WashU weekly Neuroscience publications

Chronic neuroleptic treatment combined with a high fat diet elevated [3H] flunitrazepam binding in the cerebellum
(2022) Progress in Neuro-Psychopharmacology and Biological Psychiatry, 112, art. no. 110407, . 

Richardson, B.^a b , Swenson, S.^a , Hamilton, J.^a b , Leonard, K.^c , Delis, F.^d , Gold, M.^e , Blum, K.^f , Thanos, P.K.^a b

^a Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
^b Department of Psychology, University at Buffalo, Buffalo, NY, United States
^c Department of Psychiatry, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
^d Department of Pharmacology, University at Ioannina, Ioannina, Greece
^e Washington University in St Louis, School of Medicine, St. Louis, MS, United States
^f Western University Health Sciences, Graduate School of Biomedical Sciences, Pomona, CA, United States

Abstract
Clinical and preclinical studies have shown dysfunctions in genetic expression and neurotransmission of γ-Aminobutyric acid (GABA), GABAA receptor subunits, and GABA-synthesizing enzymes GAD67 and GAD65 in schizophrenia. It is well documented that there is significant weight gain after chronic neuroleptic treatment in humans. While there are limited studies on the effects of diet on GABA signaling directly, a change in diet has been used clinically as an adjunct to treatment for schizophrenic relief. In this study, rats chronically consumed either a chow diet (CD) or a 60% high-fat diet (HFD) and drank from bottles that contained one of the following solutions: water, haloperidol (1.5 mg/kg), or olanzapine (10 mg/kg) for four weeks. Rats were then euthanized and their brains were processed for GABAA in-vitro receptor autoradiography using [3H] flunitrazepam. A chronic HFD treatment yielded significantly increased [3H] flunitrazepam binding in the rat cerebellum independent of neuroleptic treatment. The desynchronization between the prefrontal cortex and the cerebellum is associated with major cognitive and motor dysfunctions commonly found in schizophrenic symptomatology, such as slowed reaction time, motor dyscoordination, and prefrontal activations related to speech fluency and cognitive alertness. These data support the notion that there is a dietary effect on GABA signaling within the cerebellum, as well as the importance of considering nutritional intervention methods as an adjunct treatment for patients chronically treated with neuroleptics. Finally, we indicate that future studies involving the analysis of individual patient’s genetic profiles will further assist towards a precision medicine approach to the treatment of schizophrenia. © 2021 Elsevier Inc.

Author Keywords
Antipsychotics;  Cerebellum;  Dopamine;  GABAA;  Haloperidol;  Neuroleptics;  Obesity;  Olanzapine;  Reward deficiency syndrome;  Schizophrenia

Substrate reduction therapy for Krabbe disease and metachromatic leukodystrophy using a novel ceramide galactosyltransferase inhibitor
(2021) Scientific Reports, 11 (1), art. no. 14486, . 

Babcock, M.C.^a , Mikulka, C.R.^b , Wang, B.^a , Chandriani, S.^a , Chandra, S.^a , Xu, Y.^a , Webster, K.^a , Feng, Y.^a , Nelvagal, H.R.^d , Giaramita, A.^a , Yip, B.K.^a , Lo, M.^a , Jiang, X.^b , Chao, Q.^a , Woloszynek, J.C.^a , Shen, Y.^a , Bhagwat, S.^a , Sands, M.S.^b c , Crawford, B.E.^a

^a BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, United States
^b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Krabbe disease (KD) and metachromatic leukodystrophy (MLD) are caused by accumulation of the glycolipids galactosylceramide (GalCer) and sulfatide and their toxic metabolites psychosine and lysosulfatide, respectively. We discovered a potent and selective small molecule inhibitor (S202) of ceramide galactosyltransferase (CGT), the key enzyme for GalCer biosynthesis, and characterized its use as substrate reduction therapy (SRT). Treating a KD mouse model with S202 dose-dependently reduced GalCer and psychosine in the central (CNS) and peripheral (PNS) nervous systems and significantly increased lifespan. Similarly, treating an MLD mouse model decreased sulfatides and lysosulfatide levels. Interestingly, lower doses of S202 partially inhibited CGT and selectively reduced synthesis of non-hydroxylated forms of GalCer and sulfatide, which appear to be the primary source of psychosine and lysosulfatide. Higher doses of S202 more completely inhibited CGT and reduced the levels of both non-hydroxylated and hydroxylated forms of GalCer and sulfatide. Despite the significant benefits observed in murine models of KD and MLD, chronic CGT inhibition negatively impacted both the CNS and PNS of wild-type mice. Therefore, further studies are necessary to elucidate the full therapeutic potential of CGT inhibition. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHR01 NS100779
Office of Extramural Research, National Institutes of HealthOER
BioMarin Pharmaceutical
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP

Transcriptional-regulatory convergence across functional MDD risk variants identified by massively parallel reporter assays
(2021) Translational Psychiatry, 11 (1), art. no. 403, . 

Mulvey, B., Dougherty, J.D.

Departments of Genetics and Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Family and population studies indicate clear heritability of major depressive disorder (MDD), though its underlying biology remains unclear. The majority of single-nucleotide polymorphism (SNP) linkage blocks associated with MDD by genome-wide association studies (GWASes) are believed to alter transcriptional regulators (e.g., enhancers, promoters) based on enrichment of marks correlated with these functions. A key to understanding MDD pathophysiology will be elucidation of which SNPs are functional and how such functional variants biologically converge to elicit the disease. Furthermore, retinoids can elicit MDD in patients and promote depressive-like behaviors in rodent models, acting via a regulatory system of retinoid receptor transcription factors (TFs). We therefore sought to simultaneously identify functional genetic variants and assess retinoid pathway regulation of MDD risk loci. Using Massively Parallel Reporter Assays (MPRAs), we functionally screened over 1000 SNPs prioritized from 39 neuropsychiatric trait/disease GWAS loci, selecting SNPs based on overlap with predicted regulatory features—including expression quantitative trait loci (eQTL) and histone marks—from human brains and cell cultures. We identified >100 SNPs with allelic effects on expression in a retinoid-responsive model system. Functional SNPs were enriched for binding sequences of retinoic acid-receptive transcription factors (TFs), with additional allelic differences unmasked by treatment with all-trans retinoic acid (ATRA). Finally, motifs overrepresented across functional SNPs corresponded to TFs highly specific to serotonergic neurons, suggesting an in vivo site of action. Our application of MPRAs to screen MDD-associated SNPs suggests a shared transcriptional-regulatory program across loci, a component of which is unmasked by retinoids. © 2021, The Author(s).

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH1F30MH1116654, 1R01MH116999
Simons FoundationSF571009, TR002345

The informed road map to prevention of Alzheimer Disease: A call to arms
(2021) Molecular Neurodegeneration, 16 (1), art. no. 49, . 

McDade, E.^a b c , Llibre-Guerra, J.J.^a b c , Holtzman, D.M.^a b c , Morris, J.C.^a b c , Bateman, R.J.^a b c

^a Department of Neurology, Washington University in St Louis, 660 S. Euclid Avenue, Campus Box, St Louis, MO 8111, United States
^b Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Dominantly Inherited Alzheimer’s Network Trials Unit, St. Louis, MO 63110, United States

Abstract
Alzheimer disease (AD) prevention trials hold the promise to delay or prevent cognitive decline and dementia onset by intervening before significant neuronal damage occurs. In recent years, the first AD prevention trials have launched and are yielding important findings on the biology of targeting asymptomatic AD pathology. However, there are limitations that impact the design of these prevention trials, including the translation of animal models that recapitulate key stages and multiple pathological aspects of the human disease, missing target validation in asymptomatic disease, uncertain causality of the association of pathophysiologic changes with cognitive and clinical symptoms, and limited biomarker validation for novel targets. The field is accelerating advancements in key areas including the development of highly specific and quantitative biomarker measures for AD pathology, increasing our understanding of the course and relationship of amyloid and tau pathology in asymptomatic through symptomatic stages, and the development of powerful interventions that can slow or reverse AD amyloid pathology. We review the current status of prevention trials and propose key areas of needed research as a call to basic and translational scientists to accelerate AD prevention. Specifically, we review (1) sporadic and dominantly inherited primary and secondary AD prevention trials, (2) proposed targets, mechanisms, and drugs including the amyloid, tau, and inflammatory pathways and combination treatments, (3) the need for more appropriate prevention animal models and experiments, and (4) biomarkers and outcome measures needed to design human asymptomatic prevention trials. We conclude with actions needed to effectively move prevention targets and trials forward. © 2021, The Author(s).

Author Keywords
Alzheimer disease;  Clinical trials;  Primary and secondary prevention

Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P30 AG066444, R01/R56 AG053267, R1AG046179, U01AG042791, U01AG059798, U19 AG024904, U19 AG032438
National Institute on AgingNIA
Alzheimer’s AssociationAA
Biogen
F. Hoffmann-La Roche
Avid Radiopharmaceuticals
GHR FoundationGHR

A multicenter retrospective study of heterogeneous tissue aggregates obstructing ventricular catheters explanted from patients with hydrocephalus
(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 33, . 

Hariharan, P.^a , Sondheimer, J.^b , Petroj, A.^b , Gluski, J.^c , Jea, A.^d , Whitehead, W.E.^e , Sood, S.^f , Ham, S.D.^f , Rocque, B.G.^g , Marupudi, N.I.^h , McAllister, J.P., IIⁱ , Limbrick, D.^j , Del Bigio, M.R.^k , Harris, C.A.^b

^a Wayne State University Dept. of Biomedical Engineering, 6135 Woodward Avenue, Detroit, MI 48202, United States
^b Wayne State University Dept. of Chemical Engineering and Materials Science, 6135 Woodward Avenue, Detroit, MI 48202, United States
^c Dept. of Neurosurgery, Wayne State University School of Medicine, 540 E. Canfield Avenue, Detroit, MI 48201, United States
^d Riley Hospital for Children at IU Health, 705 Riley Hospital Drive, Indianapolis, IN 46202, United States
^e Texas Children’s, 6701 Fannin Street, Suite 1230.01, Houston, TX, United States
^f Departments of Neurosurgery and Pediatric Neurosurgery, Wayne State University School of Medicine and Children’s Hospital of Michigan, 3901 Beaubien Boulevard, 2nd Floor Carl’s Building, Detroit, MI 48201, United States
^g Department of Neurosurgery, University of Alabama At Birmingham, Birmingham, AL, United States
^h Children’s Hospital of Michigan Dept. of Neurosurgery, 3901 Beaubien Boulevard, 2nd Floor Carl’s Building, Detroit, MI 48201, United States
ⁱ School of Medicine Dept. of Neurological Surgery, Washington University, 425 S. Euclid Avenue, St. Louis, MO 63110, United States
^j School of Medicine Dept. of Neurological Surgery, Washington University, 660 S. Euclid Avenue, St. Louis, MO 6311, United States
^k Department of Pathology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada

Abstract
Background: Implantation of ventricular catheters (VCs) to drain cerebrospinal fluid (CSF) is a standard approach to treat hydrocephalus. VCs fail frequently due to tissue obstructing the lumen via the drainage holes. Mechanisms driving obstruction are poorly understood. This study aimed to characterize the histological features of VC obstructions and identify links to clinical factors. Methods: 343 VCs with relevant clinical data were collected from five centers. Each hole on the VCs was classified by degree of tissue obstruction after macroscopic analysis. A subgroup of 54 samples was analyzed using immunofluorescent labelling, histology and immunohistochemistry. Results: 61.5% of the 343 VCs analyzed had tissue aggregates occluding at least one hole (n = 211) however the vast majority of the holes (70%) showed no tissue aggregates. Mean age at which patients with occluded VCs had their first surgeries (3.25 yrs) was lower than in patients with non-occluded VCs (5.29 yrs, p < 0.02). Mean length of time of implantation of occluded VCs, 33.22 months was greater than for non-occluded VCs, 23.8 months (p = 0.02). Patients with myelomeningocele had a greater probability of having an occluded VC (p = 0.0426). VCs with occlusions had greater numbers of macrophages and astrocytes in comparison to non-occluded VCs (p < 0.01). Microglia comprised only 2–6% of the VC-obstructing tissue aggregates. Histologic analysis showed choroid plexus occlusion in 24%, vascularized glial tissue occlusion in 24%, prevalent lymphocytic inflammation in 29%, and foreign body giant cell reactions in 5% and no ependyma. Conclusion: Our data show that age of the first surgery and length of time a VC is implanted are factors that influence the degree of VC obstruction. The tissue aggregates obstructing VCs are composed predominantly of astrocytes and macrophages; microglia have a relatively small presence. © 2021, The Author(s).

Author Keywords
Biobank;  Hydrocephalus;  Multicenter;  Retrospective cohort;  Shunt failure;  Shunt obstruction;  Surgical outcomes;  Ventriculoperitoneal shunt

Funding details
National Institutes of HealthNIHR01NS094570
National Institute of Neurological Disorders and StrokeNINDS

Genome-wide chromatin accessibility analyses provide a map for enhancing optic nerve regeneration
(2021) Scientific Reports, 11 (1), art. no. 14924, .

Pita-Thomas, W.^a , Gonçalves, T.M.^a , Kumar, A.^a , Zhao, G.^a b , Cavalli, V.^a c d 

^a Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Retinal Ganglion Cells (RGCs) lose their ability to grow axons during development. Adult RGCs thus fail to regenerate their axons after injury, leading to vision loss. To uncover mechanisms that promote regeneration of RGC axons, we identified transcription factors (TF) and open chromatin regions that are enriched in rat embryonic RGCs (high axon growth capacity) compared to postnatal RGCs (low axon growth capacity). We found that developmental stage-specific gene expression changes correlated with changes in promoter chromatin accessibility. Binding motifs for TFs such as CREB, CTCF, JUN and YY1 were enriched in the regions of the chromatin that were more accessible in embryonic RGCs. Proteomic analysis of purified rat RGC nuclei confirmed the expression of TFs with potential role in axon growth such as CREB, CTCF, YY1, and JUND. The CREB/ATF binding motif was widespread at the open chromatin region of known pro-regenerative TFs, supporting a role of CREB in regulating axon regeneration. Consistently, overexpression of CREB fused to the VP64 transactivation domain in mouse RGCs promoted axon regeneration after optic nerve injury. Our study provides a map of the chromatin accessibility during RGC development and highlights that TF associated with developmental axon growth can stimulate axon regeneration in mature RGC. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHR35NS122260
National Eye InstituteNEIR21EY029077
National Institute of Neurological Disorders and StrokeNINDSR01NS096034
Research to Prevent BlindnessRPB
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIPR03AG070474

Frontoparietal pattern similarity analyses of cognitive control in monozygotic twins
(2021) NeuroImage, 241, art. no. 118415, . 

