Decreased voluntary alcohol intake and ventral striatal epigenetic and transcriptional remodeling in male Acss2 KO mice
(2025) Neuropharmacology, 265, art. no. 110258, .
Egervari, G.a b , Donahue, G.c d , Cardé, N.A.Q.e , Alexander, D.C.c d , Hogan, C.c d , Shaw, J.K.e , Periandri, E.M.a b , Fleites, V.e , De Biasi, M.e , Berger, S.L.c d
a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biochemistry and Molecular Biophysics, Washington University, School of Medicine, St. Louis, MO, United States
c Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
d Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Abstract
Metabolic-epigenetic interactions are emerging as key pathways in regulating alcohol-related transcriptional changes in the brain. Recently, we have shown that this is mediated by the metabolic enzyme Acetyl-CoA synthetase 2 (Acss2), which is nuclear and chromatin-bound in neurons. Mice lacking ACSS2 fail to deposit alcohol-derived acetate onto histones in the brain and show no conditioned place preference for ethanol reward. Here, we further explored the role of this pathway during voluntary alcohol intake. We found that Acss2 KO mice consume significantly less alcohol in a model of binge drinking, an effect primarily driven by males. Genome-wide transcriptional profiling of 7 key brain regions implicated in alcohol and drug use revealed that, following drinking, Acss2 KO mice exhibit blunted gene expression in the ventral striatum. Similarly to the behavioral differences, transcriptional dysregulation was more pronounced in male mice. Further, we found that the gene expression changes were associated with depletion of ventral striatal histone acetylation (H3K27ac) in Acss2 KO mice compared to WT. Taken together, our data suggest that ACSS2 plays an important role in orchestrating ventral striatal epigenetic and transcriptional changes during voluntary alcohol drinking, especially in males. Consequently, targeting this pathway could be a promising new therapeutic avenue. © 2024 The Authors
Funding details
Brain and Behavior Research FoundationBBRF
National Institutes of HealthNIHR01AA027202, R00AA028577
National Institutes of HealthNIH
YIG31527
Document Type: Article
Publication Stage: Final
Source: Scopus
Early Young Adult Death Underscores the Need for Adolescent and Young Adult Transition Programs in Neurofibromatosis Type 1
(2025) Journal of Pediatrics, 277, art. no. 114413, .
Tarnawsky, T.a , Oh, I.Y.b , Hillis, E.b , Gupta, A.b , Gutmann, D.H.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Institute for Informatics, Data Science, and Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
There are few centers with combined pediatric and adult neurofibromatosis 1 practices and transition of care programming. Using an electronic health records-based approach, we found an early death peak in the fourth decade of life largely owing to malignancy, underscoring the need for integrated neurological training and practice across the lifespan. © 2024 Elsevier Inc.
Funding details
National Institute of Neurological Disorders and StrokeNINDS1R01NS131112
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
Multi-scale neural networks classification of mild cognitive impairment using functional near-infrared spectroscopy
(2025) Biocybernetics and Biomedical Engineering, 45 (1), pp. 11-22.
Kang, M.-K.a , Hong, K.-S.a b , Yang, D.c , Kim, H.K.a
a School of Mechanical Engineering, Pusan National University; 2 Busandaehak-ro, Busan, Geumjeong-gu, 46241, South Korea
b Institute For Future, School of Automation, Qingdao University, Qingdao, 266071, China
c Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
Abstract
Mild cognitive impairment (MCI) is recognized as an early stage preceding Alzheimer’s disease. Functional near-infrared spectroscopy (fNIRS) has recently been used to differentiate MCI patients from healthy controls (HCs) by analyzing their hemodynamic responses. This paper proposes a new method that uses the entire time series data from all fNIRS channels, skipping the feature extraction step. It involves a multi-scale convolutional neural network (CNN) integrated with long short-term memory (LSTM) layers to extract spatial and temporal features simultaneously. The study involves 64 participants (37 MCI patients and 27 HCs) performing three mental tasks: N-back, Stroop, and verbal fluency tests (VFT). The algorithm’s performance was assessed using 10-fold cross-validation across oxyhemoglobin (HbO), deoxyhemoglobin (HbR), and total hemoglobin (HbT). The highest classification accuracies were achieved with HbT, reaching 93.22 % for the N-back task, 91.14 % for the Stroop task, and 89.58 % for the VFT. It was found that using all types of hemodynamic signals from all channels provides better results than analyzing the region of interest data, eliminating the need for data segmentation and feature extraction procedures. Additionally, HbR (or HbT) gives better classification accuracy than HbO. The developed method can be implemented online for clinical applications and real-time monitoring of cognitive disorders. © 2024
Author Keywords
Classification; Deep learning; Functional near-infrared spectroscopy (fNIRS); Mild cognitive impairment; Time series
Funding details
National Research Foundation of KoreaNRF
Pusan National UniversityPNU
RS-2023-00207954
Document Type: Article
Publication Stage: Final
Source: Scopus
Prenatal social disadvantage is associated with alterations in functional networks at birth
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (50), pp. e2405448121.
