“A transgenic mouse embryonic stem cell line for puromycin selection of V0V interneurons from heterogenous induced cultures” (2022) Stem Cell Research and Therapy
A transgenic mouse embryonic stem cell line for puromycin selection of V0V interneurons from heterogenous induced cultures(2022) Stem Cell Research and Therapy, 13 (1), art. no. 131, .
Pardieck, J.a b , Harb, M.a , Sakiyama-Elbert, S.E.a
a Department of Biomedical Engineering, The University of Texas at Austin, 107 W Dean Keeton St., Austin, TX 78712-1139, United Statesb Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
AbstractBackground: Spinal interneurons (INs) relay sensory and motor control information between the brain and body. When this relay circuitry is disrupted from injury or disease, it is devastating to patients due to the lack of native recovery in central nervous system (CNS) tissues. Obtaining a purified population of INs is necessary to better understand their role in normal function and as potential therapies in CNS. The ventral V0 (V0V) INs are excitatory neurons involved in locomotor circuits and are thus of interest for understanding normal and pathological spinal cord function. To achieve scalable amounts of V0V INs, they can be derived from pluripotent sources, such as mouse embryonic stem cells (mESCs), but the resultant culture is heterogenous, obscuring the specific role of V0V INs. This study generated a transgenic mESC line to enrich V0V INs from induced cultures to allow for a scalable, enriched population for future in vitro and in vivo studies. Methods: The transgenic Evx1-PAC mESC line was created by CRISPR-Cas9-mediated insertion of puromycin-N-acetyltransferase (PAC) into the locus of V0V IN marker Evx1. Evx1 and PAC mRNA expression were measured by qPCR. Viability staining helped establish the selection protocol for V0V INs derived from Evx1-PAC mESCs inductions. Immunostaining was used to examine composition of selected inductions. Cultures were maintained up to 30 days to examine maturation by expression of mature/synaptic markers, determined by immunostaining, and functional activity in co-cultures with selected motor neurons (MNs) and V2a INs on microelectrode arrays (MEAs). Results: V0V IN inductions were best selected with 4 µg/mL puromycin on day 10 to 11 and showed reduction of other IN populations and elimination of proliferative cells. Long-term selected cultures were highly neuronal, expressing neuronal nuclear marker NeuN, dendritic marker MAP2, pre-synaptic marker Bassoon, and glutamatergic marker VGLUT2, with some cholinergic VAChT-expressing cells. Functional studies on MEAs showed that co-cultures with MNs or MNs plus V2a INs created neuronal networks with synchronized bursting. Conclusions: Evx1-PAC mESCs can be used to purify V0V IN cultures for largely glutamatergic neurons that can be used in network formation studies or for rodent models requiring transplanted V0V INs. © 2022, The Author(s).
Author KeywordsNeuronal networks; Selectable transgenic mESCs; V0V spinal interneurons
Funding detailsNational Institutes of HealthNIHF31NS100432, R01NS090617
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer’s disease” (2022) Acta Neuropathologica Communications
Neutrophil-vascular interactions drive myeloperoxidase accumulation in the brain in Alzheimer’s disease(2022) Acta Neuropathologica Communications, 10 (1), art. no. 38, . Cited 1 time.
Smyth, L.C.D.a b c , Murray, H.C.d e , Hill, M.a b , van Leeuwen, E.a b , Highet, B.d e , Magon, N.J.a b , Osanlouy, M.f , Mathiesen, S.N.g h , Mockett, B.g , Singh-Bains, M.K.d e , Morris, V.K.i , Clarkson, A.N.j , Curtis, M.A.d e , Abraham, W.C.g , Hughes, S.M.h , Faull, R.L.M.d e , Kettle, A.J.a b , Dragunow, M.d k , Hampton, M.B.a b
a Centre for Free Radical Research, University of Otago, Christchurch, New Zealandb Department of Pathology and Biomedical Science, University of Otago, PO Box 4345, Christchurch, 8140, New Zealandc Department of Pathology and Immunology, Center for Brain Immunology and Glia, Washington University in St. Louis, Campus, Box 8118, St. Louis, MO, United Statesd Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealande Department of Anatomy With Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealandf Auckland Bioengineering Institute, University of Auckland, Auckland, New Zealandg Department of Psychology, University of Otago, Dunedin, New Zealandh Department of Biochemistry, University of Otago, Dunedin, New Zealandi School of Biological Science, University of Canterbury, Canterbury, New Zealandj Department of Anatomy, University of Otago, Dunedin, New Zealandk Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