Tang, R.^a , Etzel, J.A.^a , Kizhner, A.^a , Braver, T.S.^a b c

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, One Brookings Drive, Campus Box 1125, Saint Louis, MO 63130, United States
^b Department of Radiology, Washington University in St. Louis, United States
^c Department of Neuroscience, Washington University in St. Louis, Saint Louis, MO 63130, United States

Abstract
The ability to flexibly adapt thoughts and actions in a goal-directed manner appears to rely on cognitive control mechanisms that are strongly impacted by individual differences. A powerful research strategy for investigating the nature of individual variation is to study monozygotic (identical) twins. Evidence of twin effects have been observed in prior behavioral and neuroimaging studies, yet within the domain of cognitive control, it remains to be demonstrated that the neural underpinnings of such effects are specific and reliable. Here, we utilize a multi-task, within-subjects event-related neuroimaging design with functional magnetic resonance imaging to investigate twin effects through multivariate pattern similarity analyses. We focus on fronto-parietal brain regions exhibiting consistently increased activation associated with cognitive control demands across four task domains: selective attention, context processing, multi-tasking, and working memory. Healthy young adult monozygotic twin pairs exhibited increased similarity of within- and cross-task activation patterns in these fronto-parietal regions, relative to unrelated pairs. Twin activation pattern similarity effects were clearest under high control demands, were not present in a set of task-unrelated parcels or due to anatomic similarity, and were primarily observed during the within-trial timepoints in which the control demands peaked. Together, these results indicate that twin similarity in the neural representation of cognitive control may be domain-general but also functionally and temporally specific in relation to the level of control demand. The findings suggest a genetic and/or environmental basis for individual variation in cognitive control function, and highlight the potential of twin-based neuroimaging designs for exploring heritability questions within this domain. © 2021

Author Keywords
Cognitive control;  Domain-general;  Fronto-parietal network;  Pattern similarity;  Twins

Funding details
National Institutes of HealthNIHF31 AT010422, R21 AT009483, R37 MH066078

Parkinson’s disease aggravation in association with fine particle components in New York State
(2021) Environmental Research, 201, art. no. 111554, . 

Nunez, Y.^a , Boehme, A.K.^b , Li, M.^a , Goldsmith, J.^c , Weisskopf, M.G.^d , Re, D.B.^a , Navas-Acien, A.^a , van Donkelaar, A.^e f , Martin, R.V.^e f , Kioumourtzoglou, M.-A.^a

^a Department of Environmental Health Sciences, Columbia University Mailman School of Public Health, New York, NY, United States
^b Department of Epidemiology and Neurology, Columbia University, New York, NY, United States
^c Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY, United States
^d Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^e Department of Energy, Environmental & Chemical Engineering, Washington University at St. LouisMO, United States
^f Department of Physics and Atmospheric Science, Dalhousie University, Halix, NS, Canada

Abstract
Background: Long-term exposure to fine particulate matter (PM2.5) has been associated with neurodegenerative diseases, including disease aggravation in Parkinson’s disease (PD), but associations with specific PM2.5 components have not been evaluated. Objective: To characterize the association between specific PM2.5 components and PD first hospitalization, a surrogate for disease aggravation. Methods: We obtained data on hospitalizations from the New York Department of Health Statewide Planning and Research Cooperative System (2000–2014) to calculate annual first PD hospitalization counts in New York State per county. We used well-validated prediction models at 1 km2 resolution to estimate county level population-weighted annual black carbon (BC), organic matter (OM), nitrate, sulfate, sea salt (SS), and soil particle concentrations. We then used a multi-pollutant mixed quasi-Poisson model with county-specific random intercepts to estimate rate ratios (RR) of one-year exposure to each PM2.5 component and PD disease aggravation. We evaluated potential nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders. Results: We observed a total of 197,545 PD first hospitalizations in NYS from 2000 to 2014. The annual average count per county was 212 first hospitalizations. The RR (95% confidence interval) for PD aggravation was 1.06 (1.03, 1.10) per one standard deviation (SD) increase in nitrate concentrations and 1.06 (1.04, 1.09) for the corresponding increase in OM concentrations. We also found a nonlinear inverse association between PD aggravation and BC at concentrations above the 96th percentile. We found a marginal association with SS and no association with sulfate or soil exposure. Conclusion: In this study, we detected associations between the PM2.5 components OM and nitrate with PD disease aggravation. Our findings support that PM2.5 adverse effects on PD may vary by particle composition. © 2021

Author Keywords
Air pollution;  Epidemiology;  Long-term exposures;  Neurodegenerative diseases;  Parkinson’s disease;  PM2.5 chemical composition

Funding details
National Institute on AgingNIAR01 AG066793, T32 ES007142, T32 ES007322

White matter plasticity in healthy older adults: The effects of aerobic exercise
(2021) NeuroImage, 239, art. no. 118305, . 

Mendez Colmenares, A.^a b , Voss, M.W.^c , Fanning, J.^d , Salerno, E.A.^e , Gothe, N.P.^f , Thomas, M.L.^b , McAuley, E.^f , Kramer, A.F.^f g , Burzynska, A.Z.^g

^a Department of Human Development and Family Studies/Molecular, Cellular and Integrative Neurosciences, Colorado State University, Fort Collins, CO 80523, United States
^b Department of Psychology/Molecular, Cellular and Integrative Neurosciences, Colorado State University, Fort Collins, CO 80523, United States
^c Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA 52242, United States
^d Department of Health and Exercise Sciences, Wake Forest University, Winston-Salem, NC 27109, United States
^e Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63130, United States
^f Department of Kinesiology and Community Health, Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
^g Department of Psychology, Northeastern University, Boston, MA 02115, United States

Abstract
White matter deterioration is associated with cognitive impairment in healthy aging and Alzheimer’s disease. It is critical to identify interventions that can slow down white matter deterioration. So far, clinical trials have failed to demonstrate the benefits of aerobic exercise on the adult white matter using diffusion Magnetic Resonance Imaging. Here, we report the effects of a 6-month aerobic walking and dance interventions (clinical trial NCT01472744) on white matter integrity in healthy older adults (n = 180, 60–79 years) measured by changes in the ratio of calibrated T1- to T2-weighted images (T1w/T2w). Specifically, the aerobic walking and social dance interventions resulted in positive changes in the T1w/T2w signal in late-myelinating regions, as compared to widespread decreases in the T1w/T2w signal in the active control. Notably, in the aerobic walking group, positive change in the T1w/T2w signal correlated with improved episodic memory performance. Lastly, intervention-induced increases in cardiorespiratory fitness did not correlate with change in the T1w/T2w signal. Together, our findings suggest that white matter regions that are vulnerable to aging retain some degree of plasticity that can be induced by aerobic exercise training. In addition, we provided evidence that the T1w/T2w signal may be a useful and broadly accessible measure for studying short-term within-person plasticity and deterioration in the adult human white matter. © 2021 The Author(s)

Author Keywords
Aerobic exercise;  Aging;  Clinical trial;  Plasticity;  White matter

Funding details
National Institutes of HealthNIHR37 AG025667
National Institute on AgingNIA
Colorado State UniversityCSU
Abbott Nutrition

The Effect of Virtual Mindfulness-Based Interventions on Sleep Quality: A Systematic Review of Randomized Controlled Trials
(2021) Current Psychiatry Reports, 23 (9), art. no. 62, . 

Jiang, A.^a , Rosario, M.^b , Stahl, S.^c , Gill, J.M.^a , Rusch, H.L.^d

^a National Institute of Nursing Research, National Institutes of Health, Bethesda, MD, United States
^b Washington University School of Medicine, St. Louis, MO, United States
^c TEACCH Autism Program, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^d National Institutes of Health, 3 Center Drive, Building 3, Room 5E/26, Bethesda, MD 20892, United States

Abstract
Purpose of Review: We summarized peer-reviewed literature investigating the effect of virtual mindfulness-based interventions (MBIs) on sleep quality. We aimed to examine the following three questions: (1) do virtual MBIs improve sleep quality when compared with control groups; (2) does the effect persist long-term; and (3) is the virtual delivery method equally feasible compared to the in-person delivery method? Recent Findings: Findings suggest that virtual MBIs are equivalent to evidence-based treatments, and to a limited extent, more effective than non-specific active controls at reducing some aspects of sleep disturbance. Overall, virtual MBIs are more effective at improving sleep quality than usual care controls and waitlist controls. Studies provide preliminary evidence that virtual MBIs have a long-term effect on sleep quality. Moreover, while virtual MBI attrition rates are comparable to in-person MBI attrition rates, intervention adherence may be compromised in the virtual delivery method. Summary: This review highlights virtual MBIs as a potentially effective alternative to managing sleep disturbance during pandemic-related quarantine and stay-at-home periods. This is especially relevant due to barriers of accessing in-person interventions during the pandemic. Future studies are needed to explore factors that influence adherence and access to virtual MBIs, with a particular focus on diverse populations. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Author Keywords
Insomnia;  Meditation;  Mindfulness;  Sleep quality;  Virtual

Funding details
National Institutes of HealthNIH
NIH Clinical Center

The effect of patient age on discharge destination and complications after lumbar spinal fusion
(2021) Journal of Clinical Neuroscience, 91, pp. 319-326. 

Pennicooke, B.^a , Santacatterina, M.^b , Lee, J.^a , Elowitz, E.^c , Kallus, N.^d

^a Department of Neurosurgery, Washington University in St. Louis, 660 South Euclid Ave, Campus Box 8057, St. Louis, MO 63110, United States
^b Department of Biostatistics and Bioinformatics, The Biostatistics Center, The George Washington University, 6110 Executive Boulevard, Suite 750, Rockville, MD 20852, United States
^c Department of Neurosurgery, Weill Cornell Medical College, 525 East 68th Street, Whitney 6, Box 99, New York, NY 10065, United States
^d Department of Operations Research and Information Engineering, Cornell Tech, 2 West Loop Road, New York, NY 10044, United States

Abstract
Age is an important patient characteristic that has been correlated with specific outcomes after lumbar spine surgery. We performed a retrospective cohort study to model the effect of age on discharge destination and complications after a 1-level or multi-level lumbar spine fusion surgery. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was used to identify patients who underwent lumbar spinal fusion surgery from 2013 through 2017. Perioperative outcomes were compared across ages 18 to 90 using multivariable nonlinear logistic regression controlling for preoperative characteristics. A total of 61,315 patients were analyzed, with patients over 70 having a higher risk of being discharged to an inpatient rehabilitation center and receiving an intraoperative or postoperative blood transfusion. However, the rates of the other complications and outcomes analyzed in this study were not significantly different as patients age. In conclusion, advanced-age affects the discharge destination after a one- or multi-level fusion and intraoperative/postoperative blood transfusion after a one-level fusion. However, age alone does not significantly affect the risk of the other complications and outcomes assessed in this study. This study will help guide preoperative discussion with advanced-aged patients who are considering a 1-level or multi-level lumbar spine fusion surgery. © 2021 Elsevier Ltd

Author Keywords
Adverse outcomes;  Age;  Complications;  Discharge destination;  Lumbar spine fusion;  NSQIP;  Unplanned readmission

Temporal trends in smoking and nicotine dependence in relation to co-occurring substance use in the United States, 2005–2016
(2021) Drug and Alcohol Dependence, 226, art. no. 108903, . 

Wang, Y.^a b , Liu, Y.^c d , Waldron, M.^e f , Houston-Ludlam, A.N.^g , McCutcheon, V.V.^g , Lynskey, M.T.^h , Madden, P.A.F.^d f g , Bucholz, K.K.^f g , Heath, A.C.^d f g , Lian, M.^a d

^a Division of General Medical Sciences, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^b Current Institution: Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA, United States
^c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Alvin J. Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, United States
^e Department of Counseling and Educational Psychology, School of Education, Indiana University, Bloomington, IN, United States
^f Midwest Alcoholism Research Center, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King’s College, London, UK, United Kingdom

Abstract
Background: Despite an overall decline in tobacco use in the United States, secular trends of smoking and nicotine dependence with co-occurring substance use are not well characterized. Methods: We examined self-reported tobacco and other substance use in 22,245 participants age 21–59 in the United States from six waves of the National Health and Nutrition Examination Survey (NHANES). Using Joinpoint regression, we assessed secular trends of smoking and nicotine dependence as a function of co-occurring use of alcohol, prescription opioids, marijuana/hashish, cocaine/heroin/methamphetamine, or other injection drug use. Multivariable logistic regressions were fitted to identify the potential risk factors. Results: During 2005–2016, the prevalence of current smoking decreased (without co-occurring substance use: 17.0 %–12.7 %; with co-occurring use of one substance: 35.3 % to 24.6 %; with co-occurring use of two or more substances: 53.8 %–42.2 %), and moderate-to-severe nicotine dependence decreased as well (8.0 %–4.2 %, 16.0 %–8.8 %, and 23.9 %–15.7 %, respectively). Smoking and nicotine dependence were more likely in those with co-occurring use of one substance (current smoking: odds ratio [OR] = 2.22, 95 % confidence interval [CI] = 2.01–2.45); nicotine dependence: OR = 1.88, 95 % CI = 1.63–2.17) and in those with co-occurring use of two or more substances (current smoking: OR = 5.25, 95 % CI = 4.63–5.95; nicotine dependence: OR = 3.24, 95 % CI = 2.72–3.87). Conclusions: Co-occurring substance use was associated with smaller reductions in tobacco use, over time, and with increased odds of nicotine dependence. This suggests that co-occurring substance users should be regarded as a tobacco-related disparity group and prioritized for tobacco control interventions. © 2021 Elsevier B.V.

Author Keywords
Disparity;  Nicotine dependence;  Smoking;  Substance use;  Trend

Funding details
National Institutes of HealthNIHF30DA047742, R01DA044254
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAAR24 AA023487
National Center for Advancing Translational SciencesNCATSTL1TR002344

Thalamic volume and fear extinction interact to predict acute posttraumatic stress severity
(2021) Journal of Psychiatric Research, 141, pp. 325-332. 

Steuber, E.R.^a , Seligowski, A.V.^a b , Roeckner, A.R.^c , Reda, M.^d , Lebois, L.A.M.^a b , van Rooij, S.J.H.^c , Murty, V.P.^e , Ely, T.D.^c , Bruce, S.E.^f , House, S.L.^g , Beaudoin, F.L.^h , An, X.ⁱ , Zeng, D.^j , Neylan, T.C.^k , Clifford, G.D.^l , Linnstaedt, S.D.ⁱ , Germine, L.T.^a m n , Rauch, S.L.^o , Lewandowski, C.^p , Sheikh, S.^q , Jones, C.W.^r , Punches, B.E.^s , Swor, R.A.^t , McGrath, M.E.^u , Hudak, L.A.^v , Pascual, J.L.^w , Chang, A.M.^x , Pearson, C.^y , Peak, D.A.^z , Domeier, R.M.^aa , O’Neil, B.J.^ab , Rathlev, N.K.^ac , Sanchez, L.D.^ad ae , Pietrzak, R.H.^af , Joormann, J.^ag , Barch, D.M.^ah , Pizzagalli, D.A.^a , Elliott, J.M.^ai aj ak , Kessler, R.C.^al , Koenen, K.C.^am , McLean, S.A.ⁱ , Ressler, K.J.^a b , Jovanovic, T.^d , Harnett, N.G.^a b , Stevens, J.S.^c

^a Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^b Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
^c Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
^d Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, United States
^e Department of Psychology, College of Liberal Arts, Temple University, Philadelphia, PA, United States
^f Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO, United States
^g Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Emergency Medicine & Health Services, Policy, and Practice, The Alpert Medical School of Brown University, Rhode Island Hospital and The Miriam Hospital, Providence, RI, United States
ⁱ Department of Anesthesiology, Institute of Trauma Recovery, UNC School of Medicine, Chapel Hill, NC, United States
^j Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
^k San Francisco VA Healthcare System and Departments of Psychiatry and Neurology, University of California, San Francisco, CA, United States
^l Department of Biomedical Informatics, Emory University School of Medicine and Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
^m Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
ⁿ The Many Brains Project, Acton, MA, United States
^o Department of Psychiatry, McLean Hospital, Belmont, MA, United States
^p Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^q Department of Emergency Medicine, University of Florida College of Medicine -Jacksonville, Jacksonville, FL, United States
^r Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
^s Department of Emergency Medicine, University of Cincinnati College of Medicine & University of Cincinnati College of Nursing, Cincinnati, OH, United States
^t Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester Hills, MI, United States
^u Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
^v Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
^w Department of Surgery and Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^x Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, United States
^y Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
^z Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^aa Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ann Arbor, MI, United States
^ab Department of Emergency Medicine, Wayne State University, Detroit Receiving Hospital, Detroit, MI, United States
^ac Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
^ad Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
^ae Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^af U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, USA & Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^ag Department of Psychology, Yale University, New Haven, CT, United States
^ah Department of Psychological & Brain Sciences, College of Arts & Sciences, Washington University in St. Louis, St. Louis, MO, United States
^ai The Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, St LeonardsNew South Wales, Australia
^aj Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
^ak Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^al Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^am Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States

Abstract
Posttraumatic stress disorder (PTSD) is associated with lower gray matter volume (GMV) in brain regions critical for extinction of learned threat. However, relationships among volume, extinction learning, and PTSD symptom development remain unclear. We investigated subcortical brain volumes in regions supporting extinction learning and fear-potentiated startle (FPS) to understand brain-behavior interactions that may impact PTSD symptom development in recently traumatized individuals. Participants (N = 99) completed magnetic resonance imaging and threat conditioning two weeks following trauma exposure as part of a multisite observational study to understand the neuropsychiatric effects of trauma (AURORA Study). Participants completed self-assessments of PTSD (PTSD Checklist for DSM-5; PCL-5), dissociation, and depression symptoms two- and eight-weeks post-trauma. We completed multiple regressions to investigate relationships between FPS during late extinction, GMV, and PTSD symptom development. The interaction between thalamic GMV and FPS during late extinction at two weeks post-trauma predicted PCL-5 scores eight weeks (t (75) = 2.49, β = 0.28, p = 0.015) post-trauma. Higher FPS predicted higher PCL-5 scores in the setting of increased thalamic GMV. Meanwhile, lower FPS also predicted higher PCL-5 scores in the setting of decreased thalamic GMV. Thalamic GMV and FPS interactions also predicted posttraumatic dissociative and depressive symptoms. Amygdala and hippocampus GMV by FPS interactions were not associated with posttraumatic symptom development. Taken together, thalamic GMV and FPS during late extinction interact to contribute to adverse posttraumatic neuropsychiatric outcomes. Multimodal assessments soon after trauma have the potential to distinguish key phenotypes vulnerable to posttraumatic neuropsychiatric outcomes. © 2021 Elsevier Ltd

Author Keywords
Extinction;  Fear-potentiated startle;  Gray matter volume;  Posttraumatic stress disorder;  Thalamus

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHK00MH119603, K01MH118467, K01MH121653, U01MH110925
Medical Research and Materiel CommandMRMC

Comparison of CSF biomarkers in Down syndrome and autosomal dominant Alzheimer’s disease: a cross-sectional study
(2021) The Lancet Neurology, 20 (8), pp. 615-626. 

Fagan, A.M.^a , Henson, R.L.^a , Li, Y.^a , Boerwinkle, A.H.^a , Xiong, C.^b , Bateman, R.J.^a , Goate, A.^c , Ances, B.M.^a , Doran, E.^d , Christian, B.T.^e f , Lai, F.^g , Rosas, H.D.^g , Schupf, N.^h i , Krinsky-McHale, S.^j , Silverman, W.^d , Lee, J.H.^h i , Klunk, W.E.^k , Handen, B.L.^k , Allegri, R.F.^l , Chhatwal, J.P.^g , Day, G.S.^m , Graff-Radford, N.R.^m , Jucker, M.^n o , Levin, J.^p , Martins, R.N.^q , Masters, C.L.^r s , Mori, H.^t , Mummery, C.J.^u , Niimi, Y.^v , Ringman, J.M.^w , Salloway, S.^x , Schofield, P.R.^y , Shoji, M.^z , Lott, I.T.^d , Alzheimer’s Biomarker Consortium-Down Syndrome^aa ac , Dominantly Inherited Alzheimer Network^ab

^a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^b Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Department of Pediatrics, UC Irvine School of Medicine, Irvine, CA, United States
^e Department of Medical Physics, Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^f Department of Psychiatry, Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^g Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
^h Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, United States
ⁱ Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
^j New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
^k Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^l Department of Cognitive Neurology, Instituto Neurologico Fleni, Buenos Aires, Argentina
^m Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
ⁿ Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
^o German Center for Neurodegenerative Diseases, Tübingen, Germany
^p Department of Neurology, Ludwig-Maximilians-Universität München, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^q School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia
^r Florey Institute, Melbourne, VIC, Australia
^s University of Melbourne, Melbourne, VIC, Australia
^t Department of Clinical Neuroscience, Osaka City University Medical School, Abenoku, Osaka, Japan
^u Dementia Research Centre, Institute of Neurology, University College London, London, UK, United Kingdom
^v Unit for Early and Exploratory Clinical Development, University of Tokyo, Tokyo, Japan
^w Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^x Memory and Aging Program, Brown University, Butler Hospital, Providence, RI, United States
^y Neuroscience Research Australia, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
^z Geriatrics Research Institute and Hospital, Maebashi, Gunma, Japan

Abstract
Background: Due to trisomy of chromosome 21 and the resultant extra copy of the amyloid precursor protein gene, nearly all adults with Down syndrome develop Alzheimer’s disease pathology by the age of 40 years and are at high risk for dementia given their increased life expectancy compared with adults with Down syndrome in the past. We aimed to compare CSF biomarker patterns in Down syndrome with those of carriers of autosomal dominant Alzheimer’s disease mutations to enhance our understanding of disease mechanisms in these two genetic groups at high risk for Alzheimer’s disease. Methods: We did a cross-sectional study using data from adults enrolled in the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) study, a multisite longitudinal study of Alzheimer’s disease in Down syndrome, as well as a cohort of carriers of autosomal dominant Alzheimer’s disease mutations and non-carrier sibling controls enrolled in the Dominantly Inherited Alzheimer Network (DIAN) study. For ABC-DS, participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of Jan 31, 2019, were included in the analysis. DIAN participants with baseline CSF, available clinical diagnosis, and apolipoprotein E genotype as of June 30, 2018, were evaluated as comparator groups. CSF samples obtained from adults with Down syndrome, similarly aged carriers of autosomal dominant Alzheimer’s disease mutations, and non-carrier siblings (aged 30–61 years) were analysed for markers of amyloid β (Aβ1–40, Aβ1–42); tau phosphorylated at threonine 181-related processes; neuronal, axonal, or synaptic injury (total tau, visinin-like protein 1, neurofilament light chain [NfL], synaptosomal-associated protein 25); and astrogliosis and neuroinflammation (chitinase-3-like protein 1 [YKL-40]) via immunoassay. Biomarker concentrations were compared as a function of dementia status (asymptomatic or symptomatic), and linear regression was used to evaluate and compare the relationship between biomarker concentrations and age among groups. Findings: We assessed CSF samples from 341 individuals (178 [52%] women, 163 [48%] men, aged 30–61 years). Participants were adults with Down syndrome (n=41), similarly aged carriers of autosomal dominant Alzheimer’s disease mutations (n=192), and non-carrier siblings (n=108). Individuals with Down syndrome had patterns of Alzheimer’s disease-related CSF biomarkers remarkably similar to carriers of autosomal dominant Alzheimer’s disease mutations, including reductions (all p&lt;0·0080) in Aβ1–42 to Aβ1–40 ratio and increases in markers of phosphorylated tau-related processes; neuronal, axonal, and synaptic injury (p&lt;0·080); and astrogliosis and neuroinflammation, with greater degrees of abnormality in individuals with dementia. Differences included overall higher concentrations of Aβ and YKL-40 (both p&lt;0·0008) in Down syndrome and potential elevations in CSF tau (p&lt;0·010) and NfL (p&lt;0·0001) in the asymptomatic stage (ie, no dementia symptoms). Funding: National Institute on Aging, Eunice Kennedy Shriver National Institute of Child Health and Human Development, German Center for Neurodegenerative Diseases, and Japan Agency for Medical Research and Development. © 2021 Elsevier Ltd

Funding details
National Institutes of HealthNIH
National Institute on AgingNIA
Eli Lilly and Company
RocheK23AG064029
Massachusetts General HospitalMGH
Biogen
AbbVie
University of WashingtonUW
University of California, IrvineUCI
Japan Agency for Medical Research and DevelopmentAMED
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU01 AG051406, U01 AG051412, UF1AG032438
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Alzheimerfonden

Pauses during communication release behavioral habituation through recovery from synaptic depression
(2021) Current Biology, 31 (14), pp. 3145-3152.e3. 

Kohashi, T.^a b , Lube, A.J.^a , Yang, J.H.^a , Roberts-Gaddipati, P.S.^a , Carlson, B.A.^a

^a Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Neuroscience Institute, Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Japan

Abstract
During interactive communication, animals occasionally cease producing communication signals. The behavioral significance of resumed communication signals following a cessation, or silent pause, has been described in human speech: word recognition by listeners is enhanced after silent pauses, and speakers tend to place such pauses prior to words that are contextually unpredictable and that therefore have high information content.1–5 How central nervous systems process signals following pauses differently from signals during continuous communication has not been studied at a cellular level. Here we studied behavioral and neurophysiological impacts of pauses during electric communication in mormyrid fish. We found that isolated fish produced fewer and shorter pauses than fish housed in pairs, and that fish tended to produce burst displays immediately following pauses. In the electrosensory pathway, sensitivity to pauses first arose in the midbrain posterior exterolateral nucleus (ELp): evoked field potentials were enhanced as pause duration increased, with a time constant of ∼1 s. Intracellular recording from single ELp neurons suggested that this increased sensitivity resulted from a pause-associated recovery from synaptic depression that was induced by the preceding stimulation. Behavioral responses were also facilitated by longer pauses, with a similar time constant of ∼1 s. Further, during natural electric communication between pairs of fish, the insertion of artificial pauses resulted in increased signaling by the receiving fish immediately following the pause. Thus, our results suggest that pauses during communication release sensory circuits from synaptic depression, thereby maximizing the physiological and behavioral effects of subsequent communication signals. © 2021 Elsevier Inc.

Author Keywords
animal communication;  electric fish;  electromotor;  electrosensory;  interval tuning;  language;  mormyrid;  short-term synaptic plasticity;  social behavior;  temporal coding

Funding details
National Science FoundationNSFIOS-1050701, IOS-1755071
Japan Society for the Promotion of ScienceKAKEN15H06269

MRI Radiomic Signature of White Matter Hyperintensities Is Associated With Clinical Phenotypes
(2021) Frontiers in Neuroscience, 15, art. no. 691244, . 

Bretzner, M.^a b , Bonkhoff, A.K.^a , Schirmer, M.D.^a , Hong, S.^a , Dalca, A.V.^a c d , Donahue, K.L.^a , Giese, A.-K.^a , Etherton, M.R.^a , Rist, P.M.^a e , Nardin, M.^a , Marinescu, R.^a d , Wang, C.^a d , Regenhardt, R.W.^a , Leclerc, X.^b , Lopes, R.^b f , Benavente, O.R.^g , Cole, J.W.^h , Donatti, A.ⁱ , Griessenauer, C.J.^j k , Heitsch, L.^l m , Holmegaard, L.ⁿ , Jood, K.ⁿ , Jimenez-Conde, J.^o , Kittner, S.J.^h , Lemmens, R.^p q , Levi, C.R.^r s , McArdle, P.F.^t , McDonough, C.W.^u , Meschia, J.F.^v , Phuah, C.-L.^m , Rolfs, A.^w , Ropele, S.^x , Rosand, J.^y , Roquer, J.^z , Rundek, T.^z , Sacco, R.L.^z , Schmidt, R.^x , Sharma, P.^aa ab , Slowik, A.^ac , Sousa, A.^h , Stanne, T.M.ⁿ , Strbian, D.^ad , Tatlisumak, T.^ae af , Thijs, V.^ag , Vagal, A.^ah , Wasselius, J.^ai aj , Woo, D.^ak , Wu, O.^c , Zand, R.^al , Worrall, B.B.^am , Maguire, J.M.^an , Lindgren, A.^ao ap , Jern, C.ⁿ , Golland, P.^d , Kuchcinski, G.^b , Rost, N.S.^a , the MRI-GENIE GISCOME Investigators the International and Stroke Genetics Consortium^aq

^a J. Philip Kistler Stroke Research Center, Massachusetts General Hospital, Boston, MA, United States
^b Inserm, CHU Lille, U1172 – LilNCog (JPARC) -, Lille Neurosciences and Cognition, University of Lille, Lille, France
^c A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^d Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, United States
^e Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^f CNRS, Institut Pasteur de Lille, US 41 – UMS 2014 – PLBS, Lille, France
^g Department of Medicine, Division of Neurology, University of British Columbia, Vancouver, BC, Canada
^h Department of Neurology, University of Maryland School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore, MD, United States
ⁱ School of Medical Sciences, University of Campinas (UNICAMP), Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, Brazil
^j Department of Neurosurgery, Geisinger, Danville, PA, United States
^k Research Institute of Neurointervention, Paracelsus Medical University, Salzburg, Austria
^l Division of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Neurology, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO, United States
ⁿ Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
^o Department of Neurology, Neurovascular Research Group (NEUVAS), Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Universitat Autonoma de Barcelona, Barcelona, Spain
^p Department of Neurosciences, Experimental Neurology and Leuven Research Institute for Neuroscience and Disease (LIND), KU Leuven – University of Leuven, Leuven, Belgium
^q VIB, Vesalius Research Center, Laboratory of Neurobiology, Department of Neurology, University Hospitals Leuven, Leuven, Belgium
^r School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
^s Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia
^t Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
^u Department of Pharmacotherapy and Translational Research and Center for Pharmacogenomics, University of Florida, Gainesville, FL, United States
^v Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^w Centogene AG, Rostock, Germany
^x Department of Neurology, Clinical Division of Neurogeriatrics, Medical University of Graz, Graz, Austria
^y Henry and Allison McCance Center for Brain Health, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^z Department of Neurology and Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
^aa Institute of Cardiovascular Research, Royal Holloway University of London (ICR2UL), Egham, United Kingdom
^ab Ashford and St. Peter’s Hospitals, Chertsey and Ashford, United Kingdom
^ac Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
^ad Division of Neurocritical Care and Emergency Neurology, Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
^ae Department of Clinica Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
^af Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
^ag Stroke Division, Florey Institute of Neuroscience and Mental Health, Department of Neurology Austin Health, Heidelberg, VIC, Australia
^ah Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^ai Department of Clinical Sciences Lund, Radiology, Lund University, Lund, Sweden
^aj Department of Radiology, Neuroradiology, Skåne University Hospital, Malmö, Sweden
^ak Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^al Department of Neurology, Geisinger, Danville, PA, United States
^am Department of Neurology and Public Health Sciences, University of Virginia, Charlottesville, VA, United States
^an Faculty of Health, University of Technology Sydney, Ultimo, NSW, Australia
^ao Department of Neurology and Rehabilitation Medicine, Skåne University Hospital, Lund, Sweden
^ap Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden

Abstract
Objective: Neuroimaging measurements of brain structural integrity are thought to be surrogates for brain health, but precise assessments require dedicated advanced image acquisitions. By means of quantitatively describing conventional images, radiomic analyses hold potential for evaluating brain health. We sought to: (1) evaluate radiomics to assess brain structural integrity by predicting white matter hyperintensities burdens (WMH) and (2) uncover associations between predictive radiomic features and clinical phenotypes. Methods: We analyzed a multi-site cohort of 4,163 acute ischemic strokes (AIS) patients with T2-FLAIR MR images with total brain and WMH segmentations. Radiomic features were extracted from normal-appearing brain tissue (brain mask–WMH mask). Radiomics-based prediction of personalized WMH burden was done using ElasticNet linear regression. We built a radiomic signature of WMH with stable selected features predictive of WMH burden and then related this signature to clinical variables using canonical correlation analysis (CCA). Results: Radiomic features were predictive of WMH burden (R2 = 0.855 ± 0.011). Seven pairs of canonical variates (CV) significantly correlated the radiomics signature of WMH and clinical traits with respective canonical correlations of 0.81, 0.65, 0.42, 0.24, 0.20, 0.15, and 0.15 (FDR-corrected p-valuesCV1–6 &lt; 0.001, p-valueCV7 = 0.012). The clinical CV1 was mainly influenced by age, CV2 by sex, CV3 by history of smoking and diabetes, CV4 by hypertension, CV5 by atrial fibrillation (AF) and diabetes, CV6 by coronary artery disease (CAD), and CV7 by CAD and diabetes. Conclusion: Radiomics extracted from T2-FLAIR images of AIS patients capture microstructural damage of the cerebral parenchyma and correlate with clinical phenotypes, suggesting different radiographical textural abnormalities per cardiovascular risk profile. Further research could evaluate radiomics to predict the progression of WMH and for the follow-up of stroke patients’ brain health. © Copyright © 2021 Bretzner, Bonkhoff, Schirmer, Hong, Dalca, Donahue, Giese, Etherton, Rist, Nardin, Marinescu, Wang, Regenhardt, Leclerc, Lopes, Benavente, Cole, Donatti, Griessenauer, Heitsch, Holmegaard, Jood, Jimenez-Conde, Kittner, Lemmens, Levi, McArdle, McDonough, Meschia, Phuah, Rolfs, Ropele, Rosand, Roquer, Rundek, Sacco, Schmidt, Sharma, Slowik, Sousa, Stanne, Strbian, Tatlisumak, Thijs, Vagal, Wasselius, Woo, Wu, Zand, Worrall, Maguire, Lindgren, Jern, Golland, Kuchcinski and Rost.

