WashU weekly Neuroscience publications

The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease
(2020) Current Opinion in Neurobiology, 63, pp. 59-66. 

Figley, M.D.^a , DiAntonio, A.^{a b}

^a Department of Developmental Biology, Washington University School of Medicine in St. Louis, 660 Euclid Avenue, St. Louis, MO 63110, United States
^b Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Axons are essential for nervous system function and axonal pathology is a common hallmark of many neurodegenerative diseases. Over a century and a half after the original description of Wallerian axon degeneration, advances over the past five years have heralded the emergence of a comprehensive, mechanistic model of an endogenous axon degenerative process that can be activated by both injury and disease. Axonal integrity is maintained by the opposing actions of the survival factors NMNAT2 and STMN2 and pro-degenerative molecules DLK and SARM1. The balance between axon survival and self-destruction is intimately tied to axonal NAD+ metabolism. These mechanistic insights may enable axon-protective therapies for a variety of human neurodegenerative diseases including peripheral neuropathy, traumatic brain injury and potentially ALS and Parkinson’s. © 2020 Elsevier Ltd

Document Type: Review
Publication Stage: Final
Source: Scopus

Portable, field-based neuroimaging using high-density diffuse optical tomography
(2020) NeuroImage, 215, art. no. 116541, . 

Fishell, A.K.^{a b} , Arbeláez, A.M.^c , Valdés, C.P.^d , Burns-Yocum, T.M.^e , Sherafati, A.^{a f} , Richter, E.J.^g , Torres, M.^d , Eggebrecht, A.T.^{b c} , Smyser, C.D.^{b c h} , Culver, J.P.^{a b f i}

^a Washington University School of Medicine, Division of Biology and Biomedical Sciences, St. Louis, MO, United States
^b Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO, United States
^c Washington University School of Medicine, Department of Pediatrics, St. Louis, MO, United States
^d Centro Médico Imbanaco, Cali, Valle del Cauca, Colombia
^e Indiana University, Department of Psychological and Brain Sciences, Bloomington, IN, United States
^f Washington University, Department of Physics, St. Louis, MO, United States
^g Washington University, Electrical and Systems Engineering, St. Louis, MO, United States
^h Washington University School of Medicine, Department of Neurology, St. Louis, MO, United States
ⁱ Washington University, Department of Biomedical Engineering, St. Louis, MO, United States

Abstract
Behavioral and cognitive tests in individuals who were malnourished as children have revealed malnutrition-related deficits that persist throughout the lifespan. These findings have motivated recent neuroimaging investigations that use highly portable functional near-infrared spectroscopy (fNIRS) instruments to meet the demands of brain imaging experiments in low-resource environments and enable longitudinal investigations of brain function in the context of long-term malnutrition. However, recent studies in healthy subjects have demonstrated that high-density diffuse optical tomography (HD-DOT) can significantly improve image quality over that obtained with sparse fNIRS imaging arrays. In studies of both task activations and resting state functional connectivity, HD-DOT is beginning to approach the data quality of fMRI for superficial cortical regions. In this work, we developed a customized HD-DOT system for use in malnutrition studies in Cali, Colombia. Our results evaluate the performance of the HD-DOT instrument for assessing brain function in a cohort of malnourished children. In addition to demonstrating portability and wearability, we show the HD-DOT instrument’s sensitivity to distributed brain responses using a sensory processing task and measurements of homotopic functional connectivity. Task-evoked responses to the passive word listening task produce activations localized to bilateral superior temporal gyrus, replicating previously published work using this paradigm. Evaluating this localization performance across sparse and dense reconstruction schemes indicates that greater localization consistency is associated with a dense array of overlapping optical measurements. These results provide a foundation for additional avenues of investigation, including identifying and characterizing a child’s individual malnutrition burden and eventually contributing to intervention development. © 2020

Author Keywords
Functional connectivity;  Functional near-infrared spectroscopy;  High-density diffuse optical tomography;  Malnutrition;  Optical neuroimaging;  Portable neuroimaging;  Task-evoked responses

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Sex differences associated with corpus callosum development in human infants: A longitudinal multimodal imaging study
(2020) NeuroImage, 215, art. no. 116821, . 

Schmied, A.^a , Soda, T.^b , Gerig, G.^c , Styner, M.^b , Swanson, M.R.^d , Elison, J.T.^e , Shen, M.D.^b , McKinstry, R.C.^f , Pruett, J.R., Jr.^g , Botteron, K.N.^g , Estes, A.M.^h , Dager, S.R.ⁱ , Hazlett, H.C.^b , Schultz, R.T.^j , Piven, J.^b , Wolff, J.J.^a , IBIS Network^k

^a Department of Educational Psychology, University of Minnesota, Minneapolis, MN, United States
^b Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States
^c Department of Computer Science & Engineering, New York University, New York City, NY, United States
^d School of Behavioral & Brain Sciences, University of Texas at Dallas, Richardson, TX, United States
^e Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
^f Mallinckrodt Institute of Radiology, 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 Department of Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
ⁱ Department of Radiology, University of Washington, Seattle, WA, United States
^j Department of Pediatrics, University of Pennsylvania, Philadelphia, PA, United States

Abstract
The corpus callosum (CC) is the largest connective pathway in the human brain, linking cerebral hemispheres. There is longstanding debate in the scientific literature whether sex differences are evident in this structure, with many studies indicating the structure is larger in females. However, there are few data pertaining to this issue in infancy, during which time the most rapid developmental changes to the CC occur. In this study, we examined longitudinal brain imaging data collected from 104 infants at ages 6, 12, and 24 months. We identified sex differences in brain-size adjusted CC area and thickness characterized by a steeper rate of growth in males versus females from ages 6–24 months. In contrast to studies of older children and adults, CC size was larger for male compared to female infants. Based on diffusion tensor imaging data, we found that CC thickness is significantly associated with underlying microstructural organization. However, we observed no sex differences in the association between microstructure and thickness, suggesting that the role of factors such as axon density and/or myelination in determining CC size is generally equivalent between sexes. Finally, we found that CC length was negatively associated with nonverbal ability among females. © 2020 The Authors

Author Keywords
Brain imaging;  Corpus callosum;  Development;  Infants;  Sexual dimorphism

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Towards HCP-Style macaque connectomes: 24-Channel 3T multi-array coil, MRI sequences and preprocessing
(2020) NeuroImage, 215, art. no. 116800, . 

Autio, J.A.^a , Glasser, M.F.^{b c d} , Ose, T.^a , Donahue, C.J.^b , Bastiani, M.^{e f m} , Ohno, M.^a , Kawabata, Y.^g , Urushibata, Y.^h , Murata, K.^h , Nishigori, K.^{a i} , Yamaguchi, M.^{a i} , Hori, Y.^a , Yoshida, A.^a , Go, Y.^{j k l} , Coalson, T.S.^b , Jbabdi, S.^e , Sotiropoulos, S.N.^{e f m} , Kennedy, H.^{n o p q} , Smith, S.^e , Van Essen, D.C.^b , Hayashi, T.^a

^a Laboratory for Brain Connectomics Imaging, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
^b Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^c Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^d St. Luke’s Hospital, St. Louis, MO, United States
^e Wellcome Centre for Integrative Neuroimaging, Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB), University of Oxford, Oxford, United Kingdom
^f Sir Peter Mansfield Imaging Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom
^g Takashima Seisakusho Co., Ltd, Tokyo, Japan
^h Siemens Healthcare Japan, Tokyo, Japan
ⁱ Sumitomo Dainippon Pharma Co., Ltd, Osaka, Japan
^j Cognitive Genomics Research Group, Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Okazaki, Japan
^k Department of System Neuroscience, National Institute for Physiological Sciences, Okazaki, Japan
^l Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan
^m National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Queens Medical Centre, Nottingham, United Kingdom
ⁿ Université Lyon, Université Claude Bernard Lyon, France
^o Inserm, Stem Cell and Brain Research Institute, Bron, France
^p Institute of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
^q Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China

Abstract
Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enables adaptation of the Human Connectome Project (HCP) image acquisition protocols to the in-vivo macaque brain. In addition, we adapted HCP preprocessing methods to the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provides the necessary high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold accelerations for dMRI and fMRI. Automated FreeSurfer segmentation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI all performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. Analyses of functional connectivity in fMRI revealed high sensitivity as compared with those from publicly shared datasets. Tractography-based connectivity estimates correlated with tracer connectivity similarly to that achieved using ex-vivo dMRI. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available in studies of the human brain. © 2020 The Author(s)

Author Keywords
Cortex;  Diffusion;  Human connectome project;  Macaque;  Parallel imaging;  Primate;  Resting-state

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Electrically coupled inhibitory interneurons constrain long-range connectivity of cortical networks
(2020) NeuroImage, 215, art. no. 116810, . 

