WashU weekly Neuroscience publications

Spectral signature of attentional reorienting in the human brain
(2021) NeuroImage, 244, art. no. 118616, . 

Spadone, S.^a , Betti, V.^b c , Sestieri, C.^a , Pizzella, V.^a , Corbetta, M.^d e f , Della Penna, S.^a

^a Department of Neuroscience, Imaging and Clinical Sciences – and ITAB, Institute for Advanced Biomedical Technologies, G. d’Annunzio University of Chieti-Pescara, Italy
^b Department of Psychology, Sapienza University of Rome, Italy
^c IRCCS Fondazione Santa Lucia, Rome, Italy
^d Department of Neuroscience, University of Padua, Italy
^e Padova Neuroscience Center, University of Padua, Italy
^f Departments of Neurology, Radiology, Neuroscience, Washington University, St. Louis, United States

Abstract
As we move in the environment, attention shifts to novel objects of interest based on either their sensory salience or behavioral value (reorienting). This study measures with magnetoencephalography (MEG) different properties (amplitude, onset-to-peak duration) of event-related desynchronization/synchronization (ERD/ERS) of oscillatory activity during a visuospatial attention task designed to separate activity related to reorienting vs. maintaining attention to the same location, controlling for target detection and response processes. The oscillatory activity was measured both in fMRI-defined regions of interest (ROIs) of the dorsal attention (DAN) and visual (VIS) networks, previously defined as task-relevant in the same subjects, or whole-brain in a pre-defined set of cortical ROIs encompassing the main brain networks. Reorienting attention (shift cues) as compared to maintaining attention (stay cues) produced a temporal sequence of ERD/ERS modulations at multiple frequencies in specific anatomical regions/networks. An early (∼330 ms), stronger, transient theta ERS occurred in task-relevant (DAN, VIS) and control networks (VAN, CON, FPN), possibly reflecting an alert/reset signal in response to the cue. A more sustained, behaviorally relevant, low-beta band ERD peaking ∼450 ms following shift cues (∼410 for stay cues) localized in frontal and parietal regions of the DAN. This modulation is consistent with a control signal re-routing information across visual hemifields. Contralateral vs. ipsilateral shift cues produced in occipital visual regions a stronger, sustained alpha ERD (peak ∼470 ms) and a longer, transient high beta/gamma ERS (peak ∼490 ms) related to preparatory visual modulations in advance of target occurrence. This is the first description of a cascade of oscillatory processes during attentional reorienting in specific anatomical regions and networks. Among these processes, a behaviorally relevant beta desynchronization in the FEF is likely associated with the control of attention shifts. © 2021

Author Keywords
Attentional reorienting;  Beta rhythm;  Dorsal attention network;  ERD/ERS;  Magnetoencephalography;  Visual network

Funding details
759651
European Research CouncilERC
Università degli Studi di PadovaUNIPD
Fundação Bial159–2016
Università degli Studi G. d’Annunzio Chieti – PescaraUd’A

Family Savings and Children’s Non-Cognitive and Cognitive Development: Evidence from China
(2021) Children and Youth Services Review, 130, art. no. 106228, . 

Chen, Y.^a , Zhi, K.^a , Huang, J.^b

^a School of Public Affairs, Chongqing University, China
^b Saint Louis University and Washington University in St. Louis, United States

Abstract
Previous research has found positive correlations of family assets with children’s cognitive and non-cognitive development in separate studies. The association between family assets and children’s cognitive development is mediated by parental engagement in education. Using a sample (N = 3,435) from a nationally representative household survey in China, we examine whether family savings for children are associated with parental engagement as well as children’s non-cognitive and cognitive development. Children’s self-control scores and academic performance are used to measure their non-cognitive and cognitive development. Consistent with prior literature, results suggest that family savings for children are positively associated with all three dependent variables: parental engagement in education, children’s self-control, and academic performance. In addition, parental engagement in education is a mediator between family savings and child development. The association between family savings and children’s cognitive development is also partially mediated by their non-cognitive development. Practice and policy implications are discussed. © 2021 Elsevier Ltd

Author Keywords
Child development;  Cognitive development;  Family savings;  Non-cognitive development;  Parental engagement

Funding details
National Natural Science Foundation of ChinaNSFC52078077
Chongqing UniversityCQU2019GGXY03
Fundamental Research Funds for the Central Universities2018CDJSK01PT05, 2019CDJSK01PT04
National Office for Philosophy and Social SciencesNPOPSS18BGL209, 21BSH117

IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (40), art. no. e2110629118, . 