Author Keywords
brain health;  cerebrovascular disease (CVD);  machine learning;  MRI;  radiomics;  stroke

Funding details
National Institutes of HealthNIHK01 HL128791
National Institute of Neurological Disorders and StrokeNINDSR01NS086905
American Academy of NeurologyAAN
Helsingin ja Uudenmaan SairaanhoitopiiriHUS
Sahlgrenska UniversitetssjukhusetSU
Göteborgs Universitet
Sigrid Juséliuksen Säätiö
Société Française de RadiologieSFR

Endoscopic Adipofascial Radial Forearm Free Flap Reconstruction of the Skull Base: A Technical Update
(2021) Journal of Neurological Surgery, Part B: Skull Base, 82, pp. E243-E247. 

Pipkorn, P.^a , Lee, J.J.^a , Zenga, J.^b , Chicoine, M.R.^c

^a Department of Otolaryngology-Head and Neck Surgery, Washington University in St. Louis, Saint Louis, MO, United States
^b Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, United States
^c Department of Neurosurgery, Washington University in St. Louis, Saint Louis, MO, United States

Abstract
Objective While most defects after endoscopic endonasal resections can be closed with local or locoregional options, rare cases require free tissue transfer. In this setting, while minimally invasive techniques have been described, the essential procedural details are lacking. The objective of this report is to describe several key technical modifications to free flap harvest and endoscopic-assisted inset which decrease morbidity and improve reliability and efficiency. Methods A retrospective chart review was performed of consecutive patients treated at Washington University in St. Louis with endoscopic free flap reconstruction through a Caldwell-Luc/transbuccal approach between January 2016 and September 2019. Results A total of six patients underwent adipofascial radial forearm free flap with this technique, five for recalcitrant cerebrospinal fluid leak or pneumocephalus and one for osteoradionecrosis. All flaps survived and there were no flap-related complications. Five patients (83%) achieved successful healing and separation of the sinonasal cavity and intracranial space. One patient developed recurrent pneumocephalus. Three key technical modifications were identified that improve efficiency and reliability of flap delivery and inset: (1) use of an adipofascial radial forearm flap, without skin paddle; (2) wide resection of the anterior and lateral maxillary face to facilitate flap delivery; and (3) precise defect measurement and flap contouring prior to inset to prevent any need to debulk the flap in situ. Conclusion Endoscopic adipofascial radial forearm free flap delivered to the skull base through a Caldwell-Luc/transbuccal corridor is a feasible option with a high success rate and low morbidity when other reconstructive attempts have failed. © 2021 Thieme Medical Publishers, Inc.. All rights reserved.

Author Keywords
endonasal;  endoscopic;  free flap;  reconstruction;  skull base

Computed Tomography as a Predictor of Sinonasal Inverted Papilloma Origin, Skull Base Involvement, and Stage
(2021) Journal of Neurological Surgery, Part B: Skull Base, 82, pp. E335-E341. 

Lee, J.J.^a , Orlowski, H.L.P.^b , Schneider, J.S.^a , Roland, L.T.^a c e , Eldaya, R.^b , Jiramongkolchai, P.^a , Kallogjeri, D.^a , Chernock, R.D.^d , Klatt-Cromwell, C.N.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Otolaryngology-Head and Neck Surgery, Emory University School of Medicine, Atlanta, GA, United States
^d Department of Pathology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Otolaryngology-Head and Neck Surgery, San Francisco School of Medicine, University of California, San Francisco, CA, United States

Abstract
Objective To investigate the diagnostic performance of computed tomography (CT) to determine the origin, skull base involvement, and stage of sinonasal inverted papilloma (IP). Design This is a retrospective cohort study. Setting This is set at a tertiary care medical center. Participants Patients with preoperative CT imaging who underwent extirpative surgery for histologically confirmed sinonasal IP between January 2005 and October 2019. Main Outcome Measures The likely sites of tumor origin, skull base involvement, and radiographic tumor stage were determined by two board-certified neuroradiologists after re-reviewing preoperative CT imaging. These radiologic findings were then compared with intraoperative and pathologic findings. Results Of 86 patients, 74% (64/86) had IP lesions with correctly classified sites of origin on CT. CT was not sensitive for diagnosing ethmoid sinus origin (48%, 52%), frontal sinus origin (80%, 40%), and skull base origin (17%, 17%). CT was not sensitive (62%, 57%) but specific (86%, 98%) for identifying any skull base involvement. There was substantial-to-near perfect agreement between radiographic and pathologic Cannady stages (weighted κ = 0.61 for rater 1; weighted κ = 0.81 for rater 2). Interrater agreement was substantial for identifying tumor origin (κ = 0.75) and stage (weighted κ = 0.62) and moderate for identifying skull base involvement (κ = 0.43). Conclusion Interrater agreement on CT findings was substantial except on skull base involvement. CT correctly predicted site of tumor origin in up to 74% of subjects. CT was not sensitive for diagnosing skull base involvement but had substantial-to-near perfect agreement with pathologic tumor staging. CT is a useful but albeit limited adjunct for tumor localization and surgical planning for sinonasal IP. © 2021 Thieme Medical Publishers, Inc.. All rights reserved.

Author Keywords
computed tomography;  inverted papilloma;  origin;  paranasal sinus;  skull base;  stage

Funding details
National Institutes of HealthNIH5T32DC000022-30
National Center for Advancing Translational SciencesNCATSUL1TR002345

Sevoflurane and desflurane exposures following aneurysmal subarachnoid hemorrhage confer multifaceted protection against delayed cerebral ischemia
(2021) Biomedicines, 9 (7), art. no. 820, . 

Jayaraman, K.^a , Liu, M.^a , Zipfel, G.J.^b , Athiraman, U.^a

^a Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
^b Department of Neurological Surgery, Washington University in Saint Louis, Saint Louis, MO 63110, United States

Abstract
Numerous studies have demonstrated the ability of isoflurane conditioning to provide multifaceted protection against aneurysmal subarachnoid hemorrhage (SAH)-associated delayed cerebral ischemia (DCI); however, preclinical studies have not yet examined whether other commonly used inhalational anesthetics in neurological patients such as sevoflurane or desflurane are also protective against SAH-induced neurovascular deficits. We therefore sought to identify the potential for sevoflurane and desflurane conditioning to protect against DCI in an endovascular perforation mouse model of SAH. Neurological function was assessed daily via neuroscore. Large artery vasospasm and microvessel thrombosis were assessed three days after SAH or sham surgery. Four groups were examined: Sham, SAH + room air, SAH + 2% Sevoflurane, and SAH + 6% Desflurane. For the SAH groups, one hour after surgery, mice received 2% sevoflurane, 6% desflurane, or room air for one hour. We found that conditioning with sevoflurane or desflurane attenuated large artery vasospasm, reduced microvessel thrombosis, and improved neurologic function. Given their frequent clinical use and strong safety profile in patients (including those with SAH), these data strongly support further studies to validate these findings in preclinical and clinical studies and to elucidate the mechanisms by which these agents might be acting. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Aneurysmal subarachnoid hemorrhage;  Conditioning;  Delayed cerebral ischemia;  Desflurane;  Inhalational anesthesia;  Sevoflurane

Funding details
National Institutes of HealthNIHNS091603

Global waves synchronize the brain’s functional systems with fluctuating arousal
(2021) Science Advances, 7 (30), art. no. eabf2709, . 

Raut, R.V.^a , Snyder, A.Z.^a b , Mitra, A.^c , Yellin, D.^d , Fujii, N.^e , Malach, R.^d , Raichle, M.E.^a b

^a Department of Radiology, Washington University, St. Louis, MO 63110, United States
^b Department of Neurology, Washington University, St. Louis, MO 63110, United States
^c Department of Psychiatry, Stanford University, Stanford, CA 94305, United States
^d Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel
^e Laboratory for Adaptive Intelligence, RIKEN Brain Science Institute, Wako, 351-0198, Japan

Abstract
We propose and empirically support a parsimonious account of intrinsic, brain-wide spatiotemporal organization arising from traveling waves linked to arousal. We hypothesize that these waves are the predominant physiological process reflected in spontaneous functional magnetic resonance imaging (fMRI) signal fluctuations. The correlation structure (“functional connectivity”) of these fluctuations recapitulates the large-scale functional organization of the brain. However, a unifying physiological account of this structure has so far been lacking. Here, using fMRI in humans, we show that ongoing arousal fluctuations are associated with global waves of activity that slowly propagate in parallel throughout the neocortex, thalamus, striatum, and cerebellum. We show that these waves can parsimoniously account for many features of spontaneous fMRI signal fluctuations, including topographically organized functional connectivity. Last, we demonstrate similar, cortex-wide propagation of neural activity measured with electrocorticography in macaques. These findings suggest that traveling waves spatiotemporally pattern brain-wide excitability in relation to arousal. © 2021 American Association for the Advancement of Science. All rights reserved.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness
(2021) Neurocritical Care, 35, pp. 4-23. 

Claassen, J.^a , Akbari, Y.^b , Alexander, S.^c , Bader, M.K.^d , Bell, K.^e , Bleck, T.P.^f , Boly, M.^g , Brown, J.^h , Chou, S.H.-Y.ⁱ , Diringer, M.N.^j , Edlow, B.L.^k , Foreman, B.^l , Giacino, J.T.^m , Gosseries, O.ⁿ , Green, T.^o , Greer, D.M.^p , Hanley, D.F.^q , Hartings, J.A.^r , Helbok, R.^s , Hemphill, J.C.^t , Hinson, H.E.^u , Hirsch, K.^v , Human, T.^w , James, M.L.^x , Ko, N.^t , Kondziella, D.^y z , Livesay, S.^aa , Madden, L.K.^ab , Mainali, S.^ac , Mayer, S.A.^ad , McCredie, V.^ae , McNett, M.M.^af , Meyfroidt, G.^ag , Monti, M.M.^ah , Muehlschlegel, S.^ai , Murthy, S.^aj , Nyquist, P.^ak , Olson, D.M.^al , Provencio, J.J.^am , Rosenthal, E.^an , Sampaio Silva, G.^ao , Sarasso, S.^ap , Schiff, N.D.^aq , Sharshar, T.^ar , Shutter, L.ⁱ , Stevens, R.D.^ak , Vespa, P.^as , Videtta, W.^at , Wagner, A.^au , Ziai, W.^ak , Whyte, J.^av , Zink, E.^aw , Suarez, J.I.^ak , Curing Coma Campaign^ax

^a Department of Neurology, Columbia University and New York-Presbyterian Hospital, 177 Fort Washington Avenue, MHB 8 Center, Room 300, New York City, NY, 10032, USA. jc1439@columbia.edu
^b Departments of Neurology, Neurological Surgery, and Anatomy & Neurobiology and Beckman Laser Institute and Medical Clinic, University of California, Irvine, Irvine, CA, USA
^c Acute and Tertiary Care, School of Nursing and Critical Care Medicine, School of Medicine, University of Pittsburgh, PA, Pittsburgh, United States
^d Mission Hospital, Mission Viejo, CA, USA
^e Department of Physical Medicine and Rehabilitation, University of Texas Southwestern Medical Center, TX, Dallas, United States
^f Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States
^g Department of Neurology, School of Medicine and Public Health, University of Wisconsin-Madison, WI, Madison, United States
^h Office of Emergency Care Research, Division of Clinical Research, National Institute of Neurological Disorders and Stroke, MD, Bethesda, United States
ⁱ Departments of Critical Care Medicine, Neurology, Neurosurgery, School of Medicine, University of Pittsburgh, PA, Pittsburgh, United States
^j Department of Neurology, Washington University in St. Louis, St. Louis, MO, USA
^k Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital and Harvard Medical School, Harvard University, MA, Boston, United States
^l Departments of Neurology and Rehabilitation Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
^m Department of Physical Medicine and Rehabilitation, Harvard Medical School, Harvard University, MA, Boston, United States
ⁿ GIGA Consciousness After Coma Science Group, University of Liege, Liege, Belgium
^o School of Nursing, Queensland University of Technology, Kelvin Grove, Australia
^p Department of Neurology, School of Medicine, Boston University, MA, Boston, United States
^q Division of Brain Injury Outcomes, Department of Neurology, School of Medicine, Johns Hopkins University, MD, Baltimore, United States
^r Department of Neurosurgery, College of Medicine, University of Cincinnati, Cincinnati, OH, USA
^s Neurocritical Care Unit, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
^t Department of Neurology, Weill Institute for Neurosciences, School of Medicine, University of California, San Francisco, San Francisco, CA, USA
^u Department of Neurology, School of Medicine, Oregon Health & Science University, ORPortland, United States
^v Department of Neurology, Stanford University, Palo Alto, CA, USA
^w Department of Pharmacy, Barnes Jewish Hospital, St. Louis, MO, USA
^x Departments of Anesthesiology and Neurology, Duke University, Durham, United States
^y Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
^z Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
^aa College of Nursing, Rush University, Chicago, United States
^ab Center for Nursing Science, University of California, Davis, Sacramento, CA, USA
^ac Department of Neurology, The Ohio State University, Columbus, OH, USA
^ad Department of Neurology, New York Medical College, Valhalla, NY, USA
^ae Interdepartmental Division of Critical Care, Department of Respirology, University of Toronto, ON, Toronto, Canada
^af College of Nursing, The Ohio State University, Columbus, OH, USA
^ag Department of Intensive Care Medicine, University Hospitals Leuven and University of Leuven, Leuven, Belgium
^ah Departments of Neurosurgery and Psychology, Brain Injury Research Center, University of California, Los Angeles, Los Angeles, CA, USA
^ai Departments of Neurology, Anesthesiology/Critical Care, Surgery, Medical School, University of Massachusetts, MA, Worcester, United States
^aj Department of Neurology, Weill Cornell Medical College, New York City, NY, USA
^ak Division of Neurosciences Critical Care, Departments of Anesthesiology and Critical Care Medicine, Neurology, Neurosurgery, School of Medicine, Johns Hopkins University, MD, Baltimore, United States
^al Departments of Neurology and Neurosurgery, University of Texas Southwestern Medical Center, TX, Dallas, United States
^am Departments of Neurology and Neuroscience, School of Medicine, University of Virginia, VA, Charlottesville, United States
^an Department of Neurology, Harvard Medical School, Harvard University, MA, Boston, United States
^ao Department of Neurology, Albert Einstein Israelite Hospital and Universidade Federal de São Paulo, São Paulo, Brazil
^ap Department of Biomedical and Clinical Sciences “L. Sacco”, Università degli Studi di Milano, Milan, Italy
^aq Department of Neurology and Brain Mind Research Institute, Weill Cornell Medicine, Cornell University, New York City, NY, USA
^ar Department of Intensive Care, Paris Descartes University, Paris, France
^as Departments of Neurosurgery and Neurology, University of California, Los Angeles, Los Angeles, CA, USA
^at National Hospital Alejandro PosadasBuenos Aires, Argentina
^au Department of Physical Medicine and Rehabilitation, School of Medicine, University of Pittsburgh, PA, Pittsburgh, United States
^av Moss Rehabilitation Research Institute, Elkins Park, PA, United States
^aw Division of Neurosciences Critical Care, Department of Neurology, School of Medicine, Johns Hopkins University, MD, Baltimore, United States

Abstract
Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Author Keywords
Biomarkers;  Coma;  Consciousness;  Electrophysiology;  Magnetic resonance imaging

Central triage of acute stroke patients across a distributive stroke network is safe and reduces transfer denials
(2021) Stroke, pp. 2671-2675. 