AbstractIntroduction: Neutrophil accumulation is a well-established feature of Alzheimer’s disease (AD) and has been linked to cognitive impairment by modulating disease-relevant neuroinflammatory and vascular pathways. Neutrophils express high levels of the oxidant-generating enzyme myeloperoxidase (MPO), however there has been controversy regarding the cellular source and localisation of MPO in the AD brain. Materials and methods: We used immunostaining and immunoassays to quantify the accumulation of neutrophils in human AD tissue microarrays and in the brains of APP/PS1 mice. We also used multiplexed immunolabelling to define the presence of NETs in AD. Results: There was an increase in neutrophils in AD brains as well as in the murine APP/PS1 model of AD. Indeed, MPO expression was almost exclusively confined to S100A8-positive neutrophils in both human AD and murine APP/PS1 brains. The vascular localisation of neutrophils in both human AD and mouse models of AD was striking and driven by enhanced neutrophil adhesion to small vessels. We also observed rare infiltrating neutrophils and deposits of MPO around plaques. Citrullinated histone H3, a marker of neutrophil extracellular traps (NETs), was also detected in human AD cases at these sites, indicating the presence of extracellular MPO in the vasculature. Finally, there was a reduction in the endothelial glycocalyx in AD that may be responsible for non-productive neutrophil adhesion to the vasculature. Conclusion: Our report indicates that vascular changes may drive neutrophil adhesion and NETosis, and that neutrophil-derived MPO may lead to vascular oxidative stress and be a relevant therapeutic target in AD. © 2022, The Author(s).
Author KeywordsAlzheimer’s disease; Blood–brain barrier; Myeloperoxidase; Neutrophil; Neutrophil extracellular trap
Funding detailsLHR-2020–127339Aaniiih Nakoda CollegeANCHugh Green FoundationHGFHealth Research Council of New ZealandHRC15/479, 16/597, 21/710Brain Research New ZealandBRNZ1846WF
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Accuracy and reliability of diffusion imaging models” (2022) NeuroImage
Accuracy and reliability of diffusion imaging models(2022) NeuroImage, 254, art. no. 119138, .
Seider, N.A.a , Adeyemo, B.b , Miller, R.a b , Newbold, D.J.b p , Hampton, J.M.a , Scheidter, K.M.a b , Rutlin, J.c , Laumann, T.O.a , Roland, J.L.d , Montez, D.F.b , Van, A.N.b k , Zheng, A.b , Marek, S.a , Kay, B.P.b , Bretthorst, G.L.c e , Schlaggar, B.L.f g h , Greene, D.J.i , Wang, Y.c j k , Petersen, S.E.a c k l m , Barch, D.M.a c m , Gordon, E.M.c , Snyder, A.Z.b c , Shimony, J.S.c l , Dosenbach, N.U.F.b c k n o
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United Statesb Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United Statesc Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United Statesd Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO 63110, United Statese Department of Chemistry, Washington University in St Louis, MO, St. Louis, 63110, United Statesf Kennedy Krieger Institute, Baltimore, MD 21205, United Statesg Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United Statesh Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United Statesi Department of Cognitive Science, University of California, San Diego, La Jolla, CA, United Statesj Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110, United Statesk Department of Biomedical Engineering, Washington University in St Louis, St. Louis, MO 63110, United Statesl Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United Statesm Department of Psychological and Brain Sciences, Washington University in St. LouisMO 63110, United Statesn Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United Stateso Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United Statesp Department of Neurology, New York University Langone Medical Center, New York, NY 10016, United States
AbstractDiffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain’s white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927–1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL’s BedpostX [BPX], DSI Studio’s Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3’s Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI. © 2022
Funding details14–0111IK2CX001680National Institutes of HealthNIHAG053548, HD087011, HD094381, MH1000872, MH104592, MH112473, MH121276, MH121518, MH122066, MH124567, MH96773, NS088590, NS090978, NS098577, NS110332, NS115672, T32MH100019March of Dimes FoundationMDFJames S. McDonnell FoundationJSMFBrightFocus FoundationBFFA2017330SChild Neurology FoundationCNFMcDonnell Center for Systems NeuroscienceHope Center for Neurological DisordersJacobs Foundation2016121703
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Polysomnographic identification of anxiety and depression using deep learning” (2022) Journal of Psychiatric Research
Polysomnographic identification of anxiety and depression using deep learning(2022) Journal of Psychiatric Research, 150, pp. 54-63.
Thakre, T.P.a b , Kulkarni, H.c , Adams, K.S.a d , Mischel, R.e , Hayes, R.b , Pandurangi, A.a
a Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, United Statesb Center for Sleep Medicine, Virginia Commonwealth University Health, Richmond, VA, United Statesc M&H Research, LLC, San Antonio, TX, United Statesