WashU weekly Neuroscience publications

Personalized networks of social anxiety disorder and depression and implications for treatment
(2022) Journal of Affective Disorders, 298, pp. 262-276. 

Piccirillo, M.L., Rodebaugh, T.L.

Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Introduction: Social anxiety disorder (SAD) and major depressive disorder (MDD) often co-occur; however, there is limited research evaluating how cognitive-affective and behavioral factors maintain SAD and MDD for specific individuals. Evidence suggests that individuals exhibit symptom-level heterogeneity, necessitating a person-specific approach to assessment and intervention. We compared group and person-specific models of SAD-MDD comorbidity and hypothesized that individuals would demonstrate person-specific patterns of comorbidity factors that differed from the group. Methods: Cisgender women (N = 35) with SAD and a current or past major depressive episode were recruited. Ages ranged from 18 to 37 years old and a majority of women were White (n = 18; 51.43%). Brief ecological momentary assessment surveys related to SAD-MDD comorbidity were administered five times a day for a month (T = 4,357). Results: Multilevel and person-specific network analyses were used to examine between-, within-, and person-specific patterns. Intra-daily depressed mood demonstrated the strongest connections to other variables and exhibited additional, unexpected temporal effects. All models demonstrated person-specific patterns relevant to SAD-MDD comorbidity. Limitations: These results are descriptive in nature from women with a similar psychiatric profile. Future research integrating intensive EMA and personalized modeling within the context of experimental design is needed to determine the extent to which individuals truly differ from the group. Conclusions: Patterns of SAD-MDD comorbidity varied substantially across women, underscoring the potential for results from person-specific (idiographic) networks to inform the development and implementation of personalized directives for clinical assessment and intervention. © 2021 Elsevier B.V.

Author Keywords
Comorbidity;  Depression;  Network analyses;  Person-specific models;  Social anxiety disorder

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHF31MH115641
National Institute on Alcohol Abuse and AlcoholismNIAAAT3211007455

Severe acute neurotoxicity reflects absolute intra-carotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine dose in non-human primates
(2022) Journal of Neuroscience Methods, 366, art. no. 109406, . 

Norris, S.A.^a b , White, H.C.B.^a , Tanenbaum, A.^a , Williams, E.L.^a , Cruchaga, C.^c , Tian, L.^a , Schmidt, R.E.^d , Perlmutter, J.S.^{a b e f g}

^a Departments of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^b Departments of Radiology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^c Departments of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^d Departments of Pathology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^e Departments of Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^f Departments of Physical, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^g Departments of Occupational Therapy, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States

Author Keywords
Basal ganglia;  Monkey;  MPTP;  Neurotoxicity;  Striatum

Funding details
National Institute on AgingNIANS039913, NS050425, NS058714, NS075321, NS075527, NS103957, NS107281
National Institute of Neurological Disorders and StrokeNINDS
American Parkinson Disease AssociationAPDA
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish Hospital
McDonnell Center for Systems Neuroscience

The phenotypic spectrum of PCDH12 associated disorders – Five new cases and review of the literature
(2022) European Journal of Paediatric Neurology, 36, pp. 7-13. 

Fazeli, W.^a b c , Bamborschke, D.^a d , Moawia, A.^a d , Bakhtiari, S.^e f , Tafakhori, A.^g , Giersdorf, M.^a , Hahn, A.^h , Weik, A.ⁱ , Kolzter, K.^j , Shafiee, S.^k , Jin, S.C.^l , Körber, F.^m , Lee-Kirsch, M.A.ⁿ , Darvish, H.^o , Cirak, S.^a d , Kruer, M.C.^e f , Koy, A.^a

^a Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^b Institute for Molecular and Behavioral Neuroscience, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^c Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany
^d Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^e Pediatric Movement Disorders Program, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^f Departments of Child Health, Cellular & Molecular Medicine, and Neurology and Program in Genetics, University of Arizona College of Medicine Phoenix, Phoenix, AZ, United States
^g Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
^h Department of Child Neurology, Justus-Liebig-University Giessen, Giessen, Germany
ⁱ CeGAT GmbH and Praxis für Humangenetik Tübingen, Tübingen, Germany
^j Children’s Hospital Amsterdamer Straße, Kliniken der Stadt Köln, Cologne, Germany
^k Neurological Surgery Department, Mazandaran University of Medical Sciences, Sari, Iran
^l Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^m Department of Radiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
ⁿ Department of Pediatrics, Medical Faculty Carl Gustav Carus, Technical University Dresden, Dresden, Germany
^o Neuroscience Research Center, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran

Abstract
PCDH12 is a member of the non-clustered protocadherin family of calcium-dependent cell adhesion proteins, which are involved in the regulation of brain development and endothelial adhesion. To date, only 15 families have been reported with PCDH12 associated disease. The main features previously associated with PCDH12 deficiency are developmental delay, movement disorder, epilepsy, microcephaly, visual impairment, midbrain malformations, and intracranial calcifications. Here, we report novel clinical features such as onset of epilepsy after infancy, episodes of transient developmental regression, and dysplasia of the medulla oblongata associated with three different novel truncating PCDH12 mutations in five cases (three children, two adults) from three unrelated families. Interestingly, our data suggests a clinical overlap with interferonopathies, and we show an elevated interferon score in two pediatric patients. This case series expands the genetic and phenotypic spectrum of PCDH12 associated diseases and highlights the broad clinical variability. © 2021 European Paediatric Neurology Society

Author Keywords
Brain malformation;  Epilepsy;  Interferonopathy;  Intracranial calcification;  Movement disorder;  PCDH12

Funding details
Cerebral Palsy Alliance Research FoundationCPARF01318
Deutsche ForschungsgemeinschaftDFGCRC237 369799452/B21, Cl 218/1-1
Universität zu KölnUoC

Revisiting the relationship between neural correlates of sensory gating and self-reported sensory gating inventory: An MEG investigation
(2022) Neuroscience Letters, 766, art. no. 136336, . 

Jian, J.-R.^a b , Lin, Y.-Y.^a b , Connor, L.T.^c , Cheng, C.-H.^a b d e

^a Department of Occupational Therapy and Graduate Institute of Behavioral Sciences, Chang Gung University, Taoyuan, Taiwan
^b Laboratory of Brain Imaging and Neural Dynamics (BIND Lab), Chang Gung University, Taoyuan, Taiwan
^c Washington University School of Medicine, Program in Occupational Therapy & Department of Neurology, St. Louis, MO, United States
^d Healthy Aging Research Center, Chang Gung University, Taoyuan, Taiwan
^e Department of Psychiatry, Chang Gung Memorial Hospital, Linkou, Taiwan

Abstract
Background: Accumulated evidence has revealed that bilateral superior temporal gyrus (STG), inferior frontal gyrus (IFG), and inferior parietal lobule (IPL) are involved in the processes of sensory gating (SG). However, it remains unknown which neural correlate(s) of SG specifically reflect individuals’ perceptual experiences, as measured by the Sensory Gating Inventory (SGI). Thus, this study aims to investigate the relationship of SGI with cortical SG-related regions. Furthermore, we examine whether SG hemispheric asymmetry exists, which is still an inconclusive issue. Methods: Twenty-two healthy young adults performed the auditory paired-stimulus paradigm during magnetoencephalographic recordings. SG of M50 and M100 was measured as ratios (S2/S1) and differences (S1–S2). They were also evaluated with SGI, which factored into three categories of Perceptual Modulation, Distractibility, and Over-Inclusion. SG in the STG, IFG, and IPL were compared between left and right hemispheres, and were used to determine the relationship with SGI. Results: Only M100 SG differences (S1–S2) of the right IFG were significantly correlated with scores of Perceptual Modulation (partial r = -0.392, p = 0.040) and total SGI scores (partial r = -0.387, p = 0.041). However, we did not find significant lateralization of M50 SG and M100 SG in any studying region. Conclusions: The individual’s perceptual experience is specifically related to electrophysiological SG function of the right IFG. © 2021 Elsevier B.V.