Nielsen, A.N.a , Triplett, R.L.a , Bernardez, L.M.a , Tooley, U.A.b , Herzberg, M.P.b , Lean, R.E.b , Kaplan, S.a , Meyer, D.a , Kenley, J.K.a , Alexopoulos, D.a , Losielle, D.a , Latham, A.a , Smyser, T.A.b , Agrawal, A.b , Shimony, J.S.c , Jackson, J.J.d , Miller, J.P.e , Raichle, M.E.a c d f g , Warner, B.B.h , Rogers, C.E.b h , Sylvester, C.M.b , Barch, D.M.b c d , Luby, J.L.b , Smyser, C.D.a c h
a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63110, United States
e Department of Biostatistics, Washington University in St. Louis, St. Louis, MO 63110, United States
f Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
g Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Childhood exposure to social disadvantage is a major risk factor for psychiatric disorders and poor developmental, educational, and occupational outcomes, presumably because adverse exposures alter the neurodevelopmental processes that contribute to risk trajectories. Yet, given the limited social mobility in the United States and other countries, childhood social disadvantage is frequently preceded by maternal social disadvantage during pregnancy, potentially altering fetal brain development during a period of high neuroplasticity through hormonal, microbiome, epigenetic, and immune factors that cross the placenta and fetal blood-brain barrier. The current study examines prenatal social disadvantage to determine whether these exposures in utero are associated with alterations in functional brain networks as early as birth. As part of the Early Life Adversity and Biological Embedding study, mothers were recruited during pregnancy, prenatal social disadvantage was assessed across trimesters, and their healthy, full-term offspring were imaged using resting-state functional magnetic resonance imaging during the first weeks of life. Multivariate machine learning methods revealed that neonatal functional connectivity (FC) varied as a function of prenatal exposure to social disadvantage (n = 261, R = 0.43, R2 = 0.18), with validation in an independent sample. Alterations in FC associated with prenatal social disadvantage occurred brain-wide and were most pronounced in association networks (fronto-parietal, ventral attention, dorsal attention) and the somatomotor network. Amygdala FC was altered at birth, with a pattern shared across subcortical structures. These findings provide critical insights into how early in development functional networks begin to diverge in the context of social disadvantage and elucidate the functional networks that are most impacted.
Author Keywords
functional connectivity; infant; prenatal exposure; social disadvantage; socieconomic status
Document Type: Article
Publication Stage: Final
Source: Scopus
Cellular trafficking and fate mapping of cells within the nervous system after in utero hematopoietic cell transplantation
(2024) Communications Biology, 7 (1), art. no. 1624, .
Grant, M.T.a , Nelvagal, H.R.b c , Tecos, M.a , Hamed, A.a , Swanson, K.a , Cooper, J.D.b , Vrecenak, J.D.a
a Washington University in St. Louis School of Medicine, Department of Surgery, Division of Pediatric Surgery, St. Louis, MO, United States
b Washington University in St. Louis School of Medicine, Department of Pediatrics, Division of Genetics and Genomics, St. Louis, MO, United States
c University College London, School of Pharmacy, Department of Pharmacology, London, United Kingdom
Abstract
In utero hematopoietic cell transplantation (IUHCT) utilizes fetal immune tolerance to achieve durable chimerism without conditioning or immunosuppression during a unique window in fetal development. Though donor cells have been observed within the nervous system following in utero injection, the timeline and distribution of cellular trafficking across the blood-brain barrier following IUHCT is not well understood. We injected 20 × 106 adult bone marrow mononuclear cells intravenously at gestational age (GA) 12–17 days and found that donor cells were maximally concentrated in the brain with treatment between GA 13–14. Donor cell engraftment persisted within the brain at every timepoint analyzed and concentrated within the hindbrain with significantly more grafted cells than in the forebrain. Additionally, transplanted cells terminally differentiated into various nervous system cellular morphologies and also populated the enteric nervous system. This study is the first to document the timeline and distribution of donor cell trafficking into the immune-protected nervous system and serves as a foundation for the application of IUHCT to treat neurogenetic diseases. © The Author(s) 2024.
Funding details
Children’s Discovery InstituteCDIMI-II-2019-777
Children’s Discovery InstituteCDI
PR 2017281
Document Type: Article
Publication Stage: Final
Source: Scopus
Classification of iPSC-derived cultures using convolutional neural networks to identify single differentiated neurons for isolation or measurement
(2024) Discover Artificial Intelligence, 4 (1), art. no. 95, .