Tiscione, S.A.^a , Casas, M.^a , Horvath, J.D.^a , Lam, V.^a , Hino, K.^b , Ory, D.S.^c , Fernando Santana, L.^a , Simó, S.^b , Dixon, R.E.^a , Dickson, E.J.^a

^a Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, United States
^b Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616, United States
^c Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease–causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor–stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Calcium;  GPCR;  IP3R;  Neurodegeneration;  NPC1

Funding details
National Institutes of HealthNIHHL144071, R01 AG063796, R01 GM127513, R01 HL06773, R01 NS109176, R01 NS114210, T32GM099608
Ara Parseghian Medical Research FoundationAPMRF

Individual-Specific Areal-Level Parcellations Improve Functional Connectivity Prediction of Behavior
(2021) Cerebral Cortex, 31 (10), pp. 4477-4500. 

Kong, R.^a b c , Yang, Q.^a b c , Gordon, E.^d , Xue, A.^a b c , Yan, X.^a b c e , Orban, C.^a b c , Zuo, X.-N.^f g , Spreng, N.^h i j , Ge, T.^k l , Holmes, A.^m , Eickhoff, S.^n o , Yeo, B.T.T.^{a b c d e l}

^a Department of Electrical and Computer Engineering, National University of Singapore, Singapore, 117583, Singapore
^b Centre for Sleep and Cognition (CSC) and Centre for Translational Magnetic Resonance Research (TMR), National University of Singapore, Singapore, 117549, Singapore
^c N.1 Institute for Health and Institute for Digital Medicine (WisDM), National University of Singapore, Singapore, 117456, Singapore
^d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63130, United States
^e Integrative Sciences and Engineering Programme (ISEP), National University of Singapore, Singapore, 119077, Singapore
^f State Key Lab. of Cognitive Neuroscience and Learning/IDG McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China
^g National Basic Public Science Data Center, Chinese Academy of Sciences, Beijing, 100101, China
^h Department of Neurology and Neurosurgery, Laboratory of Brain and Cognition, McGill University, Montreal, QC H3A 2B4, Canada
ⁱ Departments of Psychiatry and Psychology, Neurological Institute, McGill University, Montreal, QC H3A 2B4, Canada
^j McConnell Brain Imaging Centre, Montreal Neurological Institute (MNI), McGill University, Montreal, QC H3A 2B4, Canada
^k Center for Genomic Medicine, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States
^l Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA 02129, United States
^m Department of Psychology, Yale University, New Haven, CT 06520, United States
ⁿ Medical Faculty, Institute for Systems Neuroscience, Heinrich-Heine University D sseldorf, D sseldorf, 40225, Germany
^o Research Center J lich, Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), J lich, 52425, Germany

Abstract
Resting-state functional magnetic resonance imaging (rs-fMRI) allows estimation of individual-specific cortical parcellations. We have previously developed a multi-session hierarchical Bayesian model (MS-HBM) for estimating high-quality individual-specific network-level parcellations. Here, we extend the model to estimate individual-specific areal-level parcellations. While network-level parcellations comprise spatially distributed networks spanning the cortex, the consensus is that areal-level parcels should be spatially localized, that is, should not span multiple lobes. There is disagreement about whether areal-level parcels should be strictly contiguous or comprise multiple noncontiguous components; therefore, we considered three areal-level MS-HBM variants spanning these range of possibilities. Individual-specific MS-HBM parcellations estimated using 10 min of data generalized better than other approaches using 150 min of data to out-of-sample rs-fMRI and task-fMRI from the same individuals. Resting-state functional connectivity derived from MS-HBM parcellations also achieved the best behavioral prediction performance. Among the three MS-HBM variants, the strictly contiguous MS-HBM exhibited the best resting-state homogeneity and most uniform within-parcel task activation. In terms of behavioral prediction, the gradient-infused MS-HBM was numerically the best, but differences among MS-HBM variants were not statistically significant. Overall, these results suggest that areal-level MS-HBMs can capture behaviorally meaningful individual-specific parcellation features beyond group-level parcellations. Multi-resolution trained models and parcellations are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Kong2022_ArealMSHBM). © 2021 The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
behavioral prediction;  brain parcellation;  difference;  individual;  resting-state functional connectivity

Hyaluronic acid-based gold nanoparticles for the topical delivery of therapeutics to the retina and the retinal pigment epithelium
(2021) Polymers, 13 (19), art. no. 3324, . 

