young (n = 67) and older (n = 69) adult listeners. Growth curve analysis of the pupil data indicated that older adults showed a greater evoked pupil response for spoken words than did young adults, consistent with increased cognitive load during spoken word recognition. Words from dense neighborhoods were marginally more demanding to process than words from sparse neighborhoods. There was also an interaction between age and neighborhood density, indicating larger effects of density in young adult listeners. These results highlight the importance of assessing both cognitive demands and accuracy when investigating the mechanisms underlying spoken word recognition. © 2021, The Psychonomic Society, Inc.

Author Keywords
Cognitive load; Lexical competition; Spoken word recognition

Funding details
National Science FoundationNSF
National Institutes of HealthNIHDGE-1745038

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

"Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy" (2021) Genetics in Medicine

Biallelic loss-of-function variants in the splicing regulator NSRP1 cause a severe neurodevelopmental disorder with spastic cerebral palsy and epilepsy
(2021) Genetics in Medicine, .

Calame, D.G.^a ^b ^c , Bakhtiari, S.^d ^e , Logan, R.^f , Coban-Akdemir, Z.^c ^g , Du, H.^c , Mitani, T.^c , Fatih, J.M.^c , Hunter, J.V.^h ⁱ , Herman, I.^a ^b ^c , Pehlivan, D.^a ^b ^c , Jhangiani, S.N.^j , Person, R.^k , Schnur, R.E.^k , Jin, S.C.^l , Bilguvar, K.^m , Posey, J.E.^c , Koh, S.ⁿ , Firouzabadi, S.G.^o , Alehabib, E.^p , Tafakhori, A.^q , Esmkhani, S.^r , Gibbs, R.A.^c ^j , Noureldeen, M.M.^s , Zaki, M.S.^t , Marafi, D.^c ^u , Darvish, H.^v , Kruer, M.C.^d ^e , Lupski, J.R.^b ^c ^j ^w

^a Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
^b Texas Children’s Hospital, Houston, TX, United States
^c Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^d Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^e Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine–Phoenix, Phoenix, AZ, United States
^f Division of Neurosciences, Children’s Healthcare of Atlanta, Atlanta, GA, United States
^g Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, United States
^h Department of Radiology, Baylor College of Medicine, Houston, TX, United States
ⁱ E.B. Singleton Department of Pediatric Radiology, Texas Children’s Hospital, Houston, TX, United States
^j Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
^k GeneDX, Gaithersburg, MD, United States
^l Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Genetics, Yale University, New Haven, CT, United States
ⁿ Department of Pediatrics, Children’s Hospital, University of Nebraska, Omaha, NE, United States
^o Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
^p Student Research Committee, Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
^q Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
^r Department of Basic Oncology, Division of Cancer Genetics, Oncology Institute, Istanbul University, Istanbul, Turkey
^s Department of Pediatrics, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
^t Department of Clinical Genetics, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt
^u Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
^v Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
^w Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States

Abstract
Purpose: Alternative splicing plays a critical role in mouse neurodevelopment, regulating neurogenesis, cortical lamination, and synaptogenesis, yet few human neurodevelopmental disorders are known to result from pathogenic variation in splicing regulator genes. Nuclear Speckle Splicing Regulator Protein 1 (NSRP1) is a ubiquitously expressed splicing regulator not known to underlie a Mendelian disorder. Methods: Exome sequencing and rare variant family-based genomics was performed as a part of the Baylor-Hopkins Center for Mendelian Genomics Initiative. Additional families were identified via GeneMatcher. Results: We identified six patients from three unrelated families with homozygous loss-of-function variants in NSRP1. Clinical features include developmental delay, epilepsy, variable microcephaly (Z-scores −0.95 to −5.60), hypotonia, and spastic cerebral palsy. Brain abnormalities included simplified gyral pattern, underopercularization, and/or vermian hypoplasia. Molecular analysis identified three pathogenic NSRP1 predicted loss-of-function variant alleles: c.1359_1362delAAAG (p.Glu455AlafsTer20), c.1272dupG (p.Lys425GlufsTer5), and c.52C>T (p.Gln18Ter). The two frameshift variants result in a premature termination codon in the last exon, and the mutant transcripts are predicted to escape nonsense mediated decay and cause loss of a C-terminal nuclear localization signal required for NSRP1 function. Conclusion: We establish NSRP1 as a gene for a severe autosomal recessive neurodevelopmental disease trait characterized by developmental delay, epilepsy, microcephaly, and spastic cerebral palsy. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Funding details
U54HG003273
U54 HG006504-01
National Institutes of HealthNIH873841, T32 GM007526-42, T32 NS043124-19
National Heart, Lung, and Blood InstituteNHLBI
National Human Genome Research InstituteNHGRI
National Institute of Neurological Disorders and StrokeNINDSR01NS106298, R35NS105078
International Rett Syndrome FoundationIRSF3701‐1, K08 HG008986
Muscular Dystrophy AssociationMDA512848
Uehara Memorial Foundation
Cerebral Palsy Alliance Research FoundationCPARF01318
Baylor-Hopkins Center for Mendelian GenomicsBHCMGUM1 HG006542
Spastic Paraplegia FoundationSPF

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

"Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement" (2021) Nature Neuroscience

Ventral tegmental area GABAergic inhibition of cholinergic interneurons in the ventral nucleus accumbens shell promotes reward reinforcement
(2021) Nature Neuroscience, .

Al-Hasani, R.^a ^b ^c , Gowrishankar, R.^d ^e , Schmitz, G.P.^a ^c , Pedersen, C.E.^d ^e ^f , Marcus, D.J.^d ^g , Shirley, S.E.^d , Hobbs, T.E.^d , Elerding, A.J.^d , Renaud, S.J.^c , Jing, M.^g ^h ⁱ ^j , Li, Y.^h ⁱ ^j , Alvarez, V.A.^k , Lemos, J.C.^k ^l , Bruchas, M.R.^c ^d ^e ^f ^m

^a Center for Clinical Pharmacology, University of Health Sciences and Pharmacy and Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Department of Pharmaceutical and Administrative Sciences, University of Health Science and Pharmacy, St. Louis, MO, United States
^c Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^d Center for the Neurobiology of Addiction, Pain and Emotion, University of Washington, Seattle, WA, United States
^e Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
^f Department of Bioengineering, University of Washington, Seattle, WA, United States
^g Chinese Institute for Brain Research, Beijing, China
^h State Key Laboratory of Membrane Biology, Peking University School of Life Sciences, Beijing, China
ⁱ PKU-IDG/McGovern Institute for Brain Research, Beijing, China
^j Peking-Tsinghua Center for Life Sciences, Beijing, China
^k Laboratory on Neurobiology of Compulsive Behaviors, Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, United States
^l Department of Neuroscience, University of Minnesota, Minneapolis, MN, United States
^m Department of Pharmacology, University of Washington, Seattle, WA, United States

Abstract
The long-range GABAergic input from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) is relatively understudied, and therefore its role in reward processing has remained unknown. In the present study, we show, in both male and female mice, that long-range GABAergic projections from the VTA to the ventral NAc shell, but not to the dorsal NAc shell or NAc core, are engaged in reward and reinforcement behavior. We show that this GABAergic projection exclusively synapses on to cholinergic interneurons (CINs) in the ventral NAc shell, thereby serving a specialized function in modulating reinforced reward behavior through the inhibition of ventral NAc shell CINs. These findings highlight the diversity in the structural and functional topography of VTA GABAergic projections, and their neuromodulatory interactions across the dorsoventral gradient of the NAc shell. They also further our understanding of neuronal circuits that are directly implicated in neuropsychiatric conditions such as depression and addiction. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

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