Patel, P.a b , Ali, L.K.M.a b , Kaushik, U.b , Wright, M.a b b , Green, K.b , Waligorski, J.E.a b b , Kremitzki, C.L.a b b , Bachman, G.W.a b b , Elia, S.N.a b b , Buchser, W.J.a b b
a Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
b Functional Imaging for Variant Elucidation at the McDonnell Genome Institute, St Louis, MO, United States
Abstract
Understanding neurodegenerative disease pathology requires a close examination of neurons and their processes. However, image-based single-cell analyses of neurons often require laborious and time-consuming manual classification tasks. Here, we present a machine learning (ML) approach leveraging convolutional neural network (CNN) classifiers capable of accurately identifying various classes of neuronal images, including single neurons. We developed the Single Neuron Identification Model 20-Class (SNIM20) which was trained on a dataset of induced pluripotent stem cell (iPSC)-derived motor neurons, containing over 12,000 images from 20 distinct classes. SNIM20 is built in TensorFlow and trained on images of neurons differentiated from iPSC cultures that were stained for nuclei and microtubules. This classifier demonstrated high predictive accuracy (AUC = 0.99) for distinguishing single neurons. Additionally, the 2-stage training framework can be used more broadly for cellular classification tasks. A variation was successfully trained on images of a human osteosarcoma cell line (U2OS) for single-cell classification (AUC = 0.99). While this framework was primarily designed for single-cell microraft-based identification and capture, it also works with cells in standard plate formats. We additionally explore the impact of fluorescent channels and brightfield images, class groupings, and transfer learning on the quality of the classification. This framework can both assist in high throughput neuronal or cellular identification and be used to train a custom classifier for the user’s specific needs. © The Author(s) 2024.
Author Keywords
CNN; Image classification; iPSCs; Machine learning; Microrafts; Neurons
Document Type: Article
Publication Stage: Final
Source: Scopus
MYT1L deficiency impairs excitatory neuron trajectory during cortical development
(2024) Nature Communications, 15 (1), art. no. 10308, .
Yen, A.a b , Sarafinovska, S.a b , Chen, X.a c , Skinner, D.D.d , Leti, F.d , Crosby, M.c e , Hoisington-Lopez, J.c e , Wu, Y.a b , Chen, J.a b , Li, Z.A.a b , Noguchi, K.K.b , Mitra, R.D.a c , Dougherty, J.D.a b f
a Department of Genetics, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
c Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, Saint Louis, MO, United States
d Scale Biosciences, San Diego, CA, United States
e DNA Sequencing and Innovation Lab, Washington University School of Medicine, Saint Louis, MO, United States
f Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Mutations reducing the function of MYT1L, a neuron-specific transcription factor, are associated with a syndromic neurodevelopmental disorder. MYT1L is used as a pro-neural factor in fibroblast-to-neuron transdifferentiation and is hypothesized to influence neuronal specification and maturation, but it is not clear which neuron types are most impacted by MYT1L loss. In this study, we profile 412,132 nuclei from the forebrains of wild-type and MYT1L-deficient mice at three developmental stages: E14 at the peak of neurogenesis, P1 when cortical neurons have been born, and P21 when neurons are maturing, to examine the role of MYT1L levels on neuronal development. MYT1L deficiency disrupts cortical neuron proportions and gene expression, primarily affecting neuronal maturation programs. Effects are mostly cell autonomous and persistent through development. While MYT1L can both activate and repress gene expression, the repressive effects are most sensitive to haploinsufficiency, likely mediating MYT1L syndrome. These findings illuminate MYT1L’s role in orchestrating gene expression during neuronal development, providing insights into the molecular underpinnings of MYT1L syndrome. © The Author(s) 2024.
Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Genome Technology Access CenterGTAC
University of WashingtonUW
St. Louis Children’s HospitalSLCHCDI-CORE-2019-813, CDI-CORE-2015-505
St. Louis Children’s HospitalSLCH
National Human Genome Research InstituteNHGRIT32HG000045
National Human Genome Research InstituteNHGRI
National Institute of Mental HealthNIMHR01MH124808, RF1MH126723, RF1MH117070
National Institute of Mental HealthNIMH
Autism Science FoundationASF22-007
Autism Science FoundationASF
Foundation for Barnes-Jewish HospitalFBJH4642, 3770
Foundation for Barnes-Jewish HospitalFBJH
National Institutes of HealthNIHP50 HD103525
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Correlation Between Visual Acuity and Foveal Threshold by Automated Perimetry With Size V Stimulus
(2024) Journal of Neuro-Ophthalmology, 44 (4), pp. 507-510.