Holder, D.^a , Leeseberg, K.^c , Giles, J.A.^a , Lee, J.-M.^a b d , Namazie, S.^c , Ford, A.L.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Center for Clinical Excellence, Bjc Healthcare, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Background and Purpose: Mechanical thrombectomy has dramatically increased patient volumes transferred to comprehensive stroke centers (CSCs), resulting in transfer denials for patients who need higher level of care only available at a CSC. We hypothesized that a distributive stroke network (DSN), triaging low severity acute stroke patients to a primary stroke center (PSC) upon initial telestroke consultation, would safely reduce transfer denials, thereby providing additional volume to treat severe strokes at a CSC. Methods: In 2017, a DSN was implemented, in which mild stroke patients were centrally triaged, via telestroke consultation, to a PSC based upon a simple clinical severity algorithm, while higher acuity/severity strokes were triaged to the CSC. In an observational cohort study, data on acute ischemic stroke patients presenting to regional community hospitals were collected pre-versus post-DSN implementation. Safety outcomes and rate of CSC transfer denials were compared pre-DSN versus post-DSN. Results: The pre-DSN cohort (n=150), triaged to the CSC, had a similar rate of symptomatic intracerebral hemorrhage and discharge location compared with the post-DSN cohort (n=150), triaged to the PSC. Time to stroke unit admission was faster post-DSN (2 hours 40 minutes) versus pre-DSN (3 hours 29 minutes; P<0.001). Transfer denials were reduced post-DSN (3.8%) versus pre-DSN (1.8%; P=0.02), despite an increase in telestroke consultation volume over the same period (median, 3 calls per day pre-DSN versus 5 calls per day post-DSN; P=0.001). No patients who were triaged to the PSC required subsequent transfer to the CSC. Conclusions: A DSN, triaging mild ischemic stroke patients from community hospitals to a PSC, safely reduced transfer denials to the CSC, allowing greater capacity at the CSC to treat higher acuity stroke patients © 2021 American Heart Association, Inc.

Author Keywords
cohort studies;  ischemic stroke;  patient discharge;  telemedicine;  triage

A comparison of machine learning classifiers for pediatric epilepsy using resting-state functional MRI latency data
(2021) Biomedical Reports, 15 (3), art. no. 77, . 

Nguyen, R.D.^a , Smyth, M.D.^b , Zhu, L.^c , Pao, L.P.^a , Swisher, S.K.^a , Kennady, E.H.^a , Mitra, A.^d , Patel, R.P.^e , Lankford, J.E.^f , Von Allmen, G.^f , Watkins, M.W.^f , Funke, M.E.^f , Shah, M.N.^a

^a Division of Pediatric Neurosurgery, McGovern Medical School at UTHealth, Houston, TX 77030, United States
^b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Biostatistics and Epidemiology Research Design Core, Institute for Clinical and Translational Sciences, McGovern Medical School at UTHealth, Houston, TX 77030, United States
^d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Diagnostic and Interventional Imaging, McGovern Medical School at UTHealth, Houston, TX 77030, United States
^f Department of Pediatric Neurology, McGovern Medical School at UTHealth, Houston, TX 77030, United States

Abstract
Epilepsy affects 1 in 150 children under the age of 10 and is the most common chronic pediatric neurological condition; poor seizure control can irreversibly disrupt normal brain development. The present study compared the ability of different machine learning algorithms trained with resting-state functional MRI (rfMRI) latency data to detect epilepsy. Preoperative rfMRI and anatomical MRI scans were obtained for 63 patients with epilepsy and 259 healthy controls. The normal distribution of latency z-scores from the epilepsy and healthy control cohorts were analyzed for overlap in 36 seed regions. In these seed regions, overlap between the study cohorts ranged from 0.44-0.58. Machine learning features were extracted from latency z-score maps using principal component analysis. Extreme Gradient Boosting (XGBoost), Support Vector Machines (SVM), and Random Forest algorithms were trained with these features. Area under the receiver operating characteristics curve (AUC), accuracy, sensitivity, specificity and F1-scores were used to evaluate model performance. The XGBoost model outperformed all other models with a test AUC of 0.79, accuracy of 74%, specificity of 73%, and a sensitivity of 77%. The Random Forest model performed comparably to XGBoost across multiple metrics, but it had a test sensitivity of 31%. The SVM model did not perform >70% in any of the test metrics. The XGBoost model had the highest sensitivity and accuracy for the detection of epilepsy. Development of machine learning algorithms trained with rfMRI latency data could provide an adjunctive method for the diagnosis and evaluation of epilepsy with the goal of enabling timely and appropriate care for patients. © 2021, Spandidos Publications. All rights reserved.

Author Keywords
Extreme gradient boosting;  Machine learning;  Pediatric epilepsy;  Resting-state functional MRI;  Temporal latency

Funding details
National Institute of Neurological Disorders and StrokeNINDSR21NS120085

Demographic disparities in proximity to certified stroke care in the United States
(2021) Stroke, pp. 2571-2579. Cited 1 time.

Yu, C.Y.^a d e , Blaine, T.^b c , Panagos, P.D.^b c , Kansagra, A.P.^b c

^a Washington University School of Medicin, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background and Purpose: Demographic disparities in proximity to stroke care influence time to treatment and clinical outcome but remain understudied at the national level. This study quantifies the relationship between distance to the nearest certified stroke hospital and census-derived demographics. Methods: This cross-sectional study included population data by census tract from the United States Census Bureau’s 2014-2018 American Community Survey, stroke hospitals certified by a state or national body and providing intravenous thrombolysis, and geographic data from a public mapping service. Data were retrieved from March to November 2020. Quantile regression analysis was used to compare relationships between road distance to the nearest stroke center for each census tract and tract-level demographics of age, race, ethnicity, medical insurance status, median annual income, and population density. Results: Two thousand three hundred eighty-eight stroke centers and 71 929 census tracts including 316 995 649 individuals were included. Forty-nine thousand nine hundred eighteen (69%) tracts were urban. Demographic disparities in proximity to certified stroke care were greater in nonurban areas than urban areas. Higher representation of individuals with age ≥65 years was associated with increased median distance to a certified stroke center in nonurban areas (0.51 km per 1% increase [99.9% CI, 0.42-0.59]) but not in urban areas (0.00 km [-0.01 to 0.01]). In urban and nonurban tracts, median distance was greater with higher representation of American Indian (urban: 0.10 km per 1% increase [0.06-0.14]; nonurban: 1.06 km [0.98-1.13]) or uninsured populations (0.02 km [0.00-0.03]; 0.27 km [0.15-0.38]). Each 10 000 increase in median income was associated with a decrease in median distance of 5.04 km [4.31-5.78] in nonurban tracts, and an increase of 0.17 km [0.10-0.23] in urban tracts. Conclusions: Disparities were greater in nonurban areas than in urban areas. Nonurban census tracts with greater representation of elderly, American Indian, or uninsured people, or low median income were substantially more distant from certified stroke care. © 2021 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
hospital;  income;  insurance;  stroke;  United States

Brief Report: Health Expenditures for Children with Autism and Family Financial Well-Being in China
(2021) Journal of Autism and Developmental Disorders, . 

Zhou, L.^c , Wang, J.^b , Huang, J.^a b

^a Saint Louis University, St. Louis, MO, United States
^b Washington University in St. Louis, St. Louis, MO, United States
^c Beijing City University, No. 269, North Fourth Middle Road, Haidian District, Beijing, China

Abstract
Little is known on the financial well-being of families raising children with autism spectrum disorders (ASD). Family financial well-being has important impacts on the development of children with ASD. The study uses a 2019 survey collected from Chinese families raising a child with ASD (N = 3064) to examine their financial well-being and its association with health expenditures for children. Extensive control variables (i.e., demographic and socioeconomic characteristics of children, respondents, and their families) are adjusted in analyses. Findings suggest that the amount of health expenditures is negatively associated with respondents’ perception of their financial status. The significance of health expenditures disappears after household material hardship is adjusted. Health expenditures affect financial well-being mainly through resource competitions against family needs. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Autism;  China;  Financial well-being;  Health expenditure;  Quality of life

Longitudinal cortex-wide monitoring of cerebral hemodynamics and oxygen metabolism in awake mice using multi-parametric photoacoustic microscopy
(2021) Journal of Cerebral Blood Flow and Metabolism, . 

Sciortino, V.M.^a , Tran, A.^b , Sun, N.^a e , Cao, R.^a , Sun, T.^a e , Sun, Y.-Y.^c , Yan, P.^d , Zhong, F.^a e , Zhou, Y.^a e , Kuan, C.-Y.^c , Lee, J.-M.^d e e , Hu, S.^a e

^a Department of Biomedical Engineering, University of Virginia, University of Virginia, Charlottesville, VA, United States
^b Department of Biology, University of Virginia, University of Virginia, Charlottesville, VA, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neuroscience, University of Virginia, University of Virginia, Charlottesville, VA, United States
^e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Multi-parametric photoacoustic microscopy (PAM) has emerged as a promising new technique for high-resolution quantification of hemodynamics and oxygen metabolism in the mouse brain. In this work, we have extended the scope of multi-parametric PAM to longitudinal, cortex-wide, awake-brain imaging with the use of a long-lifetime (24 weeks), wide-field (5 × 7 mm2), light-weight (2 g), dual-transparency (i.e., light and ultrasound) cranial window. Cerebrovascular responses to the window installation were examined in vivo, showing a complete recovery in 18 days. In the 22-week monitoring after the recovery, no dura thickening, skull regrowth, or changes in cerebrovascular structure and function were observed. The promise of this technique was demonstrated by monitoring vascular and metabolic responses of the awake mouse brain to ischemic stroke throughout the acute, subacute, and chronic stages. Side-by-side comparison of the responses in the ipsilateral (injury) and contralateral (control) cortices shows that despite an early recovery of cerebral blood flow and an increase in microvessel density, a long-lasting deficit in cerebral oxygen metabolism was observed throughout the chronic stage in the injured cortex, part of which proceeded to infarction. This longitudinal, functional-metabolic imaging technique opens new opportunities to study the chronic progression and therapeutic responses of neurovascular diseases. © The Author(s) 2021.

Author Keywords
cerebral vasculature;  cranial window;  longitudinal imaging;  oxygen metabolism;  Photoacoustic microscopy

Funding details
National Science FoundationNSF2023988
National Institutes of HealthNIHNS099261
American Heart AssociationAHA15SDG25960005

A Multi-center Genome-wide Association Study of Cervical Dystonia
(2021) Movement Disorders, . 

Sun, Y.V.^a b , Li, C.^a , Hui, Q.^a , Huang, Y.^a , Barbano, R.^c , Rodriguez, R.^d , Malaty, I.A.^e , Reich, S.^f , Bambarger, K.^f , Holmes, K.^f , Jankovic, J.^g , Patel, N.J.^h , Roze, E.ⁱ , Vidailhet, M.ⁱ , Berman, B.D.^j , LeDoux, M.S.^k , Espay, A.J.^l , Agarwal, P.^m , Pirio-Richardson, S.ⁿ , Frank, S.A.^o , Ondo, W.G.^p , Saunders-Pullman, R.^q , Chouinard, S.^r , Natividad, S.^s , Berardelli, A.^t , Pantelyat, A.Y.^u , Brashear, A.^v , Fox, S.H.^w , Kasten, M.^x y , Krämer, U.M.^z , Neis, M.^z aa , Bäumer, T.^x ab , Loens, S.^x ab , Borsche, M.^x z , Zittel, S.^ac , Maurer, A.^ac , Gelderblom, M.^ac , Volkmann, J.^ad , Odorfer, T.^ad , Kühn, A.A.^ae , Borngräber, F.^ae , König, I.R.^af , Cruchaga, C.^ag , Cotton, A.C.^ah , Kilic-Berkmen, G.^ah , Freeman, A.^ah , Factor, S.A.^ah , Scorr, L.^ah , Bremner, J.D.^ai aj , Vaccarino, V.^a , Quyyumi, A.A.^ak , Klein, C.^x , Perlmutter, J.S.^al , Lohmann, K.^x , Jinnah, H.A.^ah am

^a Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, United States
^b Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
^c Movement Disorders Division, University of Rochester, Rochester, NY, United States
^d Neurology One, Orlando, FL, United States
^e Department of Neurology, Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, United States
^f Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States
^g Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States
^h Department of Neurology, Henry Ford Health System, Henry Ford Hospital, Detroit, MI, United States
ⁱ Sorbonne Université, Inserm U1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle; Assistance Publique – Hôpitaux de Paris, Hôpital Salpêtrière, Département de Neurologie, Paris, France
^j Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
^k Department of Psychology, University of Memphis, Memphis, TN, United States
^l James J and Joan A Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati Academic Health Center, Cincinnati, OH, United States
^m Booth Gardner Parkinson’s Care Center, Evergreen Health, Kirkland, WA, United States
ⁿ Department of Neurology, University of New Mexico, Albuquerque, NM, United States
^o Beth Israel Deaconess Medical Center, Boston, MA, United States
^p Department of Neurology, Methodist Neurological Institute, Weill Cornell Medical School, Houston, TX, United States
^q Icahn School of Medicine at Mount Sinai, Movement Disorders, Department of Neurology, Mount Sinai Beth Israel, New York, NY, United States
^r Unité des troubles du mouvement André-Barbeau, Centre Hospitalier de l’Université de Montréal, Montreal, Canada
^s Department of Neurology, The University of Alabama at Birmingham, Birmingham, AL, United States
^t Department of Neurology and Psychiatry, Sapienza University of Rome and IRCCS Neuromed, Rome, Italy
^u Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^v Neurology, University of California, Davis, Sacramento, CA, United States
^w University of Toronto, Edmond J Safra Program in Parkinson Disease; Movement Disorder Clinic, Toronto Western Hospital, Toronto, ON, Canada
^x Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
^y Department of Psychiatry and Psychotherapy, University of Lübeck, Lübeck, Germany
^z Department of Neurology, University of Lübeck, Lübeck, Germany
^aa Institute for Health Sciences, Department of Midwifery Science, University of Lübeck, Lübeck, Germany
^ab Institute of Systemic Motor Research, University of Lübeck, Lübeck, Germany
^ac Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
^ad Department of Neurology, University Hospital Würzburg, Würzburg, Germany
^ae Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany
^af Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
^ag Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^ah Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^ai Atlanta VA Medical Center, Decatur, GA, United States
^aj Departments of Psychiatry & Behavioral Sciences and Radiology, Emory University School of Medicine, Atlanta, GA, United States
^ak Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, GA, United States
^al Department of Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^am Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States