Laradji, A.^a b , Karakocak, B.B.^a b , Kolesnikov, A.V.^c , Kefalov, V.J.^c d , Ravi, N.^a b e

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Veterans Affairs, St. Louis Medical Center, St. Louis, MO 63106, United States
^c Department of Ophthalmology, Gavin Herbert Eye Institute, University of California Irvine, Irvine, CA 92697, United States
^d Department of Physiology and Biophysics, University of California Irvine, Irvine, CA 92697, United States
^e Department of Energy, Environmental, and Chemical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
The ocular immune privilege is a phenomenon brought about by anatomical and physi-ological barriers to shield the eye from immune and inflammation responses. While this phenomenon is beneficial for eyes protection, it is, at the same time, a hindrance for drug delivery to the posterior segment of the eye to treat retinal diseases. Some ocular barriers can be bypassed by in-travitreal injections, but these are associated with several side effects and patient noncompliance, especially when frequent injections are required. As an alternative, applying drugs as an eye drop is preferred due to the safety and ease. This study investigated the possible use of topically-applied hyaluronic acid-coated gold nanoparticles as drug delivery vehicles to the back of the eye. The coated gold nanoparticles were topically applied to mouse eyes, and results were compared to topically applied uncoated gold nanoparticles and phosphate-buffered saline (PBS) solution. Retina sections from these mice were then analyzed using fluorescence microscopy, inductively coupled plasma mass spectrometry (ICP-MS), and transmission electron microscopy (TEM). All characterization techniques used in this study suggest that hyaluronic acid-coated gold nanoparticles have higher distribution in the posterior segment of the eye than uncoated gold nanoparticles. Electroretinogram (ERG) analysis revealed that the visual function of mice receiving the coated gold nanoparticles was not affected, and these nanoparticles can, therefore, be applied safely. To-gether, our results suggest that hyaluronic acid-coated gold nanoparticles constitute potential drug delivery vehicles to the retina when applied noninvasively as an eye drop. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Biocompatibility;  Gold nanoparticles;  Hyaluronic acid;  Inductively coupled plasma mass spectrometry;  Ocular drug deliv-ery;  Retina;  Retinal diseases;  Retinal pigment epithelium;  Surface functionalization;  Transmission electron microscopy

Funding details
EY025696, EY027387, P30 EY002687
Research to Prevent BlindnessRPB
Washington University in St. LouisWUSTL

Distinct and Dissociable EEG Networks Are Associated With Recovery of Cognitive Function Following Anesthesia-Induced Unconsciousness
(2021) Frontiers in Human Neuroscience, 15, art. no. 706693, . 

Rokos, A.^a , Mišić, B.^b , Berkun, K.^c , Duclos, C.^d , Tarnal, V.^e , Janke, E.^e , Picton, P.^e , Golmirzaie, G.^e , Basner, M.^f , Avidan, M.S.^g , Kelz, M.B.^h , Mashour, G.A.^e , Blain-Moraes, S.^d

^a Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
^b Neurology and Neurosurgery, McGill University, Montreal, QC, Canada
^c Cognitive Science, McGill University, Montreal, QC, Canada
^d School of Physical and Occupational Therapy, McGill University, Montreal, QC, Canada
^e Department of Anesthesiology, Center of Consciousness Science, University of Michigan Medical School, Ann Arbor, MI, United States
^f Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^g Department of Anesthesiology, Washington University School of Medicine, St. Louis, WA, United States
^h Deparment of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States