Bohm, P.E.a , Stunkel, L.a b , Van Stavern, G.P.a b
a Departments of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Departments of Neurology, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background:Visual acuity has been shown to correlate with foveal threshold as determined by automated perimetry. Although automated perimetry with size V stimulus is commonly used in neuro-ophthalmology practice, the relationship between the visual acuity and the foveal threshold with this larger stimulus is not well known.Methods:Retrospective study of patients who had undergone neuro-ophthalmology evaluation and visual field testing with automated perimetry using size V stimulus. Healthy controls were also recruited. Using visual acuity and foveal threshold, Pearson correlation coefficients were calculated, and basic foveal threshold statistics were stratified by visual acuity. Prediction intervals for visual acuities by various foveal threshold were also calculated.Results:A total of 106 unique eyes were included. The final Pearson correlation coefficient between visual acuities was -0.795 for the right eye and -0.578 for the left eye, with a pooled correlation coefficient of -0.751 (P < 0.001). A foveal threshold of at least 34 dB was present in 94.4% of eyes with 20/20 visual acuity, and a foveal threshold of greater than 35 dB was not observed in eyes with visual acuity of 20/40 or worse.Conclusions:Foveal threshold as determined by automated perimetry using size V stimulus has moderate-to-strong correlation with visual acuity in patients undergoing neuro-ophthalmology evaluation. © 2023 by North American Neuro-Ophthalmology Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
Difficult to Treat Depression: Focus on Approach, Algorithms, and Access
(2024) The Journal of Clinical Psychiatry, 85 (4), .
Karp, J.F.a , Brinton, R.D.b , Fournier, J.C.c , Harding, L.d , Jha, M.K.e , Lenze, E.J.f , Mathew, S.J.g , Meltzer-Brody, S.h , Mohr, D.C.i , Riva-Posse, P.j , Wiechers, I.k l , Williams, N.R.m
a Department of Psychiatry, College of Medicine, University of Arizona, Tucson, United States
b Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, United States
c Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, United States
d Yale University School of Medicine, New Haven, Connecticut, and Depression MD, Milford, Connecticut
e Department of Psychiatry and Center for Depression Research and Clinical Care, University of Texas Southwestern Medical Center, Dallas, TX, United States
f Department of Psychiatry, Washington University, St. Louis, MO, United States
g Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
h Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill
i Department of Preventive Medicine and the Center for Behavioral Intervention Technologies, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
j Department of Psychiatry, Emory University, Atlanta, Georgia
k Office of Mental Health, Veterans Health AdministrationWA, United States
l Department of Psychiatry and Behavioral Sciences, San Francisco School of Medicine, University of California, San Francisco, CA, United States
m Department of Psychiatry, Stanford University, Palo Alto, CA, United States
Abstract
The pandemic refocused interest on the burden of depression across the lifespan; the increased efforts to prevent and treat depression are now a priority of health care systems, insurers, patient advocates, digital therapeutic engineers, telemedicine platforms, and community health agencies. However, the challenges of treating depression to remission in adult patients who do not respond to first, second, or third levels of oral pharmacotherapy remain. The increased prevalence of these conditions is at odds with the shrinking psychiatric workforce. Since addressing difficult to treat depression is situated in a rapidly evolving treatment landscape, The University of Arizona College of Medicine-Tucson Department of Psychiatry organized and hosted the Southwest Forum on Difficult to Treat Depression: Focus on Approach, Algorithms, and Access in July 2024. The Forum convened 11 internationally renowned experts in the science and treatment of depression, in particular difficult to treat depression, for a day of teaching and discussion. Based on their expertise, participants were asked to address one of the following three themes: (1) Novel Mechanism Approaches for Difficult to Treat Depression, (2) What Do I Do Next? Evidence-Informed Algorithms to Get Patients Better Faster, and (3) Access: Providing Comprehensive Depression Care Across the Spectrum of Clinical Severity. © Copyright 2024 Physicians Postgraduate Press, Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
Validation of the Laryngeal Cognitive-affective Tool in a Taiwanese Population
(2024) Journal of Clinical Gastroenterology, art. no. 2116, .
Krause, A.J.a , Yadlapati, R.a , Wong, M.-W.b , Taft, T.c , Pandolfino, J.E.d , Gyawali, P.e , Chen, C.-L.b
a Department of Medicine, Division of Gastroenterology & Hepatology, University of California San Diego, La JollaCA, United States
b Department of Medicine, Division of Gastroenterology and Hepatology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan
c Rome Foundation Research Institute, Raleigh, NC, United States
d Department of Medicine, Division of Gastroenterology & Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
e Department of Medicine, Division of Gastroenterology, Washington University, St. Louis, MO, United States
Abstract
Background and Aim: The laryngeal cognitive-affective tool (LCAT) was recently validated in the US to assess laryngeal-specific hypervigilance and anxiety. The aim of this study was to examine LCAT validity in the Taiwanese population. Methods: This prospective single-center study enrolled adults from Hualien Tzu Chi Hospital with laryngeal symptoms for > 6 months. Results: One hundred four patients included: mean age 49.5 years (SD 13.3), 69% female, mean BMI 25.3 kg/m2 (5.8), and mean LCAT 25.9 (15.2). The LCAT had excellent internal consistency (α = 0.969) and split-half reliability (Guttman = 0.925). Conclusions: The LCAT is newly validated in the Taiwanese population and assesses laryngeal-specific cognitive-affective processes in patients with chronic laryngeal symptoms. Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.