Abstract
Background: Several monogenic causes for isolated dystonia have been identified, but they collectively account for only a small proportion of cases. Two genome-wide association studies have reported a few potential dystonia risk loci; but conclusions have been limited by small sample sizes, partial coverage of genetic variants, or poor reproducibility. Objective: To identify robust genetic variants and loci in a large multicenter cervical dystonia cohort using a genome-wide approach. Methods: We performed a genome-wide association study using cervical dystonia samples from the Dystonia Coalition. Logistic and linear regressions, including age, sex, and population structure as covariates, were employed to assess variant- and gene-based genetic associations with disease status and age at onset. We also performed a replication study for an identified genome-wide significant signal. Results: After quality control, 919 cervical dystonia patients compared with 1491 controls of European ancestry were included in the analyses. We identified one genome-wide significant variant (rs2219975, chromosome 3, upstream of COL8A1, P-value 3.04 × 10−8). The association was not replicated in a newly genotyped sample of 473 cervical dystonia cases and 481 controls. Gene-based analysis identified DENND1A to be significantly associated with cervical dystonia (P-value 1.23 × 10−6). One low-frequency variant was associated with lower age-at-onset (16.4 ± 2.9 years, P-value = 3.07 × 10−8, minor allele frequency = 0.01), located within the GABBR2 gene on chromosome 9 (rs147331823). Conclusion: The genetic underpinnings of cervical dystonia are complex and likely consist of multiple distinct variants of small effect sizes. Larger sample sizes may be needed to provide sufficient statistical power to address the presumably multi-genic etiology of cervical dystonia. © 2021 International Parkinson and Movement Disorder Society. © 2021 International Parkinson and Movement Disorder Society.

Author Keywords
cervical dystonia;  genome-wide association study (GWAS);  movement disorder;  rare disease

Funding details
KL2 TR001080
National Institutes of HealthNIHNS067501, NS096455, NS116015
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDS
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Dana Foundation
National Parkinson FoundationNPF
Dystonia Medical Research FoundationDMRF
Restless Legs Syndrome FoundationRLSF
Merck
Medtronic
Biogen
CHDI FoundationCHDI
National Center for Advancing Translational SciencesNCATSNS116025, TR001456
Teva Pharmaceutical Industries
Allergan
International Parkinson and Movement Disorder SocietyMDS
Boston Scientific CorporationBSC
Benign Essential Blepharospasm Research FoundationBEBRF
Sunovion
Parkinson’s FoundationPF
Ipsen Biopharmaceuticals
National Spasmodic Dysphonia AssociationNSDA
ACADIA PharmaceuticalsACADIA
Dystonia CoalitionNS065701
Government of South Australia
Canadian Institutes of Health ResearchCIHR
European CommissionEC
Deutsche ForschungsgemeinschaftDFGFOR 2698, FOR2488
Agence Nationale de la RechercheANR
Bundesministerium für Bildung und ForschungBMBF01GM1514B, TR‐SFB134
Deutsche Krebshilfe
Federalno Ministarstvo Obrazovanja i Nauke
Parkinson Canada
European Academy of NeurologyEAN
Merz Pharmaceuticals
H. Lundbeck A/S
Werner Otto Stiftung

What is the median volume of intracerebral hemorrhage and is it changing?
(2021) International Journal of Stroke, . 

Robinson, D.^a , Van Sanford, C.^b , Kwon, S.Y.^c , Coleman, E.^d , Sekar, P.^a , Murphy, R.^a , Flaherty, M.L.^a , Demel, S.L.^a , Aziz, Y.^a , Moomaw, C.J.^a , Haverbusch, M.^a , Khoury, J.^e , Adeoye, O.^f , Walsh, K.B.^g , Broderick, J.P.^a , Woo, D.^a

^a Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^b Department of Neurology, Providence Regional Medical Center, Everett, WA, United States
^c Department of Neurology, University of Alabama, Birmingham, Birmingham, AL, United States
^d Department of Neurology, University of Chicago, Chicago, IL, United States
^e Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital, Cincinnati, OH, United States
^f Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Emergency Medicine, University of Cincinnati, Cincinnati, OH, United States

Abstract
Objectives: Population-level estimates of the median intracerebral hemorrhage (ICH) volume would allow for the evaluation of clinical trial external validity and determination of temporal trends. We previously reported the median ICH volume in 1988. However, differences in risk factor management, neuroimaging, and demographics may have affected ICH volumes. The goal of this study is to determine the median volume of ICH within a population-based cross-sectional study, including whether it has changed over time. Methods: The Genetic and Environmental Risk Factors for Hemorrhagic Stroke study was a population-based study of ICH among residents of the Greater Cincinnati/Northern Kentucky region from 2008 through 2012. This study utilizes those data and compares with ICH cases from the same region in 1988. Initial computed tomography images of the head were reviewed, and ICH volumes were calculated using consistent methodology. Results: From 2008 through 2012, we identified 1117 cases of ICH. The median volume of ICH was 14.0 mL and was lower in black (11.6) than in white (15.5) patients. Median volumes of lobar and deep ICH were 28.8 mL and 9.8 mL, respectively. Median ICH volume changed significantly from 1988 to 2008–2012, with age-and-race-adjusted volume decreasing from 18.3 mL to 13.76 mL (p = 0.025). Conclusions: Median volume of ICH was 13.76 mL, and this should be considered in clinical trial design. Median ICH volume has apparently decreased from 1988 to 2008–2012. © 2021 World Stroke Organization.

Author Keywords
epidemiology;  Intracerebral hemorrhage;  volume

Funding details
National Institute of Neurological Disorders and StrokeNINDSNS036695, NS069763, NS100417, T32NS047996
American Heart AssociationAHA20TPA35490044

Multiple-exemplar training of generalized self-control choice in children with ADHD [Ejemplares Múltiples En La Elección De Autocontrol Generalizada En Niños Con Tdah]
(2021) Revista Mexicana de Analisis de la Conducta, 47 (1), pp. 61-92. 

Fuentes, A.L.L.^a , Chainé, S.M.^a c , Green, L.^b c c , Velasco, C.S.^a c , Torres, L.B.^a c

^a Facultad de Psicología, Universidad Nacional Autónoma de México, Mexico
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^c Facultad de Psicología, Universidad Nacional Autónoma de México, Leonard Green Department of Psychological and Brain Sciences Washington University in St. Louis, United States

Abstract
Children with Attention Deficit Hyperactivity Disorder (ADHD) are more likely to choose impatiently than controls. Delay fading with an alternative activity, signaling the delay, or self-instruction, have been shown to increase self-control choice, but we know little about their generalization. The present study evaluated the effect of multiple-exemplar training on the generalization of self-control choice across settings, behaviors, and time, in two, five-year-old boys with ADHD. We used a multiple-baseline-across-settings design. We trained self-control choice across three settings, and we assessed post-training generalization in the fourth, novel setting. We accommodated each setting with different kinds of exemplars: Reinforcers, discriminative stimuli, researchers, and conditions, during the delay of the larger reinforcer. Children showed self-control choice in the novel setting for more than 80% and maintained more than 60% at two-month follow-up. The multiple-exemplar training led ADHD children to generalize self-control choice. Future research should incorporate intra-category exemplar training and natural settings demonstrations. © 2021, Sociedad Mexicana de Analisis de la Conducta. All rights reserved.

Author Keywords
ADHD;  Delay fading;  Generalization;  Multiple-exemplar;  Self-control choice

Efficacy of Carboplatin and Isotretinoin in Children with High-risk Medulloblastoma: A Randomized Clinical Trial from the Children’s Oncology Group
(2021) JAMA Oncology, . Cited 1 time.

Leary, S.E.S.^a b , Packer, R.J.^d , Li, Y.^e , Billups, C.A.^e , Smith, K.S.^f , Jaju, A.^g , Heier, L.^h , Burger, P.ⁱ , Walsh, K.^j , Han, Y.^e , Embry, L.^k , Hadley, J.^f , Kumar, R.^f , Michalski, J.^l , Hwang, E.^m , Gajjar, A.ⁿ , Pollack, I.F.^o , Fouladi, M.^c , Northcott, P.A.^f , Olson, J.M.^a b

^a Cancer and Blood Disorders Center, Seattle Children’s, University of Washington, Fred Hutchinson Cancer Research Center, 4800 Sand Point Way NE, Mailstop MB.8.501, Seattle, WA 98105, United States
^b Department of Pediatrics, University of Washington, School of Medicine, Seattle, United States
^c Pediatric Hematology and Oncology, Nationwide Children’s Hospital, Columbus, OH, United States
^d Center for Neuroscience and Behavioral Health, Children’s National Hospital, Washington, DC, United States
^e Department of Biostatistics, St Jude Children’s Research Hospital, Memphis, TN, United States
^f Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Memphis, TN, United States
^g Department of Radiology, Ann and Robert H. Lurie Children’s Hospital, Chicago, IL, United States
^h Department of Radiology, NYP/Weill Cornell Medical Center, New York, NY, United States
ⁱ Sidney Kimmel Cancer Center, Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
^j Division of Neuropsychology, Children’s National Hospital, Washington, DC, United States
^k Pediatric Hematology/Oncology, UT Health San Antonio, San Antonio, TX, United States
^l Department of Radiation Oncology, Washington University, School of Medicine, St Louis, MO, United States
^m Center for Cancer and Blood Disorders, Children’s National Hospital, Washington, DC, United States
ⁿ Department of Oncology, St Jude Children’s Research Hospital, Memphis, TN, United States
^o Department of Neurosurgery, UPMC Children’s Hospital of Pittsburgh, Pittsburgh, PA, United States

Abstract
Importance: Brain tumors are the leading cause of disease-related death in children. Medulloblastoma is the most common malignant embryonal brain tumor, and strategies to increase survival are needed. Objective: To evaluate therapy intensification with carboplatin as a radiosensitizer and isotretinoin as a proapoptotic agent in children with high-risk medulloblastoma in a randomized clinical trial and, with a correlative biology study, facilitate planned subgroup analysis according to World Health Organization consensus molecular subgroups of medulloblastoma. Design, Setting, and Participants: A randomized clinical phase 3 trial was conducted from March 2007 to September 2018. Analysis was completed in September 2020. Patients aged 3 to 21 years with newly diagnosed high-risk medulloblastoma from Children’s Oncology Group institutions within the US, Canada, Australia, and New Zealand were included. High-risk features included metastasis, residual disease, or diffuse anaplasia. Interventions: Patients were randomized to receive 36-Gy craniospinal radiation therapy and weekly vincristine with or without daily carboplatin followed by 6 cycles of maintenance chemotherapy with cisplatin, cyclophosphamide, and vincristine with or without 12 cycles of isotretinoin during and following maintenance. Main Outcomes and Measures: The primary clinical trial end point was event-free survival, using the log-rank test to compare arms. The primary biology study end point was molecular subgroup classification by DNA methylation array. Results: Of 294 patients with medulloblastoma, 261 were evaluable after central radiologic and pathologic review; median age, 8.6 years (range, 3.3-21.2); 183 (70%) male; 189 (72%) with metastatic disease; 58 (22%) with diffuse anaplasia; and 14 (5%) with greater than 1.5-cm2 residual disease. For all participants, the 5-year event-free survival was 62.9% (95% CI, 55.6%-70.2%) and overall survival was 73.4% (95% CI, 66.7%-80.1%). Isotretinoin randomization was closed early owing to futility. Five-year event-free survival was 66.4% (95% CI, 56.4%-76.4%) with carboplatin vs 59.2% (95% CI, 48.8%-69.6%) without carboplatin (P =.11), with the effect exclusively observed in group 3 subgroup patients: 73.2% (95% CI, 56.9%-89.5%) with carboplatin vs 53.7% (95% CI, 35.3%-72.1%) without (P =.047). Five-year overall survival differed by molecular subgroup (P =.006): WNT pathway activated, 100% (95% CI, 100%-100%); SHH pathway activated, 53.6% (95% CI, 33.0%-74.2%); group 3, 73.7% (95% CI, 61.9%-85.5%); and group 4, 76.9% (95% CI, 67.3%-86.5%). Conclusions and Relevance: In this randomized clinical trial, therapy intensification with carboplatin improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma. These findings further support the value of an integrated clinical and molecular risk stratification for medulloblastoma. Trial Registration: ClinicalTrials.gov Identifier: NCT00392327. © 2021 American Medical Association. All rights reserved.

Using Computational Modeling to Capture Schizophrenia-Specific Reinforcement Learning Differences and Their Implications on Patient Classification
(2021) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . 

Geana, A.^a , Barch, D.M.^b c d , Gold, J.M.^e , Carter, C.S.^f , MacDonald, A.W., III^g , Ragland, J.D.^f , Silverstein, S.M.^h , Frank, M.J.^a

^a Department of Department of Cognitive, Linguistic, and Psychological Sciences, Brown University, Providence, RI, United States
^b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Maryland Psychiatric Research Center, Baltimore, MD, United States
^f Department of Psychiatry, University of California, Davis, CA, United States
^g Department of Psychology, University of Minnesota, Minneapolis, MN, United States
^h Department of Psychiatry, University of Rochester, Rochester, NY, United States

Abstract
Background: Psychiatric diagnosis and treatment have historically taken a symptom-based approach, with less attention on identifying underlying symptom-producing mechanisms. Recent efforts have illuminated the extent to which different underlying circuitry can produce phenotypically similar symptomatology (e.g., psychosis in bipolar disorder vs. schizophrenia). Computational modeling makes it possible to identify and mathematically differentiate behaviorally unobservable, specific reinforcement learning differences in patients with schizophrenia versus other disorders, likely owing to a higher reliance on prediction error–driven learning associated with basal ganglia and underreliance on explicit value representations associated with orbitofrontal cortex. Methods: We used a well-established probabilistic reinforcement learning task to replicate those findings in individuals with schizophrenia both on (n = 120) and off (n = 44) antipsychotic medications and included a patient comparison group of bipolar patients with psychosis (n = 60) and healthy control subjects (n = 72). Results: Using accuracy, there was a main effect of group (F3,279 = 7.87, p &lt; .001), such that all patient groups were less accurate than control subjects. Using computationally derived parameters, both medicated and unmediated individuals with schizophrenia, but not patients with bipolar disorder, demonstrated a reduced mixing parameter (F3,295 = 13.91, p &lt; .001), indicating less dependence on learning explicit value representations as well as greater learning decay between training and test (F1,289 = 12.81, p &lt; .001). Unmedicated patients with schizophrenia also showed greater decision noise (F3,295 = 2.67, p = .04). Conclusions: Both medicated and unmedicated patients showed overreliance on prediction error–driven learning as well as significantly higher noise and value-related memory decay, compared with the healthy control subjects and the patients with bipolar disorder. Additionally, the computational model parameters capturing these processes can significantly improve patient/control classification, potentially providing useful diagnosis insight. © 2021 Society of Biological Psychiatry

Author Keywords
Classification;  Computational psychiatry;  Modeling;  Reinforcement learning;  Schizophrenia

Funding details
National Institute of Mental HealthNIMHMH084821, MH084826, MH084828, MH084840, MH084861
ACADIA PharmaceuticalsACADIA

Opioid use after endoscopic skull base surgery: A descriptive, prospective, longitudinal cohort study
(2021) International Forum of Allergy and Rhinology, . 