Author Keywords
Frontal cortex;  Hemispheric asymmetry;  Magnetoencephalography (MEG);  Sensory gating (SG);  Sensory Gating Inventory (SGI)

Funding details
Chang Gung Memorial HospitalCGMHCMRPD1K0061, CMRPD1K0581
Chang Gung UniversityCGU
Ministry of Science and Technology, TaiwanMOSTMOST-108-2628-B-182-002, MOST-109-2628-B-182-012, MOST-110-2628-B-182-010
Kementerian Pendidikan MalaysiaKPMEMRPD1K0431
Healthy Aging Research Center

A novel model of acquired hydrocephalus for evaluation of neurosurgical treatments
(2021) Fluids and Barriers of the CNS, 18 (1), art. no. 49, . 

McAllister, J.P., II^a i , Talcott, M.R.^a b , Isaacs, A.M.^c , Zwick, S.H.^a , Garcia-Bonilla, M.^a , Castaneyra-Ruiz, L.^a , Hartman, A.L.^a , Dilger, R.N.^d e , Fleming, S.A.^d e , Golden, R.K.^d , Morales, D.M.^a , Harris, C.A.^f g , Limbrick, D.D., Jr^a h

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^b Division of Comparative Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, United States
^c Department of Surgery, Division of Neurosurgery, University of Calgary School of Medicine, Calgary, AB T2N 2T9, Canada
^d Department of Animal Sciences, Division of Nutritional Sciences, Neuroscience Program, University of Illinois, Champagne-Urbana, Illinois, 61801, United States
^e Traverse Science, Champaign, IL 61801, United States
^f Department of Chemical Engineering and Materials Science, Wayne State University, Detroit, MI 48202, United States
^g Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48202, United States
^h Department of Pediatrics, St. Louis Children’s Hospital, St. Louis, MO 63110, United States
ⁱ Department of Neurosurgery, BJC Institute of Health, 425 S. Euclid, Campus, Box 8057, St. Louis, MO 63143, United States

Abstract
Background: Many animal models have been used to study the pathophysiology of hydrocephalus; most of these have been rodent models whose lissencephalic cerebral cortex may not respond to ventriculomegaly in the same way as gyrencephalic species and whose size is not amenable to evaluation of clinically relevant neurosurgical treatments. Fewer models of hydrocephalus in gyrencephalic species have been used; thus, we have expanded upon a porcine model of hydrocephalus in juvenile pigs and used it to explore surgical treatment methods. Methods: Acquired hydrocephalus was induced in 33–41-day old pigs by percutaneous intracisternal injections of kaolin (n = 17). Controls consisted of sham saline-injected (n = 6) and intact (n = 4) animals. Magnetic resonance imaging (MRI) was employed to evaluate ventriculomegaly at 11–42 days post-kaolin and to plan the surgical implantation of ventriculoperitoneal shunts at 14–38-days post-kaolin. Behavioral and neurological status were assessed. Results: Bilateral ventriculomegaly occurred post-induction in all regions of the cerebral ventricles, with prominent CSF flow voids in the third ventricle, foramina of Monro, and cerebral aqueduct. Kaolin deposits formed a solid cast in the basal cisterns but the cisterna magna was patent. In 17 untreated hydrocephalic animals. Mean total ventricular volume was 8898 ± 5917 SD mm3 at 11–43 days of age, which was significantly larger than the baseline values of 2251 ± 194 SD mm3 for 6 sham controls aged 45–55 days, (p < 0.001). Past the post-induction recovery period, untreated pigs were asymptomatic despite exhibiting mild-moderate ventriculomegaly. Three out of 4 shunted animals showed a reduction in ventricular volume after 20–30 days of treatment, however some developed ataxia and lethargy, from putative shunt malfunction. Conclusions: Kaolin induction of acquired hydrocephalus in juvenile pigs produced an in vivo model that is highly translational, allowing systematic studies of the pathophysiology and clinical treatment of hydrocephalus. © 2021, The Author(s).

Author Keywords
Acquired hydrocephalus;  Animal models;  Cognition;  Hydrocephalus;  Kaolin;  Shunt;  Ventriculomegaly

Funding details
National Institutes of HealthNIH5R21NS111249-02
Washington University School of Medicine in St. LouisWUSM

GABAergic neuronal IL-4R mediates T cell effect on memory
(2021) Neuron, 109 (22), pp. 3609-3618.e9. 

Herz, J.^a b , Fu, Z.^a b , Kim, K.^a b , Dykstra, T.^a b , Wall, M.^f , Li, H.^c , Salvador, A.F.^a b g , Zou, B.^e , Yan, N.^e , Blackburn, S.M.^a b , Andrews, P.H.^f , Goldman, D.H.^a b g , Papadopoulos, Z.^a b d , Smirnov, I.^a b , Xie, X.S.^e , Kipnis, J.^a b d

^a Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, United States
^b Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Child Health Care, Children’s Hospital of Fudan University, Shanghai, China
^d Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^e AfaSci Research Laboratories, 522 Second Avenue, Redwood City, CA, United States
^f Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA, United States
^g Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, United States

Abstract
Mechanisms governing how immune cells and their derived molecules impact homeostatic brain function are still poorly understood. Here, we elucidate neuronal mechanisms underlying T cell effects on synaptic function and episodic memory. Depletion of CD4 T cells led to memory deficits and impaired long-term potentiation. Severe combined immune-deficient mice exhibited amnesia, which was reversible by repopulation with T cells from wild-type but not from IL-4-knockout mice. Behaviors impacted by T cells were mediated via IL-4 receptors expressed on neurons. Exploration of snRNA-seq of neurons participating in memory processing provided insights into synaptic organization and plasticity-associated pathways regulated by immune cells. IL-4Rα knockout in inhibitory (but not in excitatory) neurons was sufficient to impair contextual fear memory, and snRNA-seq from these mice pointed to IL-4-driven regulation of synaptic function in promoting memory. These findings provide new insights into complex neuroimmune interactions at the transcriptional and functional levels in neurons under physiological conditions. © 2021 Elsevier Inc.

Author Keywords
IL-4;  learning and memory;  meninges;  neuroimmunology;  T cells

Funding details
National Institutes of HealthNIHAG034113, AG057496, AT010416, NS096967

MR imaging differences in the circle of willis between healthy children and adults
(2021) American Journal of Neuroradiology, 42 (11), . 