Author Keywords
esophagus; gastro-esophageal reflux disease (GERD); laryngopharyngeal reflux disease
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Causal Mediation Analysis of Factors Influencing Physical Activity and Community Access Among People With Mild-to-Moderate Parkinson Disease
(2024) Archives of Physical Medicine and Rehabilitation, .
Paul, S.S.a , Porciuncula, F.b , Cavanaugh, J.T.c , Rawson, K.S.d e , Nordahl, T.J.b , Baker, T.C.b , Duncan, R.P.d e , Earhart, G.M.d e f , Ellis, T.D.b
a Discipline of Physiotherapy, Sydney School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
b Department of Physical Therapy, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, United States
c Department of Physical Therapy, University of New England, Portland, ME, United States
d Program in Physical Therapy, Washington University in St Louis School of Medicine, St Louis, MO, United States
e Department of Neurology, Washington University in St Louis School of Medicine, St Louis, MO, United States
f Department of Neuroscience, Washington University in St. Louis School of Medicine, St Louis, MO, United States
Abstract
Objective: To examine how known causal factors (exercise self-efficacy, balance, walking capacity) affect outcomes (moderate-intensity physical activity, community access) in people with Parkinson disease (PD): through a direct pathway, indirectly through potential mediators (nonmotor impairments), or through combined direct and mediated paths. Design: Causal mediation analyses using baseline and three-month data from pooled treatment groups in a randomized controlled trial. Setting: Data were collected at 2 university clinical research centers. Participants: One hundred thirty-eight people with PD. Interventions: Home and community-based walking and strength exercise program. Main Outcome Measure(s): Exposures were exercise self-efficacy, walking capacity, and balance. Potential mediators included pain, fatigue, mood (anxiety, depression, affect, apathy), stigma, and cognition (executive function and cognitive flexibility). The outcomes were physical activity and community access behavior at follow-up 3 months later. Separate models were developed for each causal factor-mediator-outcome combination. To minimize bias, all models were adjusted for known confounders (comorbidities, freezing of gait, severity of motor impairment, and/or age) and baseline values of the outcomes. Results: Self-efficacy of walking duration had a causal relationship with moderate-intensity physical activity through direct and combined paths (P<.001). Walking capacity had a causal relationship with community access through direct (P=.03-.04) and combined (P=.02-.03) paths. Balance did not affect community access (P>.05). There were no significant mediation effects through indirect pathways for either outcome. Conclusions: The effect of known causal factors on physical activity and community access was not mediated by nonmotor impairments. Walking self-efficacy and walking capacity remain the primary intervention targets for improving physical activity and community access, respectively, in people with PD. © 2024 American Congress of Rehabilitation Medicine
Author Keywords
Ambulation; Causal mediation analysis; Parkinson disease; Physical activity; Rehabilitation
Funding details
National Institutes of HealthNIHR01HD092444
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A digital version of the nine-hole peg test: Speed may be a more reliable measure of upper-limb disability than completion time in patients with multiple sclerosis
(2024) Multiple Sclerosis Journal, .
Jiang, X.a , McGinley, M.b , Johnston, J.c , Alberts, J.c , Bermel, R.b , Ontaneda, D.b , Naismith, R.T.d , Hyde, R.a , Levitt, N.a , van Beek, J.a , Sun, Z.a , Campbell, N.a , Barro, C.a
a Biogen, Cambridge, MA, United States
b Mellen Center, Cleveland Clinic, Cleveland, OH, United States
c Biomedical Engineering, Cleveland Clinic, Cleveland, OH, United States
d Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: A digital adaptation of the nine-hole peg test (9HPT) was developed with the potential to provide novel disability features for patients with multiple sclerosis (PwMS). Objectives: The objectives were to evaluate the 9HPT features based on reliability, prognosis, and discrimination between treatment groups. Methods: The MS partners Advancing Technology and Health Solutions (MS PATHS) cohort data were used to derive new features including completion time and speed. Association and reliability between features and clinical outcomes were tested by intraclass correlation coefficients (ICCs) with repeated measures. The added prognostic value of the features for a clinically meaningful decline was assessed by time-to-event analyses with likelihood ratio tests. The estimated effect size between treatment efficacy groups was acquired from linear mixed-effects models. Sample size was calculated for a hypothetical randomized clinical trial. Results: For the 10,843 PwMS, speed and completion time were associated with MS disability. Compared with time, speed showed higher reliability (ICC = 0.78 vs 0.74), added benefits in predicting disability worsening (p < 0.001), better discrimination between high- and low-efficacy groups (effect size: 0.035 vs 0.015), and an 18% reduction in required sample size for a 1-year clinical trial. Conclusion: Integrating horizontal hand distances traveled over the 9HPT pegboard can be a more reliable measure of hand function. © The Author(s), 2024.
Author Keywords
Digital assessment; disability prognosis; disease progression; feature engineering; manual dexterity test; nine-hole peg test; treatment efficacy; upper-limb function
Funding details
Biogen
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Wireless Modular Implantable Neural Device with One-touch Magnetic Assembly for Versatile Neuromodulation
(2024) Advanced Science, .