Kraft, A.W.^a , Mitra, A.^b , Rosenthal, Z.P.^c , Dosenbach, N.U.F.^{c d e g} , Bauer, A.Q.^d , Snyder, A.Z.^{c d} , Raichle, M.E.^{c d} , Culver, J.P.^{d e f} , Lee, J.-M.^{c d e}

^a Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^b Department of Psychiatry, Stanford University, Stanford, CA, United States
^c Department of Neurology, Washington University, St. Louis, United States
^d Department of Radiology, Washington University, St. Louis, United States
^e Department of Biomedical Engineering, Washington University, St. Louis, United States
^f Department of Physics, Washington University, St. Louis, United States
^g Department of Program in Occupational Therapy, Washington University, St. Louis, United States

Abstract
Spontaneous infra-slow brain activity (ISA) exhibits a high degree of temporal synchrony, or correlation, between distant brain regions. The spatial organization of ISA synchrony is not explained by anatomical connections alone, suggesting that active neural processes coordinate spontaneous activity. Inhibitory interneurons (IINs) form electrically coupled connections via the gap junction protein connexin 36 (Cx36) and networks of interconnected IINs are known to influence neural synchrony over short distances. However, the role of electrically coupled IIN networks in regulating spontaneous correlation over the entire brain is unknown. In this study, we performed OIS imaging on Cx36−/− mice to examine the role of this gap junction in ISA correlation across the entire cortex. We show that Cx36 deletion increased long-distance intra-hemispheric anti-correlation and inter-hemispheric correlation in spontaneous ISA. This suggests that electrically coupled IIN networks modulate ISA synchrony over long cortical distances. © 2020 The Authors

Author Keywords
Connexin 36;  Functional connectivity;  Gap junction;  Infra-slow activity;  Neuroimaging

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Test-retest reliability of fMRI-measured brain activity during decision making under risk
(2020) NeuroImage, 214, art. no. 116759, . 

Korucuoglu, O.^a , Harms, M.P.^a , Astafiev, S.V.^a , Kennedy, J.T.^a , Golosheykin, S.^a , Barch, D.M.^{a b} , Anokhin, A.P.^a

^a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid, St. Louis, MO 63110, United States
^b Department of Psychological & Brain Sciences, Washington University, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
Neural correlates of decision making under risk are being increasingly utilized as biomarkers of risk for substance abuse and other psychiatric disorders, treatment outcomes, and brain development. This research relies on the basic assumption that fMRI measures of decision making represent stable, trait-like individual differences. However, reliability needs to be established for each individual construct. Here we assessed long-term test-retest reliability (TRR) of regional brain activations related to decision making under risk using the Balloon Analogue Risk Taking task (BART) and identified regions with good TRRs and familial influences, an important prerequisite for the use of fMRI measures in genetic studies. A secondary goal was to examine the factors potentially affecting fMRI TRRs in one particular risk task, including the magnitude of neural activation, data analytical approaches, different methods of defining boundaries of a region, and participant motion. For the average BOLD response, reliabilities ranged across brain regions from poor to good (ICCs of 0 to 0.8, with a mean ICC of 0.17) and highest reliabilities were observed for parietal, occipital, and temporal regions. Among the regions that were of a priori theoretical importance due to their reported associations with decision making, the activation of left anterior insula and right caudate during the decision period showed the highest reliabilities (ICCs of 0.54 and 0.63, respectively). Among the regions with highest reliabilities, the right fusiform, right rostral anterior cingulate and left superior parietal regions also showed high familiality as indicated by intrapair monozygotic twin correlations (ranging from 0.66 to 0.69). Overall, regions identified by modeling the average BOLD response to a specific event type (rather than its modulation by a parametric regressor), regions including significantly activated vertices (compared to a whole parcel), and regions with greater magnitude of task-related activations showed greater reliabilities. Participant motion had a moderate negative effect on TRR. Regions activated during decision period rather than outcome period of risky decisions showed the greatest TRR and familiality. Regions with reliable activations can be utilized as neural markers of individual differences or endophenotypes in future clinical neuroscience and genetic studies of risk-taking. © 2020 The Authors

Author Keywords
BART;  Cohen’s d;  Familiality;  fMRI;  ICC;  Motion

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Dual-task costs of texting while walking forward and backward are greater for older adults than younger adults
(2020) Human Movement Science, 71, art. no. 102619, . 

Belur, P.^a , Hsiao, D.^b , Myers, P.S.^c , Earhart, G.M.^{c d e} , Rawson, K.S.^d

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^b Department of Biology, Washington University in St. Louis, United States
^c Department of Neurology, Washington University School of Medicine, United States
^d Program in Physical Therapy, Washington University School of Medicine, United States
^e Department of Neuroscience, Washington University School of Medicine, United States

Abstract
Cognitive-motor dual-tasking involves concurrent performance of two tasks with distinct cognitive and motor demands and is associated with increased fall risk. In this hypothesis-driven study, younger (18–30 years, n = 24) and older (60–75 years, n = 26) adults completed six walking tasks in triplicate. Participants walked forward and backward along a GAITRite mat, in isolation or while performing a verbal fluency task. Verbal fluency tasks involved verbally listing or typing on a smartphone as many words as possible within a given category (e.g., clothes). Using repeated measures MANOVA models, we examined how age, method of fluency task (verbal or texting), and direction of walking altered dual-task performance. Given that tasks like texting and backward walking require greater cognitive resources than verbal and forward walking tasks, respectively, we hypothesized older adults would show higher dual-task costs (DTCs) than younger adults across different task types and walking directions, with degree of impairment more apparent in texting dual-task trials compared to verbal dual-task trials. We also hypothesized that both age groups would have greater DTCs while walking backward than while walking forward, regardless of task. Independent of age group, velocity and stride length were reduced for texting compared to the verbal task during both forward and backward walking; cadence and velocity were reduced while walking forward compared to walking backward for the texting task; and stride length was reduced for forward walking compared to backward walking during the verbal task. Younger adults performed better than older adults on all tasks with the most pronounced differences seen in velocity and stride length during forward-texting and backward-texting. Interaction effects for velocity and stride length while walking forward indicated younger adults performed better than older adults for the texting task but similarly during the verbal task. An interaction for cadence during the verbal task indicated younger adults performed better than older adults while walking backward but similarly while walking forward. In summary, older adults experienced greater gait decrement for all dual-task conditions. The greater declines in velocity and stride length in combination with cadence being stable suggest reductions in velocity during texting were due to shorter strides rather than a reduced rate of stepping. Contrary to our hypotheses, we found greater DTCs while walking forward rather than backward, which may be due to reduced gait performance during single-task backward walking; thus, further decrements with dual-tasking are unlikely. These findings underscore the need for further research investigating fall risk potential associated with texting and walking among aging populations and how interventions targeting stride length during dual-task circumstances may improve performance. © 2020 Elsevier B.V.

Author Keywords
Dual-task;  Gait;  Older adults;  Texting;  Verbal fluency;  Walking

Document Type: Article
Publication Stage: Final
Source: Scopus

A direct visuosensory cortical connectivity of the human limbic system. Dissecting the trajectory of the parieto-occipito-hypothalamic tract in the human brain using diffusion weighted tractography
(2020) Neuroscience Letters, 728, art. no. 134955, . 

Kamali, A.^a , Ghazi Sherbaf, F.^b , Rahmani, F.^c , Khayat-khoei, M.^d , Aein, A.^a , Gandhi, A.^e , Shah, E.G.^f , Sair, H.I.^b , Riascos, R.F.^a , Esquenazi, Y.^g , Zhu, J.-J.^h , Keser, Z.^d , Hasan, K.M.^a

^a Department of Diagnostic and Interventional Imaging, Division of Neuroradiology, University of Texas Health Science Center at Houston, Houston, TX, United States
^b The Russell H. Morgan Department of Radiology and Radiological Science, Division of Neuroradiology, Johns Hopkins University, Baltimore, MD, United States
^c Neuroimaging Laboratory at Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, University of Texas Health Science Canter Houston, Houston, TX, United States
^e Rice University, Houston, TX, United States
^f Department of Pediatrics, University of Texas Health Science Canter Houston, Houston, TX, United States
^g Department of Neurosurgery, University of Texas Health Science Center Houston, Houston, TX, United States
^h Vivian L. Smith Department of Neurosurgery, University of Texas Health Science Center at HoustonTX, United States

Abstract
The human hypothalamus is at the center of the human limbic system anatomically and physiologically. The hypothalamus plays pivotal roles in controlling autonomic responses and instinctive behaviors such as regulating fear, aggression, learning, feeding behavior, circadian rhythm, and reproductive activities. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. The inhibitory effect of the cerebral cortex on the hypothalamus in many autonomic responses, suggests the presence of direct connection between the cortex and hypothalamic nuclei. While, there is ample information to support the cortico-hypothalamic association between the prefrontal cortex and hypothalamic nuclei, the information regarding a direct posterior cortico-hypothalamic alliance is scant. The visuosensory information may be crucial for the limbic system to regulate some of the important limbic functions. Multiple dissection animal studies revealed direct posterior cortical connectivity with the hypothalamic nuclei. However, a direct cortico-hypothalamic connectivity from the parieto-occipital cortices has not been revealed in the human brain yet. Diffusion weighted imaging (DWI) may be helpful in better visualizing the anatomy of this direct posterior cortico-limbic connectivity noninvasively in the human brain. We studied 30 healthy human subjects. Using a high-spatial and high angular resolution diffusion weighted tractography technique, for the first time, we were able to delineate and reconstruct the trajectory of the parieto-occipito-hypothalamic tract. © 2020 Elsevier B.V.

Author Keywords
Cortico-hypothalamic;  diffusion weighted imaging;  hypothalamus;  limbic;  parietal;  sensory;  tractography;  visual

Document Type: Article
Publication Stage: Final
Source: Scopus

Humanitarian Audiology
(2020) Seminars in Hearing, 41 (2), p. 081. 

Smith, S.P.

Division of Adult Audiology, School of Medicine, Washington University, Box 8115, 4566 Scott Avenue, St. Louis, MO 63110, United States

Document Type: Editorial
Publication Stage: Final
Source: Scopus

Pathogenic Variants in CEP85L Cause Sporadic and Familial Posterior Predominant Lissencephaly
(2020) Neuron, 106 (2), pp. 237-245.e8. 

Tsai, M.-H.^{a b} , Muir, A.M.^c , Wang, W.-J.^d , Kang, Y.-N.^e , Yang, K.-C.^e , Chao, N.-H.^e , Wu, M.-F.^d , Chang, Y.-C.^f , Porter, B.E.^g , Jansen, L.A.^h , Sebire, G.ⁱ , Deconinck, N.^j , Fan, W.-L.^k , Su, S.-C.^l , Chung, W.-H.^{b l m} , Almanza Fuerte, E.P.^c , Mehaffey, M.G.^c , Ng, C.-C.ⁿ , Chan, C.-K.ⁿ , Lim, K.-S.^o , Leventer, R.J.^{p q} , Lockhart, P.J.^{p q} , Riney, K.^r , Damiano, J.A.^{p s} , Hildebrand, M.S.^{p s} , Mirzaa, G.M.^{c t u} , Dobyns, W.B.^{c t u} , Berkovic, S.F.^s , Scheffer, I.E.^{p q s v} , Tsai, J.-W.^{e w x} , Mefford, H.C.^{c u} , University of Washington Center for Mendelian Genomics^y

^a Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan 833, China
^b School of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan 33302, China
^c Department of Pediatrics, University of Washington, Seattle, WA 98195, United States
^d Institute of Biochemistry and Molecular Biology, College of Life Science, National Yang-Ming University, Taipei, Taiwan, China
^e Institute of Brain Science, School of Medicine, National Yang-Ming University, Taipei, Taiwan, China
^f Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, China
^g Department of Neurology, Stanford University School of Medicine, Palo Alto, CA, United States
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Pediatrics, McGill University, Montreal, QC, Canada
^j Department of Paediatric Neurology, Hôpital Universitaire des Enfants Reine Fabiola, HUDERF, Université Libre de Bruxelles (ULB), Brussels, Belgium
^k Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Linkou, Taiwan, China
^l Whole-Genome Research Core Laboratory of Human Diseases, Chang Gung Memorial Hospital, Keelung, Taiwan, China
^m Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou, Taipei and KeelungTaiwan, China
ⁿ Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
^o Division of Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur, 50603, Malaysia
^p Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia
^q Departments of Paediatrics and Neurology, The Royal Children’s Hospital, The University of Melbourne, Melbourne, VIC 3052, Australia
^r Neurosciences Unit, Queensland Children’s Hospital and School of Medicine, University of Queensland, Brisbane, QLD 4101, Australia
^s Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, VIC 3084, Australia
^t Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA 98105, United States
^u Brotman Baty Institute for Precision Medicine, Seattle, WA, United States
^v The Florey Institute of Neuroscience and Mental Health, Melbourne, VIC 3052, Australia
^w Brain Research Center, National Yang-Ming University, Taipei, Taiwan 112, China
^x Department of Biological Science & Technology, National Chiao Tung University, Hsin-ChuTaiwan 30010, China

Abstract
Lissencephaly (LIS), denoting a “smooth brain,” is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS. © 2020 Elsevier Inc.

Tsai et al. implicate CEP85L as an important cause of posterior predominant lissencephaly, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. © 2020 Elsevier Inc.

Author Keywords
centrosome;  CEP85L;  lissencephaly;  pachygyria;  posterior predominant;  subcortical band heterotopia

Document Type: Article
Publication Stage: Final
Source: Scopus

CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy
(2020) Journal of Neuroinflammation, 17 (1), art. no. 121, . 

Runge, E.M.^{a b} , Iyer, A.K.^c , Setter, D.O.^{a b} , Kennedy, F.M.^{a b} , Sanders, V.M.^d , Jones, K.J.^{a b}

^a Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Medical Science Building 5035, Indianapolis, IN 46202, United States
^b Research and Development, Richard L. Roudebush VA Medical Center, Indianapolis, IN, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH, United States

Abstract
Background: After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA). Methods: Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. Results: CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. Conclusions: These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA. © 2020 The Author(s).

Author Keywords
Autoimmune;  Axotomy;  IL-10;  Motoneuron;  Nerve injury;  Neuroprotection;  T cell

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Rationalization is irrational and self-serving, but useful
(2020) The Behavioral and Brain Sciences, 43, p. e42. 

Quilty-Dunn, J.

Faculty of Philosophy, University of Oxford, Oxford, United Kingdom, OX2 6GG; Department of Philosophy, Washington University, St. Louis, MO63105

Abstract
Rationalization through reduction of cognitive dissonance does not have the function of representational exchange. Instead, cognitive dissonance is part of the “psychological immune system” (Gilbert 2006; Mandelbaum 2019) and functions to protect the self-concept against evidence of incompetence, immorality, and instability. The irrational forms of attitude change that protect the self-concept in dissonance reduction are useful primarily for maintaining motivation.

Document Type: Note
Publication Stage: Final
Source: Scopus

Sex differences in cancer mechanisms
(2020) Biology of Sex Differences, 11 (1), art. no. 17, . 

Rubin, J.B.^{a b} , Lagas, J.S.^a , Broestl, L.^a , Sponagel, J.^a , Rockwell, N.^a , Rhee, G.^a , Rosen, S.F.^c , Chen, S.^d , Klein, R.S.^{b c} , Imoukhuede, P.^d , Luo, J.^e

^a Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
^b Department of Neuroscience, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
^c Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States
^e Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, United States

Abstract
We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab-and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients. © 2020 The Author(s).

Author Keywords
Angiogenesis;  Cancer;  Epigenetics;  Immunity;  Metabolism;  p53;  Senescence;  Sex differences;  Tumor Suppressor

Document Type: Review
Publication Stage: Final
Source: Scopus
Access Type: Open Access

“What Were You Before the War?” Repurposing Psychiatry During the COVID-19 Pandemic
(2020) The Journal of Clinical Psychiatry, 81 (3), . 

Nicol, G.E., Karp, J.F., Reiersen, A.M., Zorumski, C.F., Lenze, E.J.

Department of Psychiatry, Healthy Mind Laboratory, Washington University School of Medicine, 600 S. Taylor Ave, Ste 121, St Louis, MO 63110

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Long-Term Physical Exercise and Mindfulness Practice in an Aging Population
(2020) Frontiers in Psychology, 11, art. no. 358, . 

Tang, Y.-Y.^a , Fan, Y.^b , Lu, Q.^b , Tan, L.-H.^c , Tang, R.^d , Kaplan, R.M.^e , Pinho, M.C.^{f g} , Thomas, B.P.^g , Chen, K.^h , Friston, K.J.ⁱ , Reiman, E.M.^h

^a Department of Psychological Sciences, Texas Tech University, Lubbock, TX, United States
^b Institute of Neuroinformatics and Laboratory for Body and Mind, Dalian University of Technology, Dalian, China
^c Center for Brain Disorders and Cognitive Science, Shenzhen University, Shenzhen, China
^d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^e Clinical Excellence Research Center, Department of Medicine, Stanford University, Stanford, CA, United States
^f Department of Radiology, UT Southwestern Medical Center, Dallas, TX, United States
^g Advanced Imaging Research Center, UT Southwestern Medical Center, Dallas, TX, United States
^h Banner Alzheimer’s Institute, Phoenix, AZ, United States
ⁱ Wellcome Centre for Human Neuroimaging, Institute of Neurology, University College London, London, United Kingdom

Abstract
Previous studies have shown that physical exercise and mindfulness meditation can both lead to improvement in physical and mental health. However, it is unclear whether these two forms of training share the same underlying mechanisms. We compared two groups of older adults with 10 years of mindfulness meditation (integrative body-mind training, IBMT) or physical exercise (PE) experience to demonstrate their effects on brain, physiology and behavior. Healthy older adults were randomly selected from a large community health project and the groups were compared on measures of quality of life, autonomic activity (heart rate, heart rate variability, skin conductance response, respiratory amplitude/rate), immune function (secretory Immunoglobulin A, sIgA), stress hormone (cortisol) and brain imaging (resting state functional connectivity, structural differences). In comparison with PE, we found significantly higher ratings for the IBMT group on dimensions of life quality. Parasympathetic activity indexed by skin conductance response and high-frequency heart rate variability also showed more favorable outcomes in the IBMT group. However, the PE group showed lower basal heart rate and greater chest respiratory amplitude. Basal sIgA level was significantly higher and cortisol concentration was lower in the IBMT group. Lastly, the IBMT group had stronger brain connectivity between the dorsal anterior cingulate cortex (dACC) and the striatum at resting state, as well as greater volume of gray matter in the striatum. Our results indicate that mindfulness meditation and physical exercise function in part by different mechanisms, with PE increasing physical fitness and IBMT inducing plasticity in the central nervous systems. These findings suggest combining physical and mental training may achieve better health and quality of life results for an aging population. © Copyright © 2020 Tang, Fan, Lu, Tan, Tang, Kaplan, Pinho, Thomas, Chen, Friston and Reiman.

Author Keywords
cortisol;  heart rate variability;  integrative body-mind training (IBMT);  mindfulness interventions;  physical exercise (PE);  quality of life;  secretory Immunoglobulin A (sIgA);  skin conductance response

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Clinical Practice Guideline: Ménière’s Disease
(2020) Otolaryngology – Head and Neck Surgery (United States), 162 (2_suppl), pp. S1-S55. Cited 1 time.

Basura, G.J.^a , Adams, M.E.^b , Monfared, A.^c , Schwartz, S.R.^d , Antonelli, P.J.^e , Burkard, R.^f , Bush, M.L.^g , Bykowski, J.^h , Colandrea, M.ⁱ , Derebery, J.^j , Kelly, E.A.^k , Kerber, K.A.^a , Koopman, C.F.^l , Kuch, A.A.^m , Marcolini, E.ⁿ , McKinnon, B.J.^o , Ruckenstein, M.J.^p , Valenzuela, C.V.^q , Vosooney, A.^r , Walsh, S.A.^s , Nnacheta, L.C.^t , Dhepyasuwan, N.^t , Buchanan, E.M.^t

^a University of Michigan Medical Center, Ann Arbor, MI, United States
^b University of Minnesota, Minneapolis, MN, United States
^c George Washington University, Washington, DC, United States
^d Virginia Mason Medical Center, Seattle, WA, United States
^e University of Florida, Gainesville, FL, United States
^f University of Buffalo, Buffalo, NY, United States
^g University of Kentucky Medical Center, Lexington, KY, United States
^h University of California San Diego, San Diego, CA, United States
ⁱ Duke University School of Nursing and Durham Veterans Affairs Medical Center, Durham, NC, United States
^j House Ear Clinic, Los Angeles, CA, United States
^k Boys Town National Research Hospital, Omaha, NE, United States
^l C.S. Mott Children’s Hospital, Ann Arbor, MI, United States
^m Vestibular Disorders Association, Portland, OR, United States
ⁿ Geisel School of Medicine at Dartmouth, Hanover, NH, United States
^o Drexel University College of Medicine, Philadelphia, PA, United States
^p University of Pennsylvania, Philadelphia, PA, United States
^q Washington University School of Medicine, St Louis, MO, United States
^r Private practice, West St Paul, MN, United States
^s Consumers United for Evidence-Based Healthcare, Baltimore, MD, United States
^t American Academy of Otolaryngology—Head and Neck Surgery, Alexandria, VA, United States

Abstract
Objective: Ménière’s disease (MD) is a clinical condition defined by spontaneous vertigo attacks (each lasting 20 minutes to 12 hours) with documented low- to midfrequency sensorineural hearing loss in the affected ear before, during, or after one of the episodes of vertigo. It also presents with fluctuating aural symptoms (hearing loss, tinnitus, or ear fullness) in the affected ear. The underlying etiology of MD is not completely clear, yet it has been associated with inner ear fluid (endolymph) volume increases, culminating in episodic ear symptoms (vertigo, fluctuating hearing loss, tinnitus, and aural fullness). Physical examination findings are often unremarkable, and audiometric testing may or may not show low- to midfrequency sensorineural hearing loss. Conventional imaging, if performed, is also typically normal. The goals of MD treatment are to prevent or reduce vertigo severity and frequency; relieve or prevent hearing loss, tinnitus, and aural fullness; and improve quality of life. Treatment approaches to MD are many and typically include modifications of lifestyle factors (eg, diet) and medical, surgical, or a combination of therapies. Purpose: The primary purpose of this clinical practice guideline is to improve the quality of the diagnostic workup and treatment outcomes of MD. To achieve this purpose, the goals of this guideline are to use the best available published scientific and/or clinical evidence to enhance diagnostic accuracy and appropriate therapeutic interventions (medical and surgical) while reducing unindicated diagnostic testing and/or imaging. © American Academy of Otolaryngology–Head and Neck Surgery Foundation 2020.

Author Keywords
electrocochleography;  endolymphatic hydrops;  endolymphatic sac decompression;  fluctuating aural symptoms;  gentamicin;  labyrinthectomy;  Meniett device;  quality of life;  sensorineural hearing loss;  sodium-restricted diet;  vestibular testing

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Clinical Practice Guideline: Ménière’s Disease Executive Summary
(2020) Otolaryngology – Head and Neck Surgery (United States), 162 (4), pp. 415-434. 

Basura, G.J.^a , Adams, M.E.^b , Monfared, A.^c , Schwartz, S.R.^d , Antonelli, P.J.^e , Burkard, R.^f , Bush, M.L.^g , Bykowski, J.^h , Colandrea, M.ⁱ , Derebery, J.^j , Kelly, E.A.^k , Kerber, K.A.^a , Koopman, C.F.^l , Kuch, A.A.^m , Marcolini, E.ⁿ , McKinnon, B.J.^o , Ruckenstein, M.J.^p , Valenzuela, C.V.^q , Vosooney, A.^r , Walsh, S.A.^s , Nnacheta, L.C.^t , Dhepyasuwan, N.^t , Buchanan, E.M.^t

^a University of Michigan Medical Center, Ann Arbor, MI, United States
^b University of Minnesota, Minneapolis, MN, United States
^c George Washington University, Washington, DC, United States
^d Virginia Mason Medical Center, Seattle, WA, United States
^e University of Florida, Gainesville, FL, United States
^f University of Buffalo, Buffalo, NY, United States
^g University of Kentucky Medical Center, Lexington, KY, United States
^h University of California San Diego, San Diego, CA, United States
ⁱ Duke University School of Nursing and Durham Veterans Affairs Medical Center, Durham, NC, United States
^j House Ear Clinic, Los Angeles, CA, United States
^k Boys Town National Research Hospital, Omaha, NE, United States
^l C.S. Mott Children’s Hospital, Ann Arbor, MI, United States
^m Vestibular Disorders Association, Portland, OR, United States
ⁿ Geisel School of Medicine at Dartmouth, Hanover, NH, United States
^o Drexel University College of Medicine, Philadelphia, PA, United States
^p University of Pennsylvania, Philadelphia, PA, United States
^q Washington University School of Medicine, St Louis, MO, United States
^r Private practice, West St Paul, MN, United States
^s Consumers United for Evidence-Based Healthcare, Baltimore, MD, United States
^t American Academy of Otolaryngology—Head and Neck Surgery, Alexandria, VA, United States

Abstract
Objective: Ménière’s disease (MD) is a clinical condition defined by spontaneous vertigo attacks (each lasting 20 minutes to 12 hours) with documented low- to midfrequency sensorineural hearing loss in the affected ear before, during, or after one of the episodes of vertigo. It also presents with fluctuating aural symptoms (hearing loss, tinnitus, or ear fullness) in the affected ear. The underlying etiology of MD is not completely clear, yet it has been associated with inner ear fluid volume increases, culminating in episodic ear symptoms (vertigo, fluctuating hearing loss, tinnitus, and aural fullness). Physical examination findings are often unremarkable, and audiometric testing may or may not show low- to midfrequency sensorineural hearing loss. Imaging, if performed, is also typically normal. The goals of MD treatment are to prevent or reduce vertigo severity and frequency; relieve or prevent hearing loss, tinnitus, and aural fullness; and improve quality of life. Treatment approaches to MD are many, and approaches typically include modifications of lifestyle factors (eg, diet) and medical, surgical, or a combination of therapies. Purpose: The primary purpose of this clinical practice guideline is to improve the quality of the diagnostic workup and treatment outcomes of MD. To achieve this purpose, the goals of this guideline are to use the best available published scientific and/or clinical evidence to enhance diagnostic accuracy and appropriate therapeutic interventions (medical and surgical) while reducing unindicated diagnostic testing and/or imaging. © American Academy of Otolaryngology–Head and Neck Surgery Foundation 2020.

Author Keywords
electrocochleography;  endolymphatic hydrops;  endolymphatic sac decompression;  fluctuating aural symptoms;  gentamicin;  labyrinthectomy;  Meniett device;  quality of life;  sensorineural hearing loss;  sodium-restricted diet;  vestibular testing

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Unc-4 acts to promote neuronal identity and development of the take-off circuit in the drosophila cns
(2020) eLife, 9, art. no. e55007, . 

Lacin, H.^{a b} , Williamson, W.R.^b , Card, G.M.^b , Skeath, J.B.^a , Truman, J.W.^{b c}

^a Department of Genetics, Washington University, Saint Louis, MO 63110, United States
^b Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 2017, United States
^c Friday Harbor Laboratories, University of Washington, Friday Harbor, WA 98250, United States

Abstract
The Drosophila ventral nerve cord (VNC) is composed of thousands of neurons born from a set of individually identifiable stem cells. The VNC harbors neuronal circuits required to execute key behaviors, such as flying and walking. Leveraging the lineage-based functional organization of the VNC, we investigated the developmental and molecular basis of behavior by focusing on lineage-specific functions of the homeodomain transcription factor, Unc-4. We found that Unc-4 functions in lineage 11A to promote cholinergic neurotransmitter identity and suppress the GABA fate. In lineage 7B, Unc-4 promotes proper neuronal projections to the leg neuropil and a specific flight-related take-off behavior. We also uncovered that Unc-4 acts peripherally to promote proprioceptive sensory organ development and the execution of specific leg-related behaviors. Through time-dependent conditional knock-out of Unc-4, we found that its function is required during development, but not in the adult, to regulate the above events. © 2020, eLife Sciences Publications Ltd. All rights reserved.

Author Keywords
And Drosophila;  Behavior;  Flight take-off;  Neuroblast;  Neuronal lineages;  Unc-4

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Contralateral Eye Involvement and Retinal Detachment in Patients with Cytomegalovirus Retinitis Treated with Intravitreous Ganciclovir
(2020) Ocular Immunology and Inflammation, . 

Ausayakhun, S.^a , Lu, L.J.^{b c} , Ausayakuhn, S.^a , Nanegrungsunk, O.^a , Apivatthakakul, A.^a , Luewattananont, D.^a , Photcharapongsakul, C.^a , Liu, Y.^{b d} , Holland, G.N.^e , Margolis, T.P.^f , Heiden, D.^g , Keenan, J.D.^{b d}

^a Department of Ophthalmology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
^b Francis I. Proctor Foundation, University of California, San Francisco, CA, United States
^c Yale University School of Medicine, New Haven, CT, United States
^d Department of Ophthalmology, University of California, San Francisco, CA, United States
^e Department of Ophthalmology, Ocular Inflammatory Disease Center, UCLA Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
^f Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Ophthalmology and Pacific Vision Foundation, California Pacific Medical Center, San Francisco, CA, United States

Abstract
Purpose: To determine the incidence of contralateral eye involvement and retinal detachment in HIV-infected patients with cytomegalovirus retinitis treated with repeated intravitreous ganciclovir. Methods: In a prospective cohort study in Northern Thailand, HIV-infected patients with cytomegalovirus retinitis were treated with antiretroviral therapy and intravitreous ganciclovir injections and followed for 3 months for contralateral cytomegalovirus retinitis and retinal detachment. Results: Of 49 participants with unilateral cytomegalovirus retinitis at enrollment, 7 developed contralateral eye involvement (4.8/100 person-months, 95% CI 1.9–9.8). Of 105 eyes without a retinal detachment at enrollment, 6 developed a retinal detachment (2.0/100 eye-months, 95% CI 0.7–4.3). Baseline clinical factors were not associated with the development of either outcome. Conclusion: Eyes treated with intravitreous ganciclovir experienced retinal detachment at a rate similar to other populations treated with systemic antivirals. The risk of contralateral eye involvement was relatively high during the first 3 months after initial diagnosis despite the institution of antiretroviral therapy. © 2020, © 2020 Taylor & Francis Group, LLC.

Author Keywords
Contralateral eye involvement;  cytomegalovirus retinitis;  ganciclovir;  HIV;  retinal detachment;  Thailand

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

Beta-amyloid (Aβ) uptake by PET imaging in older HIV+ and HIV- individuals
(2020) Journal of NeuroVirology, . 

Mohamed, M.^a , Skolasky, R.L.^{b c} , Zhou, Y.^{a d} , Ye, W.^a , Brasic, J.R.^a , Brown, A.^b , Pardo, C.A.^b , Barker, P.B.^{a e} , Wong, D.F.^{a b f g h} , Sacktor, N.^b

^a Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Neurology, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, 301 Building, Suite 2100, Baltimore, MD 21224, United States
^c Department of Orthopedic Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^d Mallinckrodt Institute of Radiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^e F.M. Kirby Center for Functional Brain Imaging, the Kennedy Krieger Institute, Baltimore, MD, United States
^f Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^g Department of Neurosciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Department of Environmental Sciences and Engineering, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States

Abstract
The causes of cognitive impairment among older HIV+ individuals may overlap with causes among elderly HIV seronegative (HIV-) individuals. The objective of this study was to determine if beta-amyloid (Aβ) deposition measured by [18F] AV-45 (florbetapir) positron emission tomography (PET) is increased in older HIV+ individuals compared to HIV- individuals. Forty-eight HIV+ and 25 HIV- individuals underwent [18F] AV-45 PET imaging. [18F] AV-45 binding to Aβ was measured by standardized uptake value ratios (SUVR) relative to the cerebellum in 16 cortical and subcortical regions of interest. Global and regional cortical SUVRs were compared by (1) serostatus, (2) HAND stage, and (3) age decade, comparing individuals in their 50s and > 60s. There were no differences in median global cortical SUVR stratified by HIV serostatus or HAND stage. The proportion of HIV+ participants in their 50s with elevated global amyloid uptake (SUVR > 1.40) was significantly higher than the proportion in HIV- participants (67% versus 25%, p = 0.04), and selected regional SUVR values were also higher (p < 0.05) in HIV+ compared to HIV- participants in their 50s. However, these group differences were not seen in participants in their 60s. In conclusion, PET imaging found no differences in overall global Aβ deposition stratified by HIV serostatus or HAND stage. Although there was some evidence of increased Aβ deposition in HIV+ individuals in their 50s compared to HIV- individuals which might indicate premature aging, the most parsimonious explanation for this is the relatively small sample size in this cross-sectional cohort study. © 2020, Journal of NeuroVirology, Inc.

Author Keywords
Amyloid;  Cognitive impairment;  HIV;  PET

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

Deep learning with diffusion basis spectrum imaging for classification of multiple sclerosis lesions
(2020) Annals of Clinical and Translational Neurology, . 

Ye, Z.^a , George, A.^a , Wu, A.T.^b , Niu, X.^a , Lin, J.^c , Adusumilli, G.^d , Naismith, R.T.^d , Cross, A.H.^d , Sun, P.^a , Song, S.-K.^a

^a Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
^c Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Objective: Multiple sclerosis (MS) lesions are heterogeneous with regard to inflammation, demyelination, axonal injury, and neuronal loss. We previously developed a diffusion basis spectrum imaging (DBSI) technique to better address MS lesion heterogeneity. We hypothesized that the profiles of multiple DBSI metrics can identify lesion-defining patterns. Here we test this hypothesis by combining a deep learning algorithm using deep neural network (DNN) with DBSI and other imaging methods. Methods: Thirty-eight MS patients were scanned with diffusion-weighted imaging, magnetization transfer imaging, and standard conventional MRI sequences (cMRI). A total of 499 regions of interest were identified on standard MRI and labeled as persistent black holes (PBH), persistent gray holes (PGH), acute black holes (ABH), acute gray holes (AGH), nonblack or gray holes (NBH), and normal appearing white matter (NAWM). DBSI, diffusion tensor imaging (DTI), and magnetization transfer ratio (MTR) were applied to the 43,261 imaging voxels extracted from these ROIs. The optimized DNN with 10 fully connected hidden layers was trained using the imaging metrics of the lesion subtypes and NAWM. Results: Concordance, sensitivity, specificity, and accuracy were determined for the different imaging methods. DBSI-DNN derived lesion classification achieved 93.4% overall concordance with predetermined lesion types, compared with 80.2% for DTI-DNN model, 78.3% for MTR-DNN model, and 74.2% for cMRI-DNN model. DBSI-DNN also produced the highest specificity, sensitivity, and accuracy. Conclusions: DBSI-DNN improves the classification of different MS lesion subtypes, which could aid clinical decision making. The efficacy and efficiency of DBSI-DNN shows great promise for clinical applications in automatic MS lesion detection and classification. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

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

A roadmap to advance delirium research: Recommendations from the NIDUS Scientific Think Tank
(2020) Alzheimer’s and Dementia, . 

Oh, E.S.^a , Akeju, O.^b , Avidan, M.S.^c , Cunningham, C.^d , Hayden, K.M.^e , Jones, R.N.^f , Khachaturian, A.S.^g , Khan, B.A.^h , Marcantonio, E.R.ⁱ , Needham, D.M.^j , Neufeld, K.J.^k , Rose, L.^l , Spence, J.^m , Tieges, Z.ⁿ , Vlisides, P.^o , Inouye, S.K.^p , NIDUS Writing Group^q

^a Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^d School of Biochemistry and Immunology & Trinity College Institute of Neuroscience, Trinity College, Dublin, Ireland
^e Department of Social Sciences and Health Policy, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States
^f Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence, RI, United States
^g Campaign to Prevent Alzheimer’s Disease, Rockville, MD, United States
^h Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
ⁱ Division of General Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
^j Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^k Department of Psychiatry and Behavioral Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^l Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, King’s College London, London, United Kingdom
^m Departments of Anesthesiology and Critical Care, McMaster University, Hamilton, ON, Canada
ⁿ Edinburgh Delirium Research Group, University of Edinburgh, Edinburgh, Scotland, United Kingdom
^o Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^p Marcus Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, United States

Abstract
Delirium is an acute disorder of attention and cognition. It occurs across the life span, yet it is particularly common among older adults, and is closely linked with underlying neurocognitive disorders. Evidence is mounting that intervening on delirium may represent an important opportunity for delaying the onset or progression of dementia. To accelerate the current understanding of delirium, the Network for Investigation of Delirium: Unifying Scientists (NIDUS) held a conference “Advancing Delirium Research: A Scientific Think Tank” in June 2019. This White Paper encompasses the major knowledge and research gaps identified at the conference: advancing delirium definition and measurement, understanding delirium pathophysiology, and prevention and treatment of delirium. A roadmap of research priorities is proposed to advance the field in a systematic, interdisciplinary, and coordinated fashion. A call is made for an international consortium and biobank targeted to delirium, as well as a public health campaign to advance the field. © 2020 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals, Inc. on behalf of Alzheimer’s Association

Author Keywords
biomarkers;  definition;  delirium;  dementia;  diagnosis;  measurement;  pathophysiology;  prevention;  public health campaign;  treatment

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

A novel sensitive assay for detection of a biomarker of pericyte injury in cerebrospinal fluid
(2020) Alzheimer’s and Dementia, . 

Sweeney, M.D.^a , Sagare, A.P.^a , Pachicano, M.^a , Harrington, M.G.^b , Joe, E.^{c d} , Chui, H.C.^{c d} , Schneider, L.S.^{c d e} , Montagne, A.^a , Ringman, J.M.^{c d} , Fagan, A.M.^{f g h} , Morris, J.C.^{f h} , Pa, J.^{c i} , Nation, D.A.^{a c j} , Toga, A.W.^{c i} , Zlokovic, B.V.^{a c}

^a Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^b Huntington Medical Research Institutes, Pasadena, CA, United States
^c Alzheimer’s Disease Research Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^d Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^e Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g The Hope Center for Neurodegenerative Disorders, Washington University School of Medicine, St. Louis, MO, United States
^h The Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Laboratory of Neuro Imaging (LONI), USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^j Department of Psychology, University of Southern California, Los Angeles, CA, United States

Abstract
Introduction: Blood-brain barrier (BBB) breakdown and loss of brain capillary pericytes contributes to cognitive impairment. Pericytes express platelet-derived growth factor receptor-β (PDGFRβ) that regulates brain angiogenesis and blood vessel stability. Elevated soluble PDGFRβ (sPDGFRβ) levels in cerebrospinal fluid (CSF) indicate pericyte injury and BBB breakdown, which is an early biomarker of human cognitive dysfunction. Methods: A combination of reagents and conditions were tested, optimized, and validated on the Meso Scale Discovery electrochemiluminescence platform to develop a new sPDGFRβ immunoassay that was used to measure sPDGFRβ in human CSF from 147 individuals. Results: We developed standard operating procedures for a highly sensitive and reproducible sPDGFRβ immunoassay with a dynamic range from 100 to 26,000 pg/mL, and confirmed elevated CSF sPDGFRβ levels in individuals with cognitive dysfunction. Discussion: This assay could be applied at different laboratories to study brain pericytes and microvascular damage in relation to cognition in disorders associated with neurovascular and cognitive dysfunction. © 2020 the Alzheimer’s Association

Author Keywords
biomarker;  blood–brain barrier;  cerebrospinal fluid;  cognitive impairment;  pericytes;  vascular

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

Astrocytic Modulation of Neuronal Activity in the Suprachiasmatic Nucleus: Insights from Mathematical Modeling
(2020) Journal of Biological Rhythms, . 