Rimmer, R.A.^a , Scott, B.^a , Pailet, J.^b , Farrell, N.F.^c , Mace, J.C.^a , Detwiller, K.Y.^a , Smith, T.L.^a , Dogan, A.^d , Gupta, S.^a , Andersen, P.^a , Cetas, J.^d , Geltzeiler, M.^a

^a Department of Otolaryngology–Head and Neck Surgery, Oregon Health and Science University, Portland, OR, United States
^b School of Medicine, Oregon Health and Science University, Portland, OR, United States
^c Department of Otolaryngology–Head and Neck Surgery, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, United States

Abstract
Background: Opioid abuse is a public health crisis and the perioperative period can be a time of first opioid exposure. Little is known about postoperative pain management after endoscopic skull base surgery (ESBS). Methods: This investigation was a single-institution, longitudinal, prospective cohort study of adult patients undergoing ESBS between November 2019 and March 2020. Participants completed preoperative questionnaires and were contacted every 48 hours postoperatively to quantify pain and opioid consumption. Results: A total of 33 patients were enrolled and 28 of 33 patients (85%) underwent ESBS for sellar pathology. Mean total morphine milligram equivalents (MME) consumed was 381.9 ± 476.0. History of a headache disorder (p = 0.025) and previous opioid use within 60 days preoperatively (p < 0.001) were significantly associated with greater opioid use. Mean duration of opioid use was 6.7 ± 5.1 (range, 0-20) days. Headache disorder (p = 0.01), depression (p = 0.03), anxiety (p = 0.03), age ≤46 years (p = 0.029), and previous opioid use (p = 0.008) were all associated with longer mean opioid use. Patients with headache disorder also reported higher mean postoperative pain scores. Fewer than half of the participants required opioids by postoperative day 8. Prescription of nonsteroidal anti-inflammatory drugs at discharge was significantly associated with less outpatient opioid use (p = 0.032). At 2-month follow-up, 37% of patients reported keeping excess opioids. Conclusion: After ESBS, greater total opioid use was significantly associated with history of headaches and previous opioid use within 60 days. Overall, opioid use declined among all patients in the postoperative period, but several factors may contribute to longer duration of use. © 2021 ARS-AAOA, LLC

Author Keywords
analgesics;  nasal surgical procedures;  neurosurgery;  opioid;  otolaryngology;  pain management;  skull base

Multiple pathways linking early socioeconomic circumstances and depressive symptoms in late Middle age in the U.S.
(2021) Aging and Mental Health, . 

Kwon, E.^a , Park, S.^b , Lee, H.^c , Lee, N.Y.^d

^a School of Pharmacy and Health Sciences, Fairleigh Dickinson University, Florham Park, NJ, United States
^b George Warren Brown School, Washington University in St. Louis, Saint Louis, MO, United States
^c Department of Social Welfare, Daegu University, Gyeongsangbuk-do, South Korea
^d Department of Social Work, University of Mississippi, University, MS, United States

Abstract
Objectives: A growing number of life course studies are examining the influence of earlier life experiences on morbidity, disability, and mortality in mid-old age. Method: Drawing from the social pathway model, this study expands the life course literature by utilizing data collected over 35 years from the National Longitudinal Survey of Youth, 1979 Cohort, spanning four life course phases (childhood, young adulthood, middle adulthood, and late-middle adulthood). Through structural equation analyses with a phantom model, we estimated depressive symptoms in late middle age as a result of pathway effects starting with childhood socio-economic status (SES) which effect young adulthood and middle adulthood. The multi-pathway life course model includes three potential mediators of middle adulthood: health risk behaviors, social activity, and negative life events. Results: We found limited support for a direct effect of childhood SES disadvantage on depressive symptoms in middle age. Instead, much of the effects of childhood SES on later-year depressive symptoms appear to be mediated by SES in young adulthood. Further, the long-term pathway is mediated through the influence of health risk behaviors and negative life events in middle adulthood. Conclusion: Our findings do not propose this chain is permanent and irreversible; rather, this study highlights the possibility that interventions focused on promoting health behaviors and improving living conditions for people from socioeconomically disadvantaged backgrounds could help reduce the instance of depression in middle age and health outcomes along the life course could be improved. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
early socioeconomic status;  Life course framework;  middle-age depressive symptoms;  pathways;  phantom modeling

Can Neighborhood Social Infrastructure Modify Cognitive Function? A Mixed-Methods Study of Urban-Dwelling Aging Americans
(2021) Journal of Aging and Health, . 

Finlay, J.^a , Esposito, M.^a b , Li, M.^a c , Kobayashi, L.C.^d , Khan, A.M.^a d , Gomez-Lopez, I.^a , Melendez, R.^a , Colabianchi, N.^a e , Judd, S.^f , Clarke, P.J.^a d

^a Social Environment and Health Program, Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
^b Department of Sociology, Washington University of St. Louis, St. Louis, MO, United States
^c Survey Methodology Program, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
^d Center for Social Epidemiology and Population Health, Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, United States
^e School of Kinesiology, University of Michigan, Ann Arbor, MI, United States
^f School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
Objectives: Socialization predicts cognitive aging outcomes. Neighborhoods may facilitate socially engaged aging and thus shape cognition. We investigated places where older adults socialized and whether availability of these sites was associated with cognitive outcomes. Methods: Qualitative analysis of interviews and ethnography with 125 older adults (mean age 71 years) in Minneapolis identified where participants socialized outside of home. This informed quantitative analysis of a national sample of 21,151 older Americans (mean age at baseline 67 years) from the Reasons for Geographic and Racial Differences in Stroke study. Multilevel generalized additive models described associations between access to key social places and cognitive function and decline. Results: Qualitative analysis identified eateries, senior centers, and civic groups as key places to socialize. We identified significant positive associations between kernel density of senior centers, civic/social organizations, and cognitive function. Discussion: Specific neighborhood social infrastructures may support cognitive health among older adults aging in place. © The Author(s) 2021.

Author Keywords
cognitive function;  environment;  neighborhoods;  social support;  well-being

Funding details
F32 AG064815-01, UL1 TR002240-02
National Institutes of HealthNIH
U.S. Department of Health and Human ServicesHHS
National Institute on AgingNIA1RF1AG057540-01
National Institute of Neurological Disorders and StrokeNINDS

Risk of intracranial haemorrhage and ischaemic stroke after convexity subarachnoid haemorrhage in cerebral amyloid angiopathy: international individual patient data pooled analysis
(2021) Journal of Neurology, . 

Hostettler, I.C.^a , Wilson, D.^a , Fiebelkorn, C.A.^b , Aum, D.^c , Ameriso, S.F.^d , Eberbach, F.^d , Beitzke, M.^e , Kleinig, T.^f , Phan, T.^g u , Marchina, S.^h , Schneckenburger, R.ⁱ , Carmona-Iragui, M.^j , Charidimou, A.^k , Mourand, I.^l , Parreira, S.^m , Ambler, G.ⁿ , Jäger, H.R.^o , Singhal, S.^g u , Ly, J.^g u , Ma, H.^g u , Touzé, E.^p , Geraldes, R.^q r , Fonseca, A.C.^m , Melo, T.^m , Labauge, P.^l , Lefèvre, P.-H.^s , Viswanathan, A.^k , Greenberg, S.M.^k , Fortea, J.^j , Apoil, M.ⁱ , Boulanger, M.^i p , Viader, F.ⁱ , Kumar, S.^h , Srikanth, V.^g u , Khurram, A.^f , Fazekas, F.^e , Bruno, V.^d , Zipfel, G.J.^c , Refai, D.^t , Rabinstein, A.^b , Graff-Radford, J.^b , Werring, D.J.^a

^a Stroke Research Centre, University College London, National Hospital of Neurology and Neurosurgery, Institute of Neurology, Queen Square, London, WC1N, United Kingdom
^b Department of Neurology, Mayo Clinic, Rochester, MN, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Institute for Neurological Research, Fleni, Buenos Aires, Argentina
^e Department of Neurology, Medical University of Graz, Graz, Austria
^f Department of Neurology, Royal Adelaide Hospital, Adelaide, Australia
^g Department of Neurology, Monash Health and Stroke and Ageing Research Group, Melbourne, Australia
^h Department of Neurology, Stroke Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
ⁱ Department of Neurology, CHU Caen Normandie, Caen, France
^j Memory Unit, Department of Neurology, Hospital de la Santa Creu I Sant Pau, Institut Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
^k J. Philip Kistler Stroke Research Center, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^l Department of Neurology, CHU de Montpellier, Hôpital Gui-de-Chauliac, Montpellier, France
^m Stroke Unit, Department of Neuroscience, Hospital de Santa Maria, University of Lisbon, Lisbon, Portugal
ⁿ Department of Statistical Science, UCL, London, WC1E 6BT, United Kingdom
^o Neuroradiological Academic Unit, Department of Brain Repair & Rehabilitation, University College London, Institute of Neurology, London, United Kingdom
^p Normandy University, UNICAEN, INSERM U1237, Caen, France
^q Nuffield Department of Clinical Neurosciences, Oxford University Hospitals, Oxford, United Kingdom
^r Neurology department, Frimley Health Foundation Trust, Camberley, United Kingdom
^s Department of Neuroradiology, CHU de Montpellier, Hôpital Gui-de-Chauliac, Montpellier, France
^t Department of Neurosurgery, Emory University, Atlanta, GA, United States
^u Department of Medicine, School of Clinical Sciences, Monash University, Melbourne, Australia

Abstract
Objective: To investigate the frequency, time-course and predictors of intracerebral haemorrhage (ICH), recurrent convexity subarachnoid haemorrhage (cSAH), and ischemic stroke after cSAH associated with cerebral amyloid angiopathy (CAA). Methods: We performed a systematic review and international individual patient-data pooled analysis in patients with cSAH associated with probable or possible CAA diagnosed on baseline MRI using the modified Boston criteria. We used Cox proportional hazards models with a frailty term to account for between-cohort differences. Results: We included 190 patients (mean age 74.5 years; 45.3% female) from 13 centers with 385 patient-years of follow-up (median 1.4 years). The risks of each outcome (per patient-year) were: ICH 13.2% (95% CI 9.9–17.4); recurrent cSAH 11.1% (95% CI 7.9–15.2); combined ICH, cSAH, or both 21.4% (95% CI 16.7–26.9), ischemic stroke 5.1% (95% CI 3.1–8) and death 8.3% (95% CI 5.6–11.8). In multivariable models, there is evidence that patients with probable CAA (compared to possible CAA) had a higher risk of ICH (HR 8.45, 95% CI 1.13–75.5, p = 0.02) and cSAH (HR 3.66, 95% CI 0.84–15.9, p = 0.08) but not ischemic stroke (HR 0.56, 95% CI 0.17–1.82, p = 0.33) or mortality (HR 0.54, 95% CI 0.16–1.78, p = 0.31). Conclusions: Patients with cSAH associated with probable or possible CAA have high risk of future ICH and recurrent cSAH. Convexity SAH associated with probable (vs possible) CAA is associated with increased risk of ICH, and cSAH but not ischemic stroke. Our data provide precise risk estimates for key vascular events after cSAH associated with CAA which can inform management decisions. © 2021, The Author(s).

Author Keywords
Cerebral amyloid angiopathy;  Intracerebral haemorrhage;  Ischemic stroke;  Non-traumatic convexity/convexal/cortical subarachnoid haemorrhage;  Stroke

Funding details
National Institutes of HealthNIH01AG026484, 01NS096730, 24 NS100591, 24 NS107154
Alzheimer’s AssociationAA
Global Brain Health InstituteGBHI
National Institute for Health ResearchNIHR
Department of Health and Social CareDH
Fondation Jérôme Lejeune
Alzheimer’s Research UKARUK
Instituto de Salud Carlos IIIISCIII
Departament de Salut, Generalitat de Catalunya
NIHR Imperial Biomedical Research CentreBRC
Fundació Víctor Grífols i Lucas76 AG057015-01

Molecular and cellular basis of genetically inherited skeletal muscle disorders
(2021) Nature Reviews Molecular Cell Biology, . 

Dowling, J.J.^a b , Weihl, C.C.^c , Spencer, M.J.^d

^a Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, ON, Canada
^b Division of Neurology and Program for Genetics and Genome Biology, The Hospital for Sick Children Peter Gilgan Centre for Research and Learning (PGCRL), Toronto, ON, Canada
^c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^d Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States

Abstract
Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue — encompassing the muscle cells (myofibres) themselves and their extracellular matrix — or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder — mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy — the field has made tremendous progress in understanding the genetic basis of these diseases, with pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to as myopathies or muscular dystrophies, and are due to variants in genes encoding muscle proteins. Many of these proteins provide structural stability to the myofibres or function in regulating sarcolemmal integrity, whereas others are involved in protein turnover, intracellular trafficking, calcium handling and electrical excitability — processes that ensure myofibre resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease, with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology. © 2021, Springer Nature Limited.

Effect of electroencephalogram-guided anaesthesia administration on 1 yr mortality: 1 yr follow-up of a randomised clinical trial
(2021) British Journal of Anaesthesia, . 

Fritz, B.A.^a , King, C.R.^a , Mickle, A.M.^a , Wildes, T.S.^a , Budelier, T.P.^a , Oberhaus, J.^a , Park, D.^a , Maybrier, H.R.^a , Ben Abdallah, A.^a , Kronzer, A.^a , McKinnon, S.L.^a , Torres, B.A.^a , Graetz, T.J.^a , Emmert, D.A.^a , Palanca, B.J.^a , Stevens, T.W.^a , Stark, S.L.^b , Lenze, E.J.^c , Avidan, M.S.^a , Abdallah, A.B.^a , Apakama, G.^a , Aranake-Chrisinger, A.^a , Bolzenius, J.^a , Burton, J.^a , Cui, V.^a , Goswami, S.^a , Gupta, S.^a , Jordan, K.^a , Muench, M.R.^a , Murphy, M.R.^a , Patel, A.^a , Spencer, J.W.^a , Strutz, P.^a , Tedeschi, C.M.^a , Trammel, E.R.^a , Upadhyayula, R.T.^a , Winter, A.C.^a , Lin, N.^d , Jacobsohn, E.^e , Fong, T.^f , Gallagher, J.^f , Inouye, S.K.^f , Schmitt, E.M.^f , Somerville, E.^b , Stark, S.^b , Melby, S.J.^g , Tappenden, J.^g , ENGAGES Research Group^h

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Anesthesiology, University of Manitoba, Winnipeg, Canada
^f Department of Medicine, Beth Israel-Deaconess Medical Center, Boston, MA, United States
^g Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Intraoperative EEG suppression duration has been associated with postoperative delirium and mortality. In a clinical trial testing anaesthesia titration to avoid EEG suppression, the intervention did not decrease the incidence of postoperative delirium, but was associated with reduced 30 day mortality. The present study evaluated whether the EEG-guided anaesthesia intervention continued to be associated with reduced 1 yr mortality. Methods: This manuscript reports 1 yr follow-up of patients from a single-centre RCT, including a post-hoc secondary outcome (1 yr mortality) in addition to pre-specified secondary outcomes. The trial included patients aged 60 yr or older undergoing surgery with general anaesthesia between January 2015 and May 2018. Patients were randomised to receive EEG-guided anaesthesia or usual care. The previously reported primary outcome was postoperative delirium. The outcome of the current study was all-cause 1 yr mortality. Results: Of the 1232 patients enrolled, 614 patients were randomised to EEG-guided anaesthesia and 618 patients to usual care. One year mortality was 57/591 (9.6%) in the guided group and 62/601 (10.3%) in the usual-care group. No significant difference in mortality was observed (adjusted absolute risk difference, –0.7%; 99.5% confidence interval, –5.8% to 4.3%; P=0.68). Conclusions: An EEG-guided anaesthesia intervention aiming to decrease duration of EEG suppression during surgery did not significantly decrease 1 yr mortality. These findings, in the context of other studies, do not provide supportive evidence for EEG-guided anaesthesia to prevent intermediate term postoperative death. Clinical trial registration: NCT02241655. © 2021 British Journal of Anaesthesia

Author Keywords
burst suppression;  depth of anaesthesia;  electroencephalogram suppression;  postoperative death;  postoperative delirium;  postoperative falls;  postoperative mortality;  quality of life

Funding details
National Institutes of HealthNIH
U.S. Food and Drug AdministrationFDAUH3 AG050312
National Institute on AgingNIA
National Institute of General Medical SciencesNIGMST32 GM108539
U.S. Department of Housing and Urban DevelopmentHUD
Patient-Centered Outcomes Research InstitutePCORI
Takeda Pharmaceutical CompanyTPC
Janssen Pharmaceuticals
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR
H. Lundbeck A/S

Brain structure and problematic alcohol use: a test of plausible causation using latent causal variable analysis
(2021) Brain Imaging and Behavior, . 

Hatoum, A.S.^a , Johnson, E.C.^a , Agrawal, A.^a , Bogdan, R.^b

^a Department of Psychiatry, Washington University St. Louis Medical School, 825 S Taylor Ave, St. Louis, MO 63110, United States
^b Department of Psychological & Brain Sciences, Washington University St. Louis, St. Louis, MO, United States

Abstract
Associations between brain structure and problematic alcohol use may reflect alcohol-induced toxicity and/or preexisting risk. Here, we applied a latent causal variable approach to genome-wide association study summary statistics of problematic alcohol use (n = 435,563) and magnetic resonance imaging-derived brain structure phenotypes (e.g., cortical volume, cortical thickness, white matter volume; ns ranging from 17,706 to 51,665) to test whether variability in brain structure may plausibly contribute to problematic alcohol use and/or whether problematic alcohol use influences brain structure. After correction for multiple testing within each modality, we find evidence that greater volume of the pars opercularis, greater thickness of the cuneus, and lower volume of the basal forebrain may plausibly contribute to problematic alcohol use. All other nominally-significant associations identify brain structure as a potential causal contributor to problematic alcohol use; there was no evidence suggesting that problematic alcohol use may cause differences in brain structure. Collectively, these results challenge common interpretations that associations between alcohol use and brain structure reflect consequences of alcohol, instead supporting emerging work suggesting that brain structure may reflect a predispositional risk factor for alcohol involvement. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Funding details
National Institutes of HealthNIHAA027827, AG052564, DA007261-17, DA046224, F32AA027435, K02DA032573, MH109532
U.S. Department of Veterans AffairsVA
Office of Research and DevelopmentORD
Health Services Research and DevelopmentHSR&D

Non-motor phenotypic subgroups in adult-onset idiopathic, isolated, focal cervical dystonia
(2021) Brain and Behavior, . 

Wadon, M.E.^a , Bailey, G.A.^a , Yilmaz, Z.^a b , Hubbard, E.^c , AlSaeed, M.^c d , Robinson, A.^c , McLauchlan, D.^a , Barbano, R.L.^e , Marsh, L.^f , Factor, S.A.^g , Fox, S.H.^h i , Adler, C.H.^j , Rodriguez, R.L.^k , Comella, C.L.^l , Reich, S.G.^m , Severt, W.L.ⁿ , Goetz, C.G.^l , Perlmutter, J.S.^o , Jinnah, H.A.^g , Harding, K.E.^p , Sandor, C.^q , Peall, K.J.^a

^a Neuroscience and Mental Health Research Institute, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, United Kingdom
^b Institute of Neurology, University College London, Queen Square, London, WC1N 3BG, United Kingdom
^c School of Medicine, Cardiff University, Heath Park Campus, Cardiff, CF14 4YS, United Kingdom
^d Division of Neurology, University of British Columbia, Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
^e Department of Neurology, University of Rochester, Elmwood Avenue, Rochester, NY NY 14642, United States
^f Menninger Department of Psychiatry, Baylor College of Medicine, Butler Boulevard, Houston, TX 77030, United States
^g Departments of Neurology & Human Genetics, Emory University, Woodruff Circle, Atlanta, GA 30322, United States
^h Edmond J Safra Program in Parkinson Disease, Movement Disorder Clinic, Toronto Western Hospital, Bathurst Street, Toronto, ON M5T 2S8, Canada
ⁱ Department of Medicine, University of Toronto, Queen’s Park Crescent West, Toronto, ON M5S 3H2, Canada
^j The Parkinson’s Disease and Movement Disorders Center, Mayo Clinic, Department of Neurology, East Shea Boulevard, Scottsdale, AZ 85259, United States
^k Department of Neurology, University of Florida, Newell Drive, Gainesville, FL 32611, United States
^l Department of Neurological Sciences, Rush University Medical Center, West Harrison Street, Chicago, IL 60612, United States
^m Department of Neurology, University of Maryland School of Medicine, south Paca Street, Baltimore, MD 21201, United States
ⁿ Beth Israel Medical Center, First Avenue, New York, NY 10003, United States
^o Neurology, Radiology, Neuroscience, Physical Therapy and Occupational Therapy, Washington University School of Medicine, South Euclid Avenue, St. Louis, MO 63110, United States
^p Department of Neurology, Aneurin Bevan University Health Board, Corporation Road, Newport, NP19 0BH, United Kingdom
^q UK Dementia Research Institute, Cardiff University, Maindy Road, Cardiff, CF24 4HQ, United Kingdom

Abstract
Background: Non-motor symptoms are well established phenotypic components of adult-onset idiopathic, isolated, focal cervical dystonia (AOIFCD). However, improved understanding of their clinical heterogeneity is needed to better target therapeutic intervention. Here, we examine non-motor phenotypic features to identify possible AOIFCD subgroups. Methods: Participants diagnosed with AOIFCD were recruited via specialist neurology clinics (dystonia wales: n = 114, dystonia coalition: n = 183). Non-motor assessment included psychiatric symptoms, pain, sleep disturbance, and quality of life, assessed using self-completed questionnaires or face-to-face assessment. Both cohorts were analyzed independently using Cluster, and Bayesian multiple mixed model phenotype analyses to investigate the relationship between non-motor symptoms and determine evidence of phenotypic subgroups. Results: Independent cluster analysis of the two cohorts suggests two predominant phenotypic subgroups, one consisting of approximately a third of participants in both cohorts, experiencing increased levels of depression, anxiety, sleep impairment, and pain catastrophizing, as well as, decreased quality of life. The Bayesian approach reinforced this with the primary axis, which explained the majority of the variance, in each cohort being associated with psychiatric symptomology, and also sleep impairment and pain catastrophizing in the Dystonia Wales cohort. Conclusions: Non-motor symptoms accompanying AOIFCD parse into two predominant phenotypic sub-groups, with differences in psychiatric symptoms, pain catastrophizing, sleep quality, and quality of life. Improved understanding of these symptom groups will enable better targeted pathophysiological investigation and future therapeutic intervention. © 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC

Author Keywords
dystonia disorders;  phenotype;  surveys and questionnaires;  torticollis

Funding details
U54 TR001456
National Institute of Neurological Disorders and StrokeNINDSU54 NS065701, U54 NS116025
Dystonia Medical Research FoundationDMRF
Jacques und Gloria Gossweiler-StiftungJGGF
Dystonia Coalition
Rare Diseases Clinical Research NetworkRDCRN
Fight for Sight UK

Kratom Alkaloids as Probes for Opioid Receptor Function: Pharmacological Characterization of Minor Indole and Oxindole Alkaloids from Kratom
(2021) ACS Chemical Neuroscience, . 

Chakraborty, S.^a b , Uprety, R.^c , Daibani, A.E.^a b , Rouzic, V.L.^c , Hunkele, A.^c , Appourchaux, K.^a , Eans, S.O.^d , Nuthikattu, N.^a , Jilakara, R.^a , Thammavong, L.^a , Pasternak, G.W.^c , Pan, Y.-X.^c e , McLaughlin, J.P.^d , Che, T.^a b f , Majumdar, S.^a b

^a Center for Clinical Pharmacology, University of Health Sciences and Pharmacy at St. Louis, Washington University, School of Medicine, St. Louis, MO 63110, United States
^b Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO 63110, United States
^c Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
^d Department of Pharmacodynamics, University of Florida, Gainesville, FL 032610, United States
^e Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
^f Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, NC 27599, United States

Abstract
Dry leaves of kratom (mitragyna speciosa) are anecdotally consumed as pain relievers and antidotes against opioid withdrawal and alcohol use disorders. There are at least 54 alkaloids in kratom; however, investigations to date have focused around mitragynine, 7-hydroxy mitragynine (7OH), and mitragynine pseudoindoxyl (MP). Herein, we probe a few minor indole and oxindole based alkaloids, reporting the receptor affinity, G-protein activity, and βarrestin-2 signaling of corynantheidine, corynoxine, corynoxine B, mitraciliatine, and isopaynantheine at mouse and human opioid receptors. We identify corynantheidine as a mu opioid receptor (MOR) partial agonist, whereas its oxindole derivative corynoxine was an MOR full agonist. Similarly, another alkaloid mitraciliatine was found to be an MOR partial agonist, while isopaynantheine was a KOR agonist which showed reduced βarrestin-2 recruitment. Corynantheidine, corynoxine, and mitraciliatine showed MOR dependent antinociception in mice, but mitraciliatine and corynoxine displayed attenuated respiratory depression and hyperlocomotion compared to the prototypic MOR agonist morphine in vivo when administered supraspinally. Isopaynantheine on the other hand was identified as the first kratom derived KOR agonist in vivo. While these minor alkaloids are unlikely to play the majority role in the biological actions of kratom, they represent excellent starting points for further diversification as well as distinct efficacy and signaling profiles with which to probe opioid actions in vivo. © 2021 American Chemical Society. All rights reserved.

Author Keywords
corynoxine;  kratom;  mitraciliatine;  oxindoles;  partial agonism;  Respiration

Funding details
National Institutes of HealthNIHDA045884, DA048379
National Cancer InstituteNCIP30 CA008748
University of WashingtonUWDA042888, DA046714

Tail of two fishies: age and afferents influence zebrafish lateral-line hair cell regeneration
(2021) Journal of Physiology, . 

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

Author Keywords
afferent fibres;  electrophysiology;  hair cells;  regeneration;  zebrafish

Pediatric Bilateral Sensorineural Hearing Loss: Minimum Test Battery and Referral Criteria for Cochlear Implant Candidacy Evaluation
(2021) Otolaryngology – Head and Neck Surgery (United States), . 

Anne, S.^a , Brown, K.D.^b , Goldberg, D.M.^a c , Adunka, O.F.^d , Kenna, M.^e , Chien, W.^f , Teagle, H.^g , Zwolan, T.A.^h , Sydlowski, S.A.^a , Roush, P.^b , Buchman, C.A.ⁱ

^a Head and Neck Institute, Cleveland Clinic, Cleveland, OH, United States
^b School of Medicine, University of North Carolina, Chapel Hill, NC, United States
^c College of Wooster, Wooster, OH, United States
^d Department of Otolaryngology–Head and Neck Surgery, The Ohio State University, Columbus, OH, United States
^e Department of Otolaryngology–Head and Neck Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^f Johns Hopkins School of Medicine, Baltimore, MD, United States
^g University of Auckland, Auckland, New Zealand
^h Department of Otolaryngology–Head and Neck Surgery, Michigan Medicine, Ann Arbor, MI, United States
ⁱ Washington University School of Medicine, St Louis, MO, United States

Abstract
Among the various cochlear implant systems approved by the Food and Drug Administration, current labeling for pediatric usage encompasses (1) bilateral profound bilateral sensorineural hearing loss in children aged 9 to 24 months and bilateral severe to profound sensorineural hearing loss in children older than 2 years; (2) use of appropriately fitted hearing aids for 3 months (this can be waived if there is evidence of ossification); and (3) demonstration of limited progress with auditory, speech, and language development. Pediatric guidelines require children to have significantly worse speech understanding before qualifying for cochlear implantation. The early years of life have been shown to be critical for speech and language development, and auditory deprivation is especially detrimental during this crucial time. Level of evidence: 2. © American Academy of Otolaryngology–Head and Neck Surgery Foundation 2021.

Author Keywords
cochlear implantation;  health-related quality of life;  neurologically impaired

Amphiphilic Distyrylbenzene Derivatives as Potential Therapeutic and Imaging Agents for Soluble and Insoluble Amyloid β Aggregates in Alzheimer’s Disease
(2021) Journal of the American Chemical Society, . 

Sun, L.^a , Cho, H.-J.^a , Sen, S.^c , Arango, A.S.^c , Huynh, T.T.^d e , Huang, Y.^a , Bandara, N.^d , Rogers, B.E.^d , Tajkhorshid, E.^c , Mirica, L.M.^a b

^a Department of Chemistry, Beckman Institute for Advanced Science and Technology, the Neuroscience Program, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Nih Center for Macromolecular Modeling and Bioinformatics, Beckman Institute for Advanced Science and Technology, Center for Biophysics and Quantitative Biology, Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
^d Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, United States
^e Department of Chemistry, Washington University, St. Louis, MO 63130, United States

Abstract
Alzheimer’s Disease (AD) is the most common neurodegenerative disease, and efficient therapeutic and early diagnostic agents for AD are still lacking. Herein, we report the development of a novel amphiphilic compound, LS-4, generated by linking a hydrophobic amyloid-binding distyrylbenzene fragment with a hydrophilic triazamacrocycle, which dramatically increases the binding affinity toward various amyloid β (Aβ) peptide aggregates, especially for soluble Aβ oligomers. Moreover, upon the administration of LS-4 to 5xFAD mice, fluorescence imaging of LS-4-treated brain sections reveals that LS-4 can penetrate the blood-brain barrier and bind to the Aβ oligomers in vivo. In addition, the treatment of 5xFAD mice with LS-4 reduces the amount of both amyloid plaques and associated phosphorylated tau aggregates vs the vehicle-treated 5xFAD mice, while microglia activation is also reduced. Molecular dynamics simulations corroborate the observation that introducing a hydrophilic moiety into the molecular structure of LS-4 can enhance the electrostatic interactions with the polar residues of the Aβ species. Finally, exploiting the Cu2+-chelating property of the triazamacrocycle, we performed a series of imaging and biodistribution studies that show the 64Cu-LS-4 complex binds to the amyloid plaques and can accumulate to a significantly larger extent in the 5xFAD mouse brains vs the wild-type controls. Overall, these results illustrate that the novel strategy, to employ an amphiphilic molecule containing a hydrophilic moiety attached to a hydrophobic amyloid-binding fragment, can increase the binding affinity for both soluble and insoluble Aβ aggregates and can thus be used to detect and regulate various Aβ species in AD. © 2021 American Chemical Society.

Funding details
National Institutes of HealthNIHP41-GM104601, R01GM114588