Kang, I.a , Bilbily, J.b c d e f , Kim, C.Y.a g , Shi, C.h , Madasu, M.K.b c d e , Jeong, E.Y.a , Parker, K.E.b c d e , Kwon, D.A.a i , Jung, B.-J.j , Yang, J.-S.a , Lee, J.a , Kabbaj, N.D.L.b c d e , Lee, W.j k l , Yoon, J.-B.a , Al-Hasani, R.b c d e , Xiao, J.h , McCall, J.G.b c d e , Jeong, J.-W.a m
a School of Electrical Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, South Korea
b Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in St. Louis, St. Louis, MO 63110, United States
d Center for Clinical Pharmacology, University of Health Sciences and Pharmacy in St. Louis and Washington University School of Medicine, St. Louis, MO 63110, United States
e Washington University Pain Center, Washington University in St. Louis, St. Louis, MO 63110, United States
f Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
g KAIST Information & Electronics Research Institute, Daejeon, 34141, South Korea
h Department of Mechanical Engineering, University of Colorado Boulder, Boulder, CO 80309, United States
i Department of Materials Science and Engineering, KAIST, Daejeon, 34141, South Korea
j Graduate School of Nanoscience and Technology, KAIST, Daejeon, 34141, South Korea
k Department of Physics, KAIST, Daejeon, 34141, South Korea
l Department of Bio and Brain Engineering, KAIST, Daejeon, 34141, South Korea
m KAIST Institute for Health Science and Technology, Daejeon, 34141, South Korea
Abstract
Multimodal neural interfaces open new opportunities in brain research by enabling more sophisticated and systematic neural circuit dissection. Integrating complementary features across distinct functional domains, these multifunctional neural probes have greatly advanced the interrogation of complex neural circuitry. However, introducing multiple functionalities into a compact form factor for freely behaving animals presents substantial design hurdles that complicate the device or require more than one device. Moreover, fixed functionality poses challenges in meeting the dynamic needs of chronic neuroscience inquiry, such as replacing consumable parts like batteries or drugs. To address these limitations, the modular implantable neural device (MIND) is introduced with a one-touch magnetic assembly mechanism. Leveraging the seamless exchange of neural interface modules such as optical stimulation, drug delivery, and electrical stimulation, MIND ensures functional adaptability, reusability, and scalability. The versatile design of MIND will facilitate brain research by enabling simplified access to multiple functional modalities as needed. © 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH.
Author Keywords
magnetic assembly; modular; neural device; neuromodulation; wireless
Funding details
National Institutes of HealthNIHR21DA055047, R25NS090985, T32DA007261, R01NS123070, R01NS117899
National Institutes of HealthNIH
National Research Foundation of KoreaNRFNRF‐2022R1A4A5033852, RS‐2024‐00335066
National Research Foundation of KoreaNRF
Korea Advanced Institute of Science and TechnologyKAIST4120200113769
Korea Advanced Institute of Science and TechnologyKAIST
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Endogenous self-peptides guard immune privilege of the central nervous system
(2024) Nature, . Cited 2 times.
Kim, M.W.a b c d , Gao, W.a b , Lichti, C.F.a b e , Gu, X.a b , Dykstra, T.a b , Cao, J.a b , Smirnov, I.a b , Boskovic, P.a b , Kleverov, D.b f , Salvador, A.F.M.a b , Drieu, A.a b , Kim, K.a b , Blackburn, S.a b , Crewe, C.g , Artyomov, M.N.b e , Unanue, E.R.a b e , Kipnis, J.a b e
a Brain Immunology and Glia (BIG) Center, School of Medicine, Washington University in St Louis, St Louis, MO, United States
b Department of Pathology and Immunology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
c Immunology Graduate Program, School of Medicine, Washington University in St Louis, St Louis, MO, United States
d Medical Scientist Training Program, School of Medicine, Washington University in St Louis, St Louis, MO, United States
e Bursky Center for Human Immunology and Immunotherapy Programs, School of Medicine, Washington University in St Louis, St Louis, MO, United States
f Computer Technologies Laboratory, ITMO University, Saint Petersburg, Russian Federation
g Department of Cell Biology and Physiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
Abstract
Despite the presence of strategically positioned anatomical barriers designed to protect the central nervous system (CNS), it is not entirely isolated from the immune system1,2. In fact, it remains physically connected to, and can be influenced by, the peripheral immune system1. How the CNS retains such responsiveness while maintaining an immunologically unique status remains an outstanding question. Here, in searching for molecular cues that derive from the CNS and enable its direct communication with the immune system, we identified an endogenous repertoire of CNS-derived regulatory self-peptides presented on major histocompatibility complex class II (MHC-II) molecules in the CNS and at its borders. During homeostasis, these regulatory self-peptides were found to be bound to MHC-II molecules throughout the path of lymphatic drainage from the brain to its surrounding meninges and its draining cervical lymph nodes. However, in neuroinflammatory disease, the presentation of regulatory self-peptides diminished. After boosting the presentation of these regulatory self-peptides, a population of suppressor CD4+ T cells was expanded, controlling CNS autoimmunity in a CTLA-4- and TGFβ-dependent manner. CNS-derived regulatory self-peptides may be the molecular key to ensuring a continuous dialogue between the CNS and the immune system while balancing overt autoreactivity. This sheds light on how we conceptually think about and therapeutically target neuroinflammatory and neurodegenerative diseases. © The Author(s) 2024.
Funding details
National Institutes of HealthNIHDPI AT010416
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Development of Dual Aurora-A and Aurora-B Degrading PROTACs for MYCN-Amplified Neuroblastoma
(2024) ChemMedChem, .
Nelson, S.E.a b , Tucker, J.R.a , Prado, M.G.a , Tierney, L.C.a , Quigley, S.L.a , Lumpkin, A.T.a , Dodd, C.J.a , Hasko, V.a , Howie, S.L.a , Aasthab , Ody, B.K.c , Yin, J.c , Heemstra, J.M.b , Turlington, M.a
a Department of Chemistry and Biochemistry, Berry College, Mount Berry, GA 30149, United States
b Department of Chemistry, Washington University in St. Louis, St. Louis, MO 63130, United States
c Department of Chemistry, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, United States
Abstract
In neuroblastoma, MYCN amplification is associated with survival rates of <50 %. Overexpression of the mitotic kinases Aurora-A and Aurora-B are also associated with low survival and exacerbate the oncogenic effects of N-Myc. As N-Myc is stabilized by Aurora-A, Aurora-A targeting proteolysis targeting chimeras (PROTACs) have been developed that reduce Aurora-A and N-Myc levels. However, simultaneous degradation of N-Myc, Aurora-A, and Aurora-B has not been previously achieved. Given the contributions of both Aurora kinases to MYCN-amplified neuroblastoma, we designed PROTACs capable of degrading both Aurora-A and Aurora-B. Dual-degrading PROTACs dAurAB2 and dAurAB5 potently degraded Aurora-A (DC50=59 nM and 8.8 nM, respectively) and Aurora-B (DC50=39 nM and 6.1 nM), eliminated 89 %–97 % of Aurora-A and Aurora-B, and reduced N-Myc levels by 38 % and 45 % in MYCN-amplified IMR32 neuroblastoma cells. Global proteomics screening revealed that while dAurAB2 demonstrated good selectivity, dAurAB5 downregulated additional targets including threonine tyrosine kinase (TTK). Interestingly, TKK is also associated with MYCN-amplified neuroblastoma, and multi-target PROTAC dAurAB5 reduced the viability of neuroblastoma IMR32 cells by 55 % at 24 hours. The development of dAurAB2 and dAurAB5 generates new modalities for inhibiting the oncogenic activities of Aurora-A, Aurora-B, N-Myc, and TTK in neuroblastoma and other cancers. © 2024 Wiley-VCH GmbH.
Author Keywords
Aurora-A; Aurora-B; N-Myc; Neuroblastoma; PROTAC
Funding details
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Déjà-vu sensation induced by cortical stimulation of the posterior cingulate cortex
(2024) Neurocase, .
Cadle, B.a , Mutchnick, I.b c , Karia, S.a c , Stilp, R.c , Nascimento, F.A.d , Karakas, C.a c
a Division of Pediatric Neurology, Department of Neurology, University of Louisville, Louisville, KY, United States
b Department of Neurological Surgery, University of Louisville School of Medicine, Louisville, KY, United States
c Norton Children’s Neuroscience Institute and Children’s Hospital, Louisville, KY, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
We report a case of a 19-year-old woman with drug-resistant focal epilepsy whose typical seizure semiology involved sensations of déjà-vu. She underwent intracranial stimulation, leading to déjà-vu upon stimulation of the posterior cingulate cortex (PCC). Most reports of induced déjà-vu and epilepsy-associated déjà-vu emphasize networks including temporal lobe, especially the rhinal cortices, as the generator of this phenomenon. However, evidence from healthy individuals and those with confirmed cingulate epilepsy suggests that the PCC may play a role in some experiences of déjà-vu or other dreamy state phenomena. This case adds to the body of evidence suggesting a role for the PCC in déjà-vu. It also highlights the importance of including the PCC in intracranial investigations of some suspected temporal lobe epilepsies. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
cortical stimulation; Déjà-vu; epilepsy; posterior cingulate gyrus
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Correlating clinical course with baseline subcortical shape in provisional tic disorder
(2024) CNS Spectrums, .