Sueviriyapan, N.^a , Tso, C.F.^b , Herzog, E.D.^b , Henson, M.A.^a

^a Department of Chemical Engineering and the Institute for Applied Life Sciences, University of Massachusetts, Amherst, MA, United States
^b Department of Biology, Washington University in St. Louis, Saint Louis, MO, United States

Abstract
The suprachiasmatic nucleus (SCN) of the hypothalamus consists of a highly heterogeneous neuronal population networked together to allow precise and robust circadian timekeeping in mammals. While the critical importance of SCN neurons in regulating circadian rhythms has been extensively studied, the roles of SCN astrocytes in circadian system function are not well understood. Recent experiments have demonstrated that SCN astrocytes are circadian oscillators with the same functional clock genes as SCN neurons. Astrocytes generate rhythmic outputs that are thought to modulate neuronal activity through pre- and postsynaptic interactions. In this study, we developed an in silico multicellular model of the SCN clock to investigate the impact of astrocytes in modulating neuronal activity and affecting key clock properties such as circadian rhythmicity, period, and synchronization. The model predicted that astrocytes could alter the rhythmic activity of neurons via bidirectional interactions at tripartite synapses. Specifically, astrocyte-regulated extracellular glutamate was predicted to increase neuropeptide signaling from neurons. Consistent with experimental results, we found that astrocytes could increase the circadian period and enhance neural synchronization according to their endogenous circadian period. The impact of astrocytic modulation of circadian rhythm amplitude, period, and synchronization was predicted to be strongest when astrocytes had periods between 0 and 2 h longer than neurons. Increasing the number of neurons coupled to the astrocyte also increased its impact on period modulation and synchrony. These computational results suggest that signals that modulate astrocytic rhythms or signaling (e.g., as a function of season, age, or treatment) could cause disruptions in circadian rhythm or serve as putative therapeutic targets. © 2020 The Author(s).

Author Keywords
astrocytes;  circadian rhythms;  mathematical modeling;  neuronal coupling;  suprachiasmatic nucleus

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

A review of glioblastoma immunotherapy
(2020) Journal of Neuro-Oncology, . 

Medikonda, R.^a , Dunn, G.^b , Rahman, M.^c , Fecci, P.^d , Lim, M.^a

^a Department of Neurosurgery, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Phipps 123, Baltimore, MD 21287, United States
^b Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Neurosurgery, University of Florida, Gainesville, FL, United States
^d Department of Neurosurgery, Duke University Hospital, Durham, NC, United States

Abstract
Introduction: Glioblastoma is a very aggressive cancer with dismal prognosis despite standard of care including surgical resection, radiation therapy, and chemotherapy. There is interest in applying immunotherapy to glioblastoma as this modality has demonstrated remarkable improvements in the management of several solid tumors including melanoma, renal cell carcinoma, and non-small cell lung cancer. This review aims to provide an overview of the current state of glioblastoma immunotherapy. Methods: Literature search was performed on PubMed between 1961 and 2020. Results: Initial clinical trials of checkpoint inhibitors and vaccine therapy for glioblastoma have largely been disappointing for both primary and recurrent glioblastoma. This failure has been attributed to glioblastoma’s highly immunosuppressive environment and multiple mechanisms of therapy resistance including high tumor heterogeneity, low mutational burden, systemic immunosuppression, and local immune dysfunction. Conclusions: Current clinical trials are exploring combination therapy and novel treatment strategies beyond immune checkpoint therapies and vaccine therapy such as CAR T cells. There is also an effort to establish synergy between immunotherapy and current standard of care. Furthermore, recent advances in personalized neoantigen vaccines suggest a shift towards personalized, patient-specific GBM treatment. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
GBM Immunotherapy;  Glioblastoma;  Immunotherapy

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

Genetic drift does not sufficiently explain patterns of electric signal variation among populations of the mormyrid electric fish Paramormyrops kingsleyae
(2020) Evolution, . 

Picq, S.^a , Sperling, J.^b , Cheng, C.J.^b , Carlson, B.A.^c , Gallant, J.R.^a

^a Department of Integrative Biology, Michigan State University, East Lansing, MI 48824, United States
^b Department of Neurobiology and Behavior, Cornell University, Ithaca, NY 14853, United States
^c Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Communication signals serve crucial survival and reproductive functions. In Gabon, the widely distributed mormyrid fish Paramormyrops kingsleyae emits an electric organ discharge (EOD) signal with a dual role in communication and electrolocation that exhibits remarkable variation: populations of P. kingsleyae have either biphasic or triphasic EODs, a feature that characterizes interspecific signal diversity among the Paramormyrops genus. We quantified variation in EODs of 327 P. kingsleyae from nine populations and compared it to genetic variation estimated from microsatellite loci. We found no correlation between electric signal and genetic distances, suggesting that EOD divergence cannot be explained by drift alone. An alternative hypothesis is that EOD differences are used for mate discrimination, which would require P. kingsleyae be capable of differentiating between divergent EOD waveforms. Using a habituation-dishabituation assay, we found that P. kingsleyae can discriminate between biphasic and triphasic EOD types. Nonetheless, patterns of genetic and electric organ morphology divergence provide evidence for hybridization between these signal types. Although reproductive isolation with respect to signal type is incomplete, our results suggest that EOD variation in P. kingsleyae could be a cue for assortative mating. © 2020 The Authors. Evolution © 2020 The Society for the Study of Evolution.

Author Keywords
Animal communication;  electric organ;  electrocytes;  genetic drift;  signal evolution;  weakly electric fish

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

Borderline Personality Traits Are Not Correlated With Brain Structure in 2 Large Samples
(2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . 

Baranger, D.A.A.^a , Few, L.R.^b , Sheinbein, D.H.^c , Agrawal, A.^b , Oltmanns, T.F.^c , Knodt, A.R.^d , Barch, D.M.^{b c} , Hariri, A.R.^d , Bogdan, R.^c

^a Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^d Department of Psychology and Neuroscience, Duke University, Durham, NC, United States

Abstract
Background: Borderline personality disorder is associated with severe psychiatric presentations and has been linked to variability in brain structure. Dimensional models of borderline personality traits (BPTs) have become influential; however, associations between BPTs and brain structure remain poorly understood. Methods: We tested whether BPTs are associated with regional cortical thickness, cortical surface area, and subcortical volumes (n = 152 brain structure metrics) in data from the Duke Neurogenetics Study (n = 1299) and Human Connectome Project (n = 1099). Positive control analyses tested whether BPTs are associated with related behaviors (e.g., suicidal thoughts and behaviors, psychiatric diagnoses) and experiences (e.g., adverse childhood experiences). Results: While BPTs were robustly associated with all positive control measures, they were not significantly associated with any brain structure metrics in the Duke Neurogenetics Study or Human Connectome Project, or in a meta-analysis of both samples. The strongest findings from the meta-analysis showed a positive association between BPTs and volumes of the left ventral diencephalon and thalamus (p values < .005 uncorrected, p values > .1 false discovery rate–corrected). Contrasting high and low BPT decile groups (n = 552) revealed no false discovery rate–significant associations with brain structure. Conclusions: We find replicable evidence that BPTs are not associated with brain structure despite being correlated with independent behavioral measures. Prior reports linking brain morphology to borderline personality disorder may be driven by factors other than traits (e.g., severe presentations, comorbid conditions, severe childhood adversity, or medication) or reflect false positives. The etiology or consequences of BPTs may not be attributable to brain structure measured via magnetic resonance imaging. Future studies of BPTs will require much larger sample sizes to detect these very small effects. © 2020 Society of Biological Psychiatry

Author Keywords
Alcohol;  Borderline personality;  Brain structure;  Impulsivity;  Personality trait;  Suicidal thoughts

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

An in vivo proton magnetic resonance spectroscopy study with optimized echo-time technique for concurrent quantification and T2 measurement targeting glutamate in the rat brain
(2020) Magnetic Resonance Materials in Physics, Biology and Medicine, . 

Yoo, C.-H.^{a b c} , Baek, H.-M.^b , Song, K.-H.^d , Woo, D.-C.^c , Choe, B.-Y.^a

^a Department of Biomedicine and Health Sciences, Research Institute of Biomedical Engineering, College of Medicine, The Catholic University of Korea, #222 Banpo-Daero Seocho-Gu, Seoul, 06591, South Korea
^b Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, South Korea
^c Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
^d Biomedical MR Laboratory, Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States

Abstract
Objective: The present study applied in vivo proton magnetic resonance spectroscopy (1H MRS) to concurrently measure the concentration and T2 relaxation time of glutamate with the concept of optimized-for-quantification-and-T2-measurement-of-glutamate (OpQT2-Glu). Materials and methods: 7T MRS scans of the OpQT2-Glu were acquired from the prefrontal cortex of five rats. The echo-time-(TE)-specific J-modulation of glutamate was investigated by spectral simulations and analyses for selecting the eight TEs appropriate for T2 estimation of glutamate. The OpQT2-Glu results were compared to those of the typical short-TE MRS and T2 measurements. Results: No significant differences were observed between the OpQT2-Glu and typical short-TE MRS (p &gt; 0.050). The estimated glutamate T2 (67.75 ms) of the OpQT2-Glu was similar to the multiple TE MRS for the T2 measurement (71.58 ms) with enhanced signal-to-noise ratio and reliability. Discussion: The results revealed that the quantification reliability of the OpQT2-Glu was comparable to that of the single short-TE MRS and its estimation reliability for the T2 relaxation time of glutamate was enhanced compared to the multiple TE MRS for T2 measurement. Despite certain limitations, the quantification and T2 estimation of glutamate can be concurrently performed within an acceptable scan time via high-field in vivo 1H MRS with the OpQT2-Glu. © 2020, European Society for Magnetic Resonance in Medicine and Biology (ESMRMB).