Guilliams, K.P.^a b c , Gupta, N.^c , Srinivasan, S.^c , Binkley, M.M.^a , Ying, C.^c , Couture, L.^c , Gross, J.^f , Wallace, A.^g , McKinstry, R.C.^b c , Vo, K.^c , Lee, J.-M.^a c d , An, H.^c , Goyal, M.S.^a c e

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^f Division of Neuroradiology, Midwest Radiology, St. Paul, MN, United States
^g Department of Neurointerventional Surgery, Ascension Columbia St. Mary’s Hospital, Milwaukee, WI, United States

Abstract
BACKGROUND AND PURPOSE: Asymmetries in the circle of Willis have been associated with several conditions, including migraines and stroke, but they may also be age-dependent. This study examined the impact of age and age-dependent changes in cerebral perfusion on circle of Willis anatomy in healthy children and adults. MATERIALS AND METHODS: We performed an observational, cross-sectional study of bright and black-blood imaging of the proximal cerebral vasculature using TOF-MRA and T2 sampling perfection with application-optimized contrasts by using different flip angle evolution (T2-SPACE) imaging at the level of the circle of Willis in 23 healthy children and 43 healthy adults (4–74 years of age). We compared arterial diameters measured manually and cerebral perfusion via pseudocontinuous arterial spin-labeling between children and adults. RESULTS: We found that the summed cross-sectional area of the circle of Willis is larger in children than in adults, though the effect size was smaller with T2-SPACE-based measurements than with TOF-MRA. The circle of Willis is also more symmetric in children, and nonvisualized segments occur more frequently in adults than in children. Moreover, the size and symmetry of the circle of Willis correlate with cerebral perfusion. CONCLUSIONS: Our results demonstrate that the circle of Willis is different in size and symmetry in healthy children compared with adults, likely associated with developmental changes in cerebral perfusion. Further work is needed to understand why asymmetric vasculature develops in some but not all adults. Copyright 2021 by American Society of Neuroradiology.

Funding details
National Institutes of HealthNIHK23NS099472, R01AG057536
McDonnell Center for Systems Neuroscience

Phase transition specified by a binary code patterns the vertebrate eye cup
(2021) Science Advances, 7 (46), art. no. eabj9846, . 

Balasubramanian, R.^a , Min, X.^a , Quinn, P.M.J.^a , Giudice, Q.L.^b , Tao, C.^a , Polanco, K.^c , Makrides, N.^a , Peregrin, J.^a , Bouaziz, M.^a , Mao, Y.^a , Wang, Q.^a , da Costa, B.L.^a , Buenaventura, D.^d , Wang, F.^e , Ma, L.^f , Tsang, S.H.^a g h i , Fabre, P.J.^b , Zhang, X.^a g

^a Department of Ophthalmology, Columbia University, New York, NY, United States
^b Department of Basic Neurosciences, University of Geneva, Geneva, Switzerland
^c Department of Psychology, Columbia University, New York, NY, United States
^d Department of Biology, City College of New York, New York, NY, United States
^e Center for Cancer Biology and Nutrition, Institute of Biosciences and Technology, Texas A&M, Houston, TX, United States
^f Division of Dermatology, Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
^g Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, United States
^h Jonas Children’s Vision Care, Bernard and Shirley Brown Glaucoma Laboratory, Columbia Stem Cell Initiative, Institute of Human Nutrition, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
ⁱ Edward S. Harkness Eye Institute, New York Presbyterian Hospital, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, United States

Abstract
The developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE), and the ciliary margin (CM). By single-cell analysis, we showed that fibroblast growth factor (FGF) signaling regulates the CM in its stem cell-like property of self-renewal, differentiation, and survival, which is balanced by an evolutionarily conserved Wnt signaling gradient. FGF promotes Wnt signaling in the CM by stabilizing β-catenin in a GSK3β-independent manner. While Wnt signaling converts the NR to either the CM or the RPE depending on FGF signaling, FGF transforms the RPE to the NR or CM dependent on Wnt activity. The default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in human retinal organoid. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling. © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

Funding details
R01EY018213, R01EY024698, R01EY026682, R01EY031354, R21AG050437, R24EY027285, R24EY028758, U01 EY030580, U54OD020351
National Institutes of HealthNIH5P30EY019007, EY025933
Knights Templar Eye FoundationKTEF
Research to Prevent BlindnessRPB
Curing Retinal Blindness Foundation
Natural Sciences and Engineering Research Council of CanadaNSERC
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNFPZ00P3_174032
Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorCAPES

Unbiased high-content screening reveals Aβ- And tau-independent synaptotoxic activities in human brain homogenates from Alzheimer’s patients and high-pathology controls
(2021) PLoS ONE, 16 (11 November), art. no. e0259335, . 

Jiang, H.^a , Esparza, T.J.^a b c , Kummer, T.T.^a , Brody, D.L.^a c d

^a Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
^b HenryM Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
^c National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
^d Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, United States

Abstract
Alzheimer’s disease (AD) is tightly correlated with synapse loss in vulnerable brain regions. It is assumed that specific molecular entities such as Aβ and tau cause synapse loss in AD, yet unbiased screens for synaptotoxic activities have not been performed. Here, we performed size exclusion chromatography on soluble human brain homogenates from AD cases, high pathology non-demented controls, and low pathology age-matched controls using our novel high content primary cultured neuron-based screening assay. Both presynaptic and postsynaptic toxicities were elevated in homogenates from AD cases and high pathology non-demented controls to a similar extent, with more modest synaptotoxic activities in homogenates from low pathology normal controls. Surprisingly, synaptotoxic activities were found in size fractions peaking between the 17-44 kDa size standards that did not match well with Aβ and tau immunoreactive species in these homogenates. The fractions containing previously identified high molecular weight soluble amyloid beta aggregates/ “oligomers”were non-toxic in this assay. Furthermore, immunodepletion of Aβ and tau did not reduce synaptotoxic activity. This result contrasts with previous findings involving the same methods applied to 3xTg-AD mouse brain extracts. The nature of the synaptotoxic species has not been identified. Overall, our data indicates one or more potential Aβ and tau independent synaptotoxic activities in human AD brain homogenates. This result aligns well with the key role of synaptic loss in the early cognitive decline and may provide new insight into AD pathophysiology. © 2021 This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders
(2021) Nature Genetics, 53 (11), pp. 1543-1552. 

Eijsbouts, C.^a b , Zheng, T.^c d , Kennedy, N.A.^e , Bonfiglio, F.^c d , Anderson, C.A.^f , Moutsianas, L.^f g , Holliday, J.^h , Shi, J.ⁱ , Shringarpure, S.ⁱ , Agee, M.ⁱ , Aslibekyan, S.ⁱ , Auton, A.ⁱ , Bell, R.K.ⁱ , Bryc, K.ⁱ , Clark, S.K.ⁱ , Elson, S.L.ⁱ , Fletez-Brant, K.ⁱ , Fontanillas, P.ⁱ , Furlotte, N.A.ⁱ , Gandhi, P.M.ⁱ , Heilbron, K.ⁱ , Hicks, B.ⁱ , Hinds, D.A.ⁱ , Huber, K.E.ⁱ , Jewett, E.M.ⁱ , Jiang, Y.ⁱ , Kleinman, A.ⁱ , Lin, K.-H.ⁱ , Litterman, N.K.ⁱ , Luff, M.K.ⁱ , McCreight, J.C.ⁱ , McIntyre, M.H.ⁱ , McManus, K.F.ⁱ , Mountain, J.L.ⁱ , Mozaffari, S.V.ⁱ , Nandakumar, P.ⁱ , Noblin, E.S.ⁱ , Northover, C.A.M.ⁱ , O’Connell, J.ⁱ , Petrakovitz, A.A.ⁱ , Pitts, S.J.ⁱ , Poznik, G.D.ⁱ , Sathirapongsasuti, J.F.ⁱ , Shastri, A.J.ⁱ , Shelton, J.F.ⁱ , Tian, C.ⁱ , Tung, J.Y.ⁱ , Tunney, R.J.ⁱ , Vacic, V.ⁱ , Wang, X.ⁱ , Zare, A.S.ⁱ , Voda, A.-I.^j k , Kashyap, P.^l , Chang, L.^af , Mayer, E.^w , Heitkemper, M.^ag , Sayuk, G.S.^ah , Ringel-Kulka, T.^ai , Ringel, Y.^aj ak , Chey, W.D.^al , Eswaran, S.^al , Merchant, J.L.^am , Shulman, R.J.^an , Bujanda, L.^ao ap aq , Garcia-Etxebarria, K.^ao aq , Dlugosz, A.^ar , Lindberg, G.^ar , Schmidt, P.T.^ar , Karling, P.^as , Ohlsson, B.^at , Walter, S.^au , Faresjö, Å.O.^av , Simren, M.^aw , Halfvarson, J.^ax , Portincasa, P.^ay , Barbara, G.^az , Usai-Satta, P.^ba , Neri, M.^bb , Nardone, G.^bc , Cuomo, R.^bd , Galeazzi, F.^be , Bellini, M.^bf , Latiano, A.^bg , Houghton, L.^bh bi bj , Jonkers, D.^bk , Kurilshikov, A.^u , Weersma, R.K.^bl , Netea, M.^bm , Tesarz, J.^bn , Gauss, A.^bo , Goebel-Stengel, M.^bp bq , Andresen, V.^br , Frieling, T.^bs , Pehl, C.^bt , Schaefert, R.^bu bv , Niesler, B.^bw bx , Lieb, W.^by , Hanevik, K.^bz , Langeland, N.^bz , Wensaas, K.-A.^ca , Litleskare, S.^cb , Gabrielsen, M.E.^cc , Thomas, L.^cd , Thijs, V.^ce , Lemmens, R.^cf , Van Oudenhove, L.^cg , Wouters, M.^cg , Farrugia, G.^l , Franke, A.^m , Hübenthal, M.^m n , Abecasis, G.^o , Zawistowski, M.^o , Skogholt, A.H.^p q , Ness-Jensen, E.^q r s , Hveem, K.^q , Esko, T.^t , Teder-Laving, M.^t , Zhernakova, A.^u , Camilleri, M.^v , Boeckxstaens, G.^w , Whorwell, P.J.^x , Spiller, R.^y , McVean, G.^a , D’Amato, M.^{c d m z aa ab} , Jostins, L.^a j ac , Parkes, M.^ad ae , 23andMe Research Team^ch , The Bellygenes Initiative^ch

^a Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford, United Kingdom
^b Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
^c Center for Molecular Medicine & Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
^d School of Biological Sciences, Monash University, Clayton, VIC, Australia
^e IBD Pharmacogenetics, College of Medicine and Health, University of Exeter, Exeter, United Kingdom
^f Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, United Kingdom
^g William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom
^h Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
ⁱ 23andMe, Inc., Sunnyvale, CA, United States
^j Kennedy Institute of Rheumatology, University of Oxford, Oxford, United Kingdom
^k Saint Edmund Hall, University of Oxford, Oxford, United Kingdom
^l Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
^m Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
ⁿ Department of Dermatology, Quincke Research Center, University Hospital Schleswig-Holstein, Kiel, Germany
^o Department of Biostatistics, University of Michigan, School of Public Health, Ann Arbor, MI, United States
^p Department of Laboratory Medicine, Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway
^q Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway
^r Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway
^s Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
^t Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
^u Department of Genetics, University Medical Center Groningen, Groningen, Netherlands
^v Clinical Enteric Neuroscience Translational and Epidemiological Research and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, United States
^w David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
^x Neurogastroenterology Unit, Wythenshawe Hospital, Centre for Gastrointestinal Sciences, University of Manchester, Manchester, United Kingdom
^y Nottingham Digestive Diseases Centre, National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, United Kingdom
^z Biodonostia Health Research Institute, San Sebastian, Spain
^aa Gastrointestinal Genetics Lab, CIC bioGUNE – Basque Research and Technology Alliance, Derio, Spain
^ab IKERBASQUE, The Basque Science Foundation, Bilbao, Spain
^ac Christ Church, University of Oxford, Oxford, United Kingdom
^ad Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge, United Kingdom
^ae Department of Gastroenterology, Cambridge University Hospital, Cambridge, United Kingdom
^af Division of Digestive Diseases/Gastroenterology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, United States
^ag Department of Biobehavioral Nursing and Health Informatics, University of Washington, Seattle, WA, United States
^ah Division of Gastroenterology, Washington University School of Medicine, St. Louis, MO, United States
^ai Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^aj Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^ak Division of Gastroenterology and Hepatology, Meir Medical Center, affiliated to Tel-Aviv University, Kfar Saba, Israel
^al Division of Gastroenterology, Michigan Medicine, Ann Arbor, MI, United States
^am Division of Gastroenterology, University of Arizona College of Medicine, Tucson, AZ, United States
^an Children’s Nutrition Research Center, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, United States
^ao Universidad del País Vasco, San Sebastian, Spain
^ap Department of Gastrointestinal and Liver Diseases, Biodonostia Health Research Institute, Sebastian, Spain
^aq Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto Carlos III, Madrid, Spain
^ar Department of Medicine Solna, Karolinska Institutet, Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
^as Division of Medicine, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
^at Department of Internal Medicine, Lund University, Skåne University Hospital, Lund, Sweden
^au Division of Neuro and Inflammation Science, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
^av Department of Health, Medicine and Caring Science/Society and Health/Public health, Linköpings University, Linköping, Sweden
^aw Department of Internal Medicine & Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
^ax Department of Gastroenterology, School of Medical Sciences, Örebro University, Örebro, Sweden
^ay Department of Biomedical Sciences and Human Oncology, Clinica Medica ‘A. Murri’, University of Bari Medical School, Bari, Italy
^az Department of Medical and Surgical Sciences, University of Bologna, St. Orsola – Malpighi Hospital, Bologna, Italy
^ba S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy
^bb Department of Medicine and Aging Sciences and CESI, G. D’Annunzio University & Foundation, Chieti, Italy
^bc Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy
^bd Gastroenterology Unit, Department of Medical Science, ‘Sant’Anna e San Sebastiano’ Hospital, Caserta, Italy
^be Unità Operativa Complessa Gastroenterologia, Padova University Hospital, Padova, Italy
^bf Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy
^bg Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico ‘Casa Sollievo della Sofferenza’ Hospital, San Giovanni Rotondo, Italy
^bh Division of Gastroenterology and Surgical Sciences, Leeds Institute of Medical Research at St. James’s, University of Leeds, Leeds, United Kingdom
^bi Department of Gastroenterology, Mayo Clinic, Jacksonville, FL, United States
^bj GI Sciences, Division of Diabetes, Endocrinology & Gastroenterology, University of Manchester, Manchester, United Kingdom
^bk Department of Internal Medicine, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, Netherlands
^bl Department of Gastroenterology and Hepatology, University Medical Center Groningen, Groningen, Netherlands
^bm Department of Internal Medicine and Radboud Center of Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands
^bn Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Heidelberg, Germany
^bo Department of Gastroenterology, Infectious Diseases and Intoxications, University of Heidelberg, Heidelberg, Germany
^bp Department of Psychosomatic Medicine, University Hospital Tübingen, Tübingen, Germany
^bq Department of Internal Medicine and Gastroenterology, HELIOS Clinic Rottweil, Rottweil, Germany
^br Israelitisches Krankenhaus, Hamburg, Germany
^bs Helios Klinik Krefeld, Krefeld, Germany
^bt Krankenhaus Vilsbiburg, Vilsbiburg, Germany
^bu Department of Psychosomatic Medicine, Division of Internal Medicine, University Hospital Basel, Basel, Switzerland
^bv Faculty of Medicine, University of Basel, Basel, Switzerland
^bw Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany
^bx Interdisciplinary Center for Neurosciences, Heidelberg University, Heidelberg, Germany
^by Institute of Epidemiology, Christian-Albrechts-University Kiel, Kiel, Germany
^bz Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway
^ca Research Unit for General Practice, NORCE Norwegian Research Centre, Bergen, Norway
^cb Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
^cc KG Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
^cd KG Jebsen Center for Genetic Epidemiology, Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
^ce Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
^cf Department of Neurosciences, Katholieke Universiteit Leuven, Leuven, Belgium
^cg Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium

Abstract
Irritable bowel syndrome (IBS) results from disordered brain–gut interactions. Identifying susceptibility genes could highlight the underlying pathophysiological mechanisms. We designed a digestive health questionnaire for UK Biobank and combined identified cases with IBS with independent cohorts. We conducted a genome-wide association study with 53,400 cases and 433,201 controls and replicated significant associations in a 23andMe panel (205,252 cases and 1,384,055 controls). Our study identified and confirmed six genetic susceptibility loci for IBS. Implicated genes included NCAM1, CADM2, PHF2/FAM120A, DOCK9, CKAP2/TPTE2P3 and BAG6. The first four are associated with mood and anxiety disorders, expressed in the nervous system, or both. Mirroring this, we also found strong genome-wide correlation between the risk of IBS and anxiety, neuroticism and depression (rg > 0.5). Additional analyses suggested this arises due to shared pathogenic pathways rather than, for example, anxiety causing abdominal symptoms. Implicated mechanisms require further exploration to help understand the altered brain–gut interactions underlying IBS. © 2021, The Author(s).

Funding details
EXC2167
2018-27
National Institutes of HealthNIH115950, R01 DK 92179
National Institute of Mental HealthNIMH
National Institute on Drug AbuseNIDA
National Human Genome Research InstituteNHGRI
National Cancer InstituteNCI
National Institute of Neurological Disorders and StrokeNINDS
Li Ka Shing FoundationLKSF
Wellcome TrustWT093885/Z/10/Z, 098051, 100956/Z/13/Z, 203141/Z/16/Z, 215097/Z/18/Z, 280750/Z/17
FP7 Ideas: European Research CouncilIDEAS-ERC; de:IDEEN-EFR; es:IDEAS-CEI; fr:IDÉES-CER; it:IDEE-CER; pl:POMYSŁY-ERBN715772
Nottingham University Hospitals NHS Trust
Kennedy Trust for Rheumatology ResearchKTRR
Economic and Social Research CouncilESRC
National Institute for Health ResearchNIHRBRC-1215-20003
University of CambridgeBRC-1215-20014
Oxford UniversityBRC-1215-20008
University of ManchesterBRC-1215-20007
European Research CouncilERC
University of Nottingham
National Heart and Lung InstituteNHLI
Eusko Jaurlaritza2015111133
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
Ministerio de Economía y CompetitividadMINECO
VetenskapsrådetVR2017-02403
Instituto de Salud Carlos IIIISCIIIFIS PI17/00308
Seventh Framework ProgrammeFP7313010

Estradiol protects against noise-induced hearing loss and modulates auditory physiology in female mice
(2021) International Journal of Molecular Sciences, 22 (22), art. no. 12208, . 

Shuster, B.^a , Casserly, R.^a , Lipford, E.^a , Olszewski, R.^b , Milon, B.^a , Viechweg, S.^c , Davidson, K.^c , Enoch, J.^c , McMurray, M.^a , Rutherford, M.A.^d , Ohlemiller, K.K.^d , Hoa, M.^b , Depireux, D.A.^e , Mong, J.A.^c , Hertzano, R.^a f g

^a Department of Otorhinolaryngology—Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD 21201, United States
^b Auditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, MD 20892, United States
^c Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD 21201, United States
^d Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Otolith Labs, Washington, DC 20036, United States
^f Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, United States
^g Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, United States

Abstract
Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17β-estradiol (E2 ), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)-and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Auditory physiology;  Cochlear synaptopa-thy;  Estrogen;  Inner ear;  Mouse model;  Noise-induced hearing loss;  Sex-differences

Funding details
National Institutes of HealthNIHR01DC013817
U.S. Department of DefenseDODMR130240, W81XWH2110578
National Institute on Deafness and Other Communication DisordersNIDCDR01DC014712, Z01DC000088
School of Medicine, University of MarylandSOM, UMD

Resting-State Functional Magnetic Resonance Imaging Networks as a Quantitative Metric for Impact of Neurosurgical Interventions
(2021) Frontiers in Neuroscience, 15, art. no. 665016, . 

Yang, P.H.^a , Hacker, C.D.^a , Patel, B.^a , Daniel, A.G.S.^b , Leuthardt, E.C.^{a b c d e}

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^d Center for Innovation in Neuroscience and Technology, Washington University School of Medicine, St. Louis, MO, United States
^e Brain Laser Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Resting-state functional MRI (rs-fMRI) has been used to evaluate brain network connectivity as a result of intracranial surgery but has not been used to compare different neurosurgical procedures. Laser interstitial thermal therapy (LITT) is an alternative to conventional craniotomy for the treatment of brain lesions such as tumors and epileptogenic foci. While LITT is thought of as minimally invasive, its effect on the functional organization of the brain is still under active investigation and its impact on network changes compared to conventional craniotomy has not yet been explored. We describe a novel computational method for quantifying and comparing the impact of two neurosurgical procedures on brain functional connectivity. Methods: We used a previously described seed-based correlation analysis to generate resting-state network (RSN) correlation matrices, and compared changes in correlation patterns within and across RSNs between LITT and conventional craniotomy for treatment of 24 patients with singular intracranial tumors at our institution between 2014 and 2017. Specifically, we analyzed the differences in patient-specific changes in the within-hemisphere correlation patterns of the contralesional hemisphere. Results: In a post-operative follow-up period up to 2 years within-hemisphere connectivity of the contralesional hemisphere after surgery was more highly correlated to the pre-operative state in LITT patients when compared to craniotomy patients (P = 0.0287). Moreover, 4 out of 11 individual RSNs demonstrated significantly higher degrees of correlation between pre-operative and post-operative network connectivity in patients who underwent LITT (all P < 0.05). Conclusion: Rs-fMRI may be used as a quantitative metric to determine the impact of different neurosurgical procedures on brain functional connectivity. Global and individual network connectivity in the contralesional hemisphere may be more highly preserved after LITT when compared to craniotomy for the treatment of brain tumors. Copyright © 2021 Yang, Hacker, Patel, Daniel and Leuthardt.

Author Keywords
brain neoplasms/diagnostic imaging;  brain neoplasms/surgery;  functional neuroimaging;  humans;  laser therapy;  magnetic resonance imaging

Funding details
National Institutes of HealthNIH
Center for Information TechnologyCIT
Center for Scientific ReviewCSR
Office of Extramural Research, National Institutes of HealthOER
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIPR25NS090978

Endocannabinoid System Unlocks the Puzzle of Autism Treatment via Microglia
(2021) Frontiers in Psychiatry, 12, art. no. 734837, . 

Su, T.^a , Yan, Y.^b , Li, Q.^c , Ye, J.^d , Pei, L.^e f g

^a Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
^b Department of Neurology, People’s Hospital of Dongxihu District, Wuhan, China
^c Development and Service Center for Science and Technology Talents, The Ministry of Science and Technology, Beijing, China
^d Department of Radiation Oncology, Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
^e Collaborative Innovation Center for Brain Science, The Institute for Brain Research, Huazhong University of Science and Technology, Wuhan, China
^f Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
^g Department of Anesthesiology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States

Abstract
Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of social reward behavior, which has attracted considerable attention from neuroscientists and neurologists. Both animal models and clinical studies have shown that the ECS is a potential target for the treatment of autism, but the mechanism is still unknown. In the brain, microglia express a complete ECS signaling system. Studies also have shown that modulating ECS signaling can regulate the functions of microglia. By comprehensively reviewing previous studies and combining with our recent work, this review addresses the effects of targeting ECS on microglia, and how this can contribute to maintain the positivity of the central nervous system, and thus improve the symptoms of autism. This will provide insights for revealing the mechanism and developing new treatment strategies for autism. Copyright © 2021 Su, Yan, Li, Ye and Pei.

Author Keywords
autism spectrum disorder;  endocannabinoid system;  immune;  microglia;  neurodevelopmental disorders

Funding details
University of Birmingham
National Natural Science Foundation of ChinaNSFC81804188, 81870932

Specific RNA interactions promote TDP-43 multivalent phase separation and maintain liquid properties
(2021) EMBO Reports, . 

Grese, Z.R.^a , Bastos, A.C.S.^a , Mamede, L.D.^a , French, R.L.^a , Miller, T.M.^b , Ayala, Y.M.^a

^a Edward Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
TDP-43 is an RNA-binding protein that forms ribonucleoprotein condensates via liquid-liquid phase separation (LLPS) and regulates gene expression through specific RNA interactions. Loss of TDP-43 protein homeostasis and dysfunction are tied to neurodegenerative disorders, mainly amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Alterations of TDP-43 LLPS properties may be linked to protein aggregation. However, the mechanisms regulating TDP-43 LLPS are ill-defined, particularly how TDP-43 association with specific RNA targets regulates TDP-43 condensation remains unclear. We show that RNA binding strongly promotes TDP-43 LLPS through sequence-specific interactions. RNA-driven condensation increases with the number of adjacent TDP-43-binding sites and is also mediated by multivalent interactions involving the amino and carboxy-terminal TDP-43 domains. The physiological relevance of RNA-driven TDP-43 condensation is supported by similar observations in mammalian cellular lysate. Importantly, we find that TDP-43-RNA association maintains liquid-like properties of the condensates, which are disrupted in the presence of ALS-linked TDP-43 mutations. Altogether, RNA binding plays a central role in modulating TDP-43 condensation while maintaining protein solubility, and defects in this RNA-mediated activity may underpin TDP-43-associated pathogenesis. © 2021 The Authors

Author Keywords
amyotrophic lateral sclerosis;  liquid-liquid phase separation;  ribonucleoprotein (RNP) granules;  RNA-binding protein;  TDP-43

Funding details
R01 NS078398, W81XWH‐20‐1‐0241
R01 NS114289, R56 NS105806
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Institute of Neurological Disorders and StrokeNINDS

Prior histories of posttraumatic stress disorder and major depression and their onset and course in the three months after a motor vehicle collision in the AURORA study
(2021) Depression and Anxiety, . 

Joormann, J.^a , Ziobrowski, H.N.^b , King, A.J.^b , Gildea, S.M.^b , Lee, S.^b , Sampson, N.A.^b , House, S.L.^c , Beaudoin, F.L.^d e f g , An, X.^h , Stevens, J.S.ⁱ , Zeng, D.^j , Neylan, T.C.^k l , Clifford, G.D.^m n , Linnstaedt, S.D.^h , Germine, L.T.^o p q , Bollen, K.A.^r s t , Rauch, S.L.^p r u , Haran, J.P.^v , Storrow, A.B.^w , Musey, P.I., Jr.^x , Hendry, P.L.^y , Sheikh, S.^y , Jones, C.W.^z , Punches, B.E.^aa ab , McGrath, M.E.^ac , Hudak, L.A.^ad , Pascual, J.L.^ae af ag , Seamon, M.J.^ag ah , Chang, A.M.^ai , Pearson, C.^aj , Peak, D.A.^ak , Domeier, R.M.^al , Rathlev, N.K.^am , O’Neil, B.J.^aj , Sanchez, L.D.^an ao , Bruce, S.E.^ap , Miller, M.W.^aq ar , Pietrzak, R.H.^as at , Barch, D.M.^au , Pizzagalli, D.A.^r av , Harte, S.E.^aw ax , Elliott, J.M.^{ay az ba bb} , Koenen, K.C.^bc , McLean, S.A.^h bd , Kessler, R.C.^b

^a Department of Psychology, Yale University, New Haven, CT, United States
^b Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^c Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Emergency Medicine, The Alpert Medical School of Brown University, Providence, RI, United States
^e Department of Health Services, Policy, and Practice, The Alpert Medical School of Brown University, Providence, RI, United States
^f Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, United States
^g Department of Emergency Medicine, The Miriam Hospital, Providence, RI, United States
^h Department of Anesthesiology, Institute for Trauma Recovery, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
ⁱ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
^j Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, United States
^k Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States
^l Department of Neurology, University of California San Francisco, San Francisco, CA, United States
^m Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
ⁿ Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
^o Department of Biomedical Engineering, Emory University, Atlanta, GA, United States
^p Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
^q The Many Brains Project, Inc., Belmont, MA, United States
^r Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^s Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^t Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^u Department of Psychiatry, McLean Hospital, Belmont, MA, United States
^v Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, United States
^w Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^x Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^y Department of Emergency Medicine, University of Florida College of Medicine – Jacksonville, Jacksonville, FL, United States
^z Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
^aa Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^ab College of Nursing, University of Cincinnati, Cincinnati, OH, United States
^ac Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
^ad Department of Emergency Medicine, Emory University School of Medicine, Atlanta, GA, United States
^ae Department of Surgery, University of Pennsylvania, Philadelphia, PA, United States
^af Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States
^ag Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ah Department of Surgery, Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, United States
^ai Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, United States
^aj Department of Emergency Medicine, Wayne State University, Detroit, MA, United States
^ak Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^al Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ypsilanti, MI, United States
^am Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
^an Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^ao Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^ap Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO, United States
^aq Behavioral Science Division, National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States
^ar Department of Psychiatry, Boston University School of Medicine, Boston, MA, United States
^as Clinical Neurosciences Division, National Center for PTSD, VA Connecticut Healthcare System, West Haven, CT, United States
^at Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^au Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^av Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
^aw Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^ax Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
^ay Kolling Institute of Medical Research, University of Sydney, Sydney, NSW, Australia
^az Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
^ba Allied Health Network, Northern Sydney Local Health District, Sydney, NSW, Australia
^bb Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^bc Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, United States
^bd Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Background: A better understanding of the extent to which prior occurrences of posttraumatic stress disorder (PTSD) and major depressive episode (MDE) predict psychopathological reactions to subsequent traumas might be useful in targeting posttraumatic preventive interventions. Methods: Data come from 1306 patients presenting to 29 U.S. emergency departments (EDs) after a motor vehicle collision (MVC) in the advancing understanding of recovery after trauma study. Patients completed self-reports in the ED and 2-weeks, 8-weeks, and 3-months post-MVC. Associations of pre-MVC probable PTSD and probable MDE histories with subsequent 3-months post-MVC probable PTSD and probable MDE were examined along with mediation through intervening peritraumatic, 2-, and 8-week disorders. Results: 27.6% of patients had 3-month post-MVC probable PTSD and/or MDE. Pre-MVC lifetime histories of these disorders were not only significant (relative risk = 2.6–7.4) but were dominant (63.1% population attributable risk proportion [PARP]) predictors of this 3-month outcome, with 46.6% prevalence of the outcome among patients with pre-MVC disorder histories versus 9.9% among those without such histories. The associations of pre-MVC lifetime disorders with the 3-month outcome were mediated largely by 2- and 8-week probable PTSD and MDE (PARP decreasing to 22.8% with controls for these intervening disorders). Decomposition showed that pre-MVC lifetime histories predicted both onset and persistence of these intervening disorders as well as the higher conditional prevalence of the 3-month outcome in the presence of these intervening disorders. Conclusions: Assessments of pre-MVC PTSD and MDE histories and follow-ups at 2 and 8 weeks could help target early interventions for psychopathological reactions to MVCs. © 2021 Wiley Periodicals LLC

Author Keywords
major depression;  motor vehicle collision;  posttraumatic stress disorder;  trauma

Funding details
National Science FoundationNSF
National Institutes of HealthNIH
National Institute of Mental HealthNIMHU01MH110925
Medical Research and Materiel CommandMRMC
Bill and Melinda Gates FoundationBMGF
Gordon and Betty Moore FoundationGBMF
Boehringer IngelheimBI
Eli Lilly and Company
AstraZeneca
Microsoft ResearchMSR
Google
Takeda Pharmaceutical CompanyTPC
Janssen Pharmaceuticals
MathWorks
Hologic

Evaluation of 2D FLAIR hyperintensity of the optic nerve and optic nerve head and visual parameters in idiopathic intracranial hypertension
(2021) Journal of Neuroradiology, . 

Orlowski, H.^a , Sharma, A.^a , Alvi, F.^b , Arora, J.^c , Parsons, M.S.^a , Van Stavern, G.P.^d

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd. St. LouisMO, United States
^b Washington University School of Medicine, 660 S. Euclid Ave. St. LouisMO, United States
^c Division of Biostatistics, Washington University School of Medicine, 660 S. Euclid Ave, CB, St. Louis, MO 8067, United States
^d Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 517 S. Euclid Ave, St. Louis, MO, United States

Abstract
Background and purpose: T2/FLAIR hyperintensity of the optic nerve/optic nerve head has been described as a sensitive finding in idiopathic intracranial hypertension using post-contrast 3D-T2/FLAIR imaging. The purpose of this study is to assess whether hyperintensity on non-enhanced 2D-T2/FLAIR imaging occurs more likely in diseased patients than controls and to evaluate the relationship between FLAIR signal and visual parameters Materials and methods: A retrospective case-control study was performed of patients with idiopathic intracranial hypertension and controls who underwent orbital MRI. Three neuroradiologists reviewed the FLAIR images, subjectively evaluating for hyperintense signal within the optic nerves/optic nerve heads using a 5-point Likert Scale. Quantitative assessment of optic nerve signal using regions of interests was performed. Clinical parameters were extracted. The diagnostic performance was evaluated, and Spearman correlation calculated to assess the relationship between FLAIR signal and visual outcomes. Results: The sensitivity of abnormal FLAIR signal within the optic nerves and optic nerve heads in patients with idiopathic intracranial hypertension ranged from 25–54% and 4–29%, respectively, with specificities ranging from 67–92% and 83–100%. Quantitative assessment revealed a significant difference in CNR between cases and controls in the left posterior optic nerve (p=.002). A positive linear relationship existed between abnormal optic nerve head signal and papilledema grade (OD: p=.02, OS: p=.008) but not with other visual parameters. Conclusion: T2/FLAIR hyperintensity in the optic nerve/optic nerve head may support the diagnosis of idiopathic intracranial hypertension but its absence should not dissuade it. If present, abnormal signal in the optic nerve head correlates with papilledema. © 2021 Elsevier Masson SAS

Author Keywords
FLAIR imaging;  Idiopathic intracranial hypertension;  Magnetic resonance imaging;  Orbits;  Papilledema

Residential distance from the reporting hospital and survival among adolescents, and young adults diagnosed with CNS tumors
(2021) Journal of Neuro-Oncology, . 

Johnson, K.J.^a , Wang, X.^a , Barnes, J.M.^b , Delavar, A.^c

^a Brown School, Washington University in St. Louis, One Brookings Drive, Campus Box 1196, St. Louis, MO 63130, United States
^b Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^c University of California San Diego School of Medicine, La Jolla, CA 92093, United States

Abstract
Purpose: Prior research shows that residential distance to a treatment facility may be an important factor in central nervous system (CNS) tumor outcomes. Our goal was to examine residential distance to the reporting hospital and overall survival in adolescents and young adults (AYA) diagnosed with CNS tumors. Methods: National Cancer Database data on AYA 15–39 years old diagnosed with CNS and Other Intracranial and Intraspinal Neoplasms (CNS tumors) from 2010 to 2014 were obtained. Distance between the case’s residence at diagnosis or initial treatment and the reporting hospital was classified in miles as short (≤ 12.5), intermediate (> 12.5 and < 50), and long (≥ 50). Cox proportional hazards regression models were used for analyses. Results: Among 9335 AYA diagnosed with CNS tumors, hazard ratios (HRs) were 1.06 (95% CI 0.96–1.17) and 0.82 (95% CI 0.73–0.93) for those with residences at intermediate and long vs. short distances, respectively, after adjusting for age, sex, race/ethnicity, and zip-code level education and income. After adjusting for the facility volume of CNS tumor patients, the association was attenuated for long vs. short distance residences (HR 0.92, 95% CI 0.81–1.04). The HRs varied by tumor type, race/ethnicity, and zip-code level income with significantly lower hazards of death for those with residences at long vs. short distances for low-grade astrocytic tumors, ependymomas, non-Hispanic Whites, and those from higher-income areas. Conclusions: Living at long distances for CNS tumor care may be associated with better survival in AYA patients. This may be explained by travel to facilities with more experience treating CNS tumors. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Adolescents and young adults;  CNS tumors;  Survival;  Travel distance

Funding details
University of WashingtonUW

Solvent exposed occupations and risk of Parkinson disease in Finland
(2021) Clinical Parkinsonism and Related Disorders, 4, art. no. 100092, . 

Nielsen, S.S.^a , Warden, M.N.^a , Sallmén, M.^b , Sainio, M.^b , Uuksulainen, S.^b , Checkoway, H.^c d , Hublin, C.^b , Racette, B.A.^a e

^a Washington University School of Medicine in St. Louis, Department of Neurology, 660 S. Euclid Avenue, St. Louis, MO 63110, United States
^b Finnish Institute of Occupational Health, PO Box 18, FI-00032 Tyoterveyslaitos, Arinatie 3 A, Helsinki, 00370, Finland
^c University of California, San Diego, Herbert Wertheim School of Public Health, 9500 Gilman Drive, La Jolla, CA 92093, United States
^d University of California, San Diego, Department of Neurosciences, 9500 Gilman Drive, La Jolla, CA 92093, United States
^e University of the Witwatersrand, School of Public Health, Faculty of Health Sciences, 27 St. Andrews Road, Parktown, Johannesburg 2193, South Africa

Abstract
Introduction: Epidemiologic and toxicology studies suggest that exposure to various solvents, especially chlorinated hydrocarbon solvents, might increase Parkinson disease (PD) risk. Methods: In a population-based case-control study in Finland, we examined whether occupations with potential for solvent exposures were associated with PD. We identified newly diagnosed cases age 45–84 from a nationwide medication reimbursement register in 1995–2014. From the population register, we randomly selected non-PD controls matched on sex, along with birth and diagnosis years (age). We included 11,757 cases and 23,236 controls with an occupation in the 1990 census, corresponding to age 40–60. We focused on 28 occupations with ≥ 5% probability of solvent exposure according to the Finnish Job Exposure Matrix. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression modeling, adjusting for age, sex, socioeconomic status, and smoking probability. Results: Similar proportions of cases (5.5%) and controls (5.6%) had an occupation with potential exposure to any solvents. However, all occupations with a point estimate above one, and all significantly or marginally significantly associated with PD (electronic/telecommunications worker [OR = 1.63, 95% CI 1.05–2.50], laboratory assistant [OR = 1.40, 95% CI 0.98–1.99], and machine/engine mechanic [OR = 1.23, 95% CI 0.99–1.52]) entailed potential for exposure to chlorinated hydrocarbon solvents, specifically. Secondary analyses indicated exposure to polycyclic aromatic hydrocarbons and some metals might contribute to the association for mechanics. Conclusion: PD risk might be slightly increased in occupations with potential exposure to chlorinated hydrocarbon solvents. Confirmation is required in additional studies that adjust for other occupational exposures and smoking. © 2021 The Author(s)

Author Keywords
1,1,1-trichloroethane;  Methylene chloride;  Parkinson disease;  Solvents;  Trichloroethylene

Independently validated sex-specific nomograms for predicting survival in patients with newly diagnosed glioblastoma: NRG Oncology RTOG 0525 and 0825
(2021) Journal of Neuro-Oncology, . 

Patil, N.^a , Somasundaram, E.^b , Waite, K.A.^c , Lathia, J.D.^d e , Machtay, M.^f , Gilbert, M.R.^g , Connor, J.R.^f , Rubin, J.B.^h , Berens, M.E.ⁱ , Buerki, R.A.^a , Choi, S.^a , Sloan, A.E.^a b e , Penas-Prado, M.^j , Ashby, L.S.^k , Blumenthal, D.T.^l , Werner-Wasik, M.^m , Hunter, G.K.ⁿ , Flickinger, J.C.^o , Wendland, M.M.^p , Panet-Raymond, V.^q , Robins, H.I.^r , Pugh, S.L.^s , Mehta, M.P.^t , Barnholtz-Sloan, J.S.^a b c u

^a University Hospitals, Cleveland, OH, United States
^b Case Western Reserve University School of Medicine, Cleveland, OH, United States
^c Division of Cancer Epidemiology and Genetics (DCEG), Trans-Divisional Research Program (TDRP) National Cancer Institute (NCI) National Institutes of Health (NIH), Shady Grove, MD, United States
^d Cleveland Clinic Foundation, Cleveland, OH, United States
^e Case Comprehensive Cancer Center, Cleveland, OH, United States
^f Penn State Milton S Hershey Medical Center, Hershey, PA, United States
^g National Cancer Institute, Neuro-Oncology Branch, Bethesda, MD, United States
^h Washington University of St Louis, St. Louis, MO, United States
ⁱ TGen, Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, AZ, United States
^j National Cancer Institute, Neuro-Oncology Branch; Accruals for University of Texas-MD Anderson Cancer Center (Houston, TX, USA), Bethesda, MD, United States
^k Barrow Neurology Clinics Accruals for Arizona Oncology Services Foundation, Phoenix, AZ, United States
^l Tel-Aviv Medical Center, Tel-Aviv University, Tel Aviv-Yafo, Israel
^m Thomas Jefferson University Hospital, Philadelphia, PA, United States
ⁿ Intermountain Medical Center, Salt Lake City, UT, United States
^o UPMC-Shadyside Hospital, Pittsburgh, PA, United States
^p USON- Willamette Valley Cancer Center, Eugene, OR, United States
^q McGill University Health Center, Montreal, QC, Canada
^r University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^s NRG Oncology Statistics and Data Management Center, American College of Radiology, Philadelphia, PA, United States
^t Miami Cancer Institute, Miami, FL, United States
^u Center for Biomedical Informatics and Information Technology (CBITT), National Cancer Institute (NCI)/National Institutes of Health (NIH), Shady Grove, MD, United States

Abstract
Background/purpose: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. Methods: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. Results: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. Conclusions: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here—https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Author Keywords
Glioblastoma;  Nomogram;  Sex differences;  Survival

Funding details
National Cancer InstituteNCI
Genentech5P30CA043703-30S1
Merck

Treatment of Neonatal Seizures: Comparison of Treatment Pathways From 11 Neonatal Intensive Care Units
(2021) Pediatric Neurology, . 

Keene, J.C.^a , Morgan, L.A.^a , Abend, N.S.^b , Bates, S.V.^c , Bauer Huang, S.L.^d , Chang, T.^e , Chu, C.J.^f , Glass, H.C.^g h , Massey, S.L.^b , Ostrander, B.ⁱ , Pardo, A.C.^j , Press, C.A.^k , Soul, J.S.^l , Shellhaas, R.A.^m , Thomas, C.^n o , Natarajan, N.^a

^a Division of Pediatric Neurology, Departments of Neurology and Pediatrics, University of Washington, Seattle Children’s Hospital, Seattle, WA, United States
^b Division of Neurology, Departments of Neurology and Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
^c Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^d Division of Pediatric & Developmental Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Neurology, Children’s National Hospital, George Washington University, Washington, DC, United States
^f Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^g Department of Neurology and Weill Institute for Neuroscience, University of California, San Francisco, San Francisco, CA, United States
^h Department of Pediatrics, UCSF Benioff Children’s Hospital, San Francisco, San Francisco, CA, United States
ⁱ Division of Pediatric Neurology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
^j Ann & Robert H. Lurie Children’s Hospital, Department of Pediatrics, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
^k Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States
^l Department of Neurology, Harvard Medical School and Boston Children’s Hospital, Boston, MA, United States
^m Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, United States
ⁿ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
^o Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States

Abstract
Objective: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability. Methods: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose. Results: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing. Conclusions: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation. © 2021 Elsevier Inc.

Author Keywords
Antiseizure medication;  Fosphenytoin;  Guideline;  Levetiracetam;  Neonatal critical care;  Neonatal seizures;  Phenobarbital;  Protocol

Funding details
National Institutes of HealthNIH
Patient-Centered Outcomes Research InstitutePCORI
Pediatric Epilepsy Research FoundationPERF
Renewable Energy Research Center, University of DhakaRERC