Abstract
The temporal trajectories and neural mechanisms of recovery of cognitive function after a major perturbation of consciousness is of both clinical and neuroscientific interest. The purpose of the present study was to investigate network-level changes in functional brain connectivity associated with the recovery and return of six cognitive functions after general anesthesia. High-density electroencephalograms (EEG) were recorded from healthy volunteers undergoing a clinically relevant anesthesia protocol (propofol induction and isoflurane maintenance), and age-matched healthy controls. A battery of cognitive tests (motor praxis, visual object learning test, fractal-2-back, abstract matching, psychomotor vigilance test, digital symbol substitution test) was administered at baseline, upon recovery of consciousness (ROC), and at half-hour intervals up to 3 h following ROC. EEG networks were derived using the strength of functional connectivity measured through the weighted phase lag index (wPLI). A partial least squares (PLS) analysis was conducted to assess changes in these networks: (1) between anesthesia and control groups; (2) during the 3-h recovery from anesthesia; and (3) for each cognitive test during recovery from anesthesia. Networks were maximally perturbed upon ROC but returned to baseline 30–60 min following ROC, despite deficits in cognitive performance that persisted up to 3 h following ROC. Additionally, during recovery from anesthesia, cognitive tests conducted at the same time-point activated distinct and dissociable functional connectivity networks across all frequency bands. The results highlight that the return of cognitive function after anesthetic-induced unconsciousness is task-specific, with unique behavioral and brain network trajectories of recovery. © Copyright © 2021 Rokos, Mišić, Berkun, Duclos, Tarnal, Janke, Picton, Golmirzaie, Basner, Avidan, Kelz, Mashour and Blain-Moraes.

Author Keywords
anesthesia;  brain networks;  cognitive function;  electroencephalography;  functional connectivity;  partial least squares

Trajectory of Long-Term Outcome in Severe Pediatric Diffuse Axonal Injury: An Exploratory Study
(2021) Frontiers in Neurology, 12, art. no. 704576, . 

Lang, S.-S.^a , Kilbaugh, T.^b , Friess, S.^c , Sotardi, S.^d , Kim, C.T.^e , Mazandi, V.^b , Zhang, B.^f , Storm, P.B.^a , Heuer, G.G.^a , Tucker, A.^a , Ampah, S.B.^f , Griffis, H.^f , Raghupathi, R.^g , Huh, J.W.^b

^a Division of Neurosurgery, Department of Neurosurgery, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^b Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^c Department of Pediatrics, St. Louis Children’s Hospital, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^d Department of Radiology and Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^e Department of Physical Medicine and Rehabilitation and Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^f Data Science and Biostatistics Unit, Department of Biomedical and Health Informatics, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^g Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, United States

Abstract
Introduction: Pediatric severe traumatic brain injury (TBI) is one of the leading causes of disability and death. One of the classic pathoanatomic brain injury lesions following severe pediatric TBI is diffuse (multifocal) axonal injury (DAI). In this single institution study, our overarching goal was to describe the clinical characteristics and long-term outcome trajectory of severe pediatric TBI patients with DAI. Methods: Pediatric patients (<18 years of age) with severe TBI who had DAI were retrospectively reviewed. We evaluated the effect of age, sex, Glasgow Coma Scale (GCS) score, early fever ≥ 38.5°C during the first day post-injury, the extent of ICP-directed therapy needed with the Pediatric Intensity Level of Therapy (PILOT) score, and MRI within the first week following trauma and analyzed their association with outcome using the Glasgow Outcome Score—Extended (GOS-E) scale at discharge, 6 months, 1, 5, and 10 years following injury. Results: Fifty-six pediatric patients with severe traumatic DAI were analyzed. The majority of the patients were >5 years of age and male. There were 2 mortalities. At discharge, 56% (30/54) of the surviving patients had unfavorable outcome. Sixty five percent (35/54) of surviving children were followed up to 10 years post-injury, and 71% (25/35) of them made a favorable recovery. Early fever and extensive DAI on MRI were associated with worse long-term outcomes. Conclusion: We describe the long-term trajectory outcome of severe pediatric TBI patients with pure DAI. While this was a single institution study with a small sample size, the majority of the children survived. Over one-third of our surviving children were lost to follow-up. Of the surviving children who had follow-up for 10 years after injury, the majority of these children made a favorable recovery. © Copyright © 2021 Lang, Kilbaugh, Friess, Sotardi, Kim, Mazandi, Zhang, Storm, Heuer, Tucker, Ampah, Griffis, Raghupathi and Huh.

Author Keywords
diffuse axonal injury (DAI);  fever;  intracranial hypertension (IH);  outcome;  pediatric;  traumatic brain injury