Author Keywords
Brain metabolism and microenvironment;  Glutamate;  In vivo proton magnetic resonance spectroscopy

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

Feasibility and safety of transradial access for pediatric neurointerventions
(2020) Journal of NeuroInterventional Surgery, art. no. 015835, . 

Srinivasan, V.M.^a , Hadley, C.C.^a , Prablek, M.^a , Lopresti, M.^b , Chen, S.H.^c , Peterson, E.C.^d , Sweid, A.^e , Jabbour, P.^e , Young, C.^f , Levitt, M.^f , Osbun, J.W.^g , Burkhardt, J.-K.^{b h} , Johnson, J.^b , Kan, P., Dr.^b

^a Neurosurgery, Baylor College of Medicine, Houston, TX, United States
^b Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, United States
^c Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, United States
^d Neurological Surgery, University of Miami, Miami, FL, United States
^e Neurological Surgery, Thomas Jefferson University Hospital, Philadelphia, PA, United States
^f Neurological Surgery, University of Washington, Seattle, WA, United States
^g Neurosurgery, Washington University in St Louis School of Medicine, St Louis, MO, United States
^h Department of Neurosurgery, Texas Children’s Hospital, Houston, TX, United States

Abstract
Background: Diagnostic cerebral angiograms are increasingly being performed by transradial access (TRA) in adults, following data from the coronary literature supporting fewer access-site complications. Despite this ongoing trend in neuroangiography, there has been no discussion of its use in the pediatric population. Pediatric TRA has scarcely been described even for coronary or other applications. This is the first dedicated large study of transradial access for neuroangiography in pediatric patients. Methods: A multi-institutional series of consecutively performed pediatric transradial angiograms and interventions was collected. This included demographic, procedural, outcomes, and safety data. Data was prospectively recorded and retrospectively analyzed. Results: Thirty-seven diagnostic angiograms and 24 interventions were performed in 47 pediatric patients. Mean age, height, and weight was 14.1 years, 158.6 cm, and 57.1 kg, respectively. The radial artery measured 2.09+/-0.54 mm distally, and 2.09+/-0.44 mm proximally. Proximal and distal angiography were performed for both diagnostic and interventional application (17 distal angiograms, two distal interventions). Clinically significant vasospasm occurred in eight patients (13.1%). Re-access was successfully performed 11 times in seven patients. Conversion to femoral access occurred in five cases (8.2%). The only access-related complication was a small asymptomatic wrist hematoma after TR band removal. Conclusions: Transradial access in pediatric patients is safe and feasible. It can be performed successfully in many cases but carries some unique challenges compared with the adult population. Despite the challenge of higher rates of vasospasm and conversion to femoral access, it is worth exploring further, given the potential benefits. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
angiography;  catheter;  technique;  ultrasound

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

A Family-Based Genome Wide Association Study of Externalizing Behaviors
(2020) Behavior Genetics, . 

Barr, P.B.^a , Salvatore, J.E.^{a b} , Wetherill, L.^c , Anokhin, A.^d , Chan, G.^e , Edenberg, H.J.^f , Kuperman, S.^g , Meyers, J.^h , Nurnberger, J.^c , Porjesz, B.^h , Schuckit, M.ⁱ , Dick, D.M.^{a j}

^a Department of Psychology, Virginia Commonwealth University, 8 North Harrison St, Richmond, VA 23284, United States
^b Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
^c Department of Medical and Molecular Genetics, School of Medicine, Indiana University, Indianapolis, IN, United States
^d Department of Psychiatry, School of Medicine, Washington University in St. Louis, St Louis, MO, United States
^e Department of Psychiatry, School of Medicine, University of Connecticut, Farmington, CT, United States
^f Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN, United States
^g Department of Psychiatry, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
^h Department of Psychiatry & Behavioral Sciences, SUNY Down State Medical Center, SUNY Downstate, Brooklyn, NY, United States
ⁱ Department of Psychiatry, School of Medicine, University of California, San Diego, San Diego, CA, United States
^j Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Shared genetic factors contribute to the high degree of comorbidity among externalizing problems (e.g. substance use and antisocial behavior). We leverage this common genetic etiology to identify genetic influences externalizing problems in participants from the Collaborative Study on the Genetics of Alcoholism (European ancestry = 7568; African ancestry = 3274). We performed a family-based genome-wide association study (GWAS) on externalizing scores derived from criterion counts of five DSM disorders (alcohol dependence, alcohol abuse, illicit drug dependence, illicit drug abuse, and either antisocial personality disorder or conduct disorder). We meta analyzed these results with a similar measure of externalizing in an independent sample, Spit for Science (combined sample N = 15,112). We did not discover any robust genome-wide significant signals. Polygenic scores derived from the ancestry-specific GWAS summary statistics predicted externalizing problems in an independent European ancestry sample, but not in those of African ancestry. However, these PRS were no longer significant after adjusting for multiple testing. Larger samples with deep phenotyping are necessary for the discovery of SNPs related to externalizing problems. © 2020, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Externalizing;  GWAS;  Polygenic Scores;  Substance use

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

Predicting Recovery and Outcome after Pediatric Stroke: Results from the International Pediatric Stroke Study
(2020) Annals of Neurology, . 

Felling, R.J.^a , Rafay, M.F.^b , Bernard, T.J.^c , Carpenter, J.L.^d , Dlamini, N.^{e f} , Hassanein, S.M.A.^g , Jordan, L.C.^h , Noetzel, M.J.ⁱ , Rivkin, M.J.^j , Shapiro, K.A.^k , Slim, M.^{e f} , deVeber, G.^{e f} , the International Pediatric Stroke Study Group^l

^a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Pediatrics and Child Health, University of Manitoba, Children’s Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
^c Department of Pediatrics, University of Colorado, Aurora, CO, United States
^d Departments of Pediatrics and Neurology, George Washington University Children’s National Medical Center, Washington, DC, United States
^e Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada
^f Child Health Evaluative Sciences Program, Hospital for Sick Children, Toronto, ON, Canada
^g Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
^h Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, Nashville, TN, United States
ⁱ Departments of Neurology and Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^j Departments of Neurology, Radiology, and Psychiatry, Boston Children’s Hospital and Harvard Medical School, Boston, MA, United States
^k Department of Neurology, University of California, San Francisco, San Francisco, CA, United States

Abstract
Objective: To characterize predictors of recovery and outcome following pediatric arterial ischemic stroke, hypothesizing that age influences recovery after stroke. Methods: We studied children enrolled in the International Pediatric Stroke Study between January 1, 2003 and July 31, 2014 with 2-year follow-up after arterial ischemic stroke. Outcomes were defined at discharge by clinician grading and at 2 years by the Pediatric Stroke Outcome Measure. Demographic, clinical, and radiologic outcome predictors were examined. We defined changes in outcome from discharge to 2 years as recovery (improved outcome), emerging deficit (worse outcome), or no change. Results: Our population consisted of 587 patients, including 174 with neonatal stroke and 413 with childhood stroke, with recurrent stroke in 8.2% of childhood patients. Moderate to severe neurological impairment was present in 9.4% of neonates versus 48.8% of children at discharge compared to 8.0% versus 24.7% after 2 years. Predictors of poor outcome included age between 28 days and 1 year (compared to neonates, odds ratio [OR] = 3.58, p < 0.05), underlying chronic disorder (OR = 2.23, p < 0.05), and involvement of both small and large vascular territories (OR = 2.84, p < 0.05). Recovery patterns differed, with emerging deficits more common in children <1 year of age (p < 0.05). Interpretation: Outcomes after pediatric stroke are generally favorable, but moderate to severe neurological impairments are still common. Age between 28 days and 1 year appears to be a particularly vulnerable period. Understanding the timing and predictors of recovery will allow us to better counsel families and target therapies to improve outcomes after pediatric stroke. ANN NEUROL 2020. © 2020 American Neurological Association

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