Che, T.a , Kim, S.b , Greene, D.J.c , Heywood, A.d , Ding, J.e , Hershey, T.f , Schlaggar, B.L.g h , Black, K.J.i , Wang, L.a d
a Department of Psychiatry and Behavioral Health, Ohio State University, Wexner Medical Center, Columbus, OH, United States
b Departments of Psychiatry and Radiology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
c Department of Cognitive Science, University of California, La Jolla, San Diego, CA, United States
d Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
e Department of Mathematics and Statistics, Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
f Departments of Psychiatry, Neurology, Psychological and Brain Sciences and Radiology, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
g Kennedy Krieger Institute, Baltimore, MD, United States
h Departments of Neurology and Pediatrics, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
i Departments of Psychiatry, Neurology, Radiology and Neuroscience, Washington University, St. Louis School of Medicine, St. Louis, MO, United States
Abstract
Objective This study examined children at the onset of tic disorder (tics for less than 9 months: NT group), a population on which little research exists. Here, we investigate relationships between the baseline shape and volume of subcortical nuclei, diagnosis, and tic symptom outcomes. Methods 187 children were assessed at baseline and a 12-month follow-up: 88 with NT, 60 tic-free healthy controls (HC), and 39 with chronic tic disorder/Tourette syndrome (TS), using T1-weighted MRI and total tic scores (TTS) from the Yale Global Tic Severity Scale to evaluate symptom change. Subcortical surface maps were generated using FreeSurfer-initialized large deformation diffeomorphic metric mapping. Linear regression models correlated baseline structural shapes with follow-up TTS while accounting for covariates, with relationships mapped onto structure surfaces. Results We found that the NT group had a larger right hippocampus compared to HC. Surface maps illustrate distinct patterns of inward deformation in the putamen and outward deformation in the thalamus for NT compared to controls. We also found patterns of outward deformation in almost all studied structures when comparing the TS group to controls. The NT group also showed consistent outward deformation compared to TS in the caudate, accumbens, putamen, and thalamus. Subsequent analyses including clinical symptoms revealed that a larger pallidum and thalamus at baseline correlated with less improvement of tic symptoms at follow-up. Conclusion These observations constitute some of the first prognostic biomarkers for tic disorders and suggest that these subregional shape and volume differences may be associated with the outcome of tic disorders. © The Author(s), 2024.
Author Keywords
FreeSurfer; neuroanatomy; neurodevelopmental disorders; structural MRI; subcortical shape; Tic disorders; tourette syndrome
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Major depression symptom severity associations with willingness to exert effort and patch foraging strategy
(2024) Psychological Medicine, .
Bustamante, L.A.a b , Barch, D.M.c , Solis, J.d , Oshinowo, T.e , Grahek, I.f , Konova, A.B.d , Daw, N.D.g , Cohen, J.D.g
a Princeton Neuroscience Institute, Princeton University, Princeton, NJ, United States
b Department of Psychological & Brain Science, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychological & Brain Science and Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychiatry, Rutgers University, New Brunswick, NJ, United States
e Princeton Neuroscience Institute, Department of Molecular Biology, Princeton University, Princeton, NJ, United States
f Department of Cognitive and Psychological Sciences, Brown University, Providence, RI, United States
g Princeton Neuroscience Institute, Department of Psychology, Princeton University, Princeton, NJ, United States
Abstract
Background Individuals with major depressive disorder (MDD) can experience reduced motivation and cognitive function, leading to challenges with goal-directed behavior. When selecting goals, people maximize ‘expected value’ by selecting actions that maximize potential reward while minimizing associated costs, including effort ‘costs’ and the opportunity cost of time. In MDD, differential weighing of costs and benefits are theorized mechanisms underlying changes in goal-directed cognition and may contribute to symptom heterogeneity. Methods We used the Effort Foraging Task to quantify cognitive and physical effort costs, and patch leaving thresholds in low effort conditions (reflecting perceived opportunity cost of time) and investigated their shared versus distinct relationships to clinical features in participants with MDD (N = 52, 43 in-episode) and comparisons (N = 27). Results Contrary to our predictions, none of the decision-making measures differed with MDD diagnosis. However, each of the measures was related to symptom severity, over and above effects of ability (i.e. performance). Greater anxiety symptoms were selectively associated with lower cognitive effort cost (i.e. greater willingness to exert effort). Anhedonia and behavioral apathy were associated with increased physical effort costs. Finally, greater overall depression was related to decreased patch leaving thresholds. Conclusions Markers of effort-based decision-making may inform understanding of MDD heterogeneity. Increased willingness to exert cognitive effort may contribute to anxiety symptoms such as worry. Decreased leaving threshold associations with symptom severity are consistent with reward rate-based accounts of reduced vigor in MDD. Future research should address subtypes of depression with or without anxiety, which may relate differentially to cognitive effort decisions. Copyright © The Author(s), 2024.
Author Keywords
anxiety; cognitive control; computational psychiatry; effort-based decision-making; foraging; major depressive disorder; physical effort
Document Type: Article
Publication Stage: Article in Press
Source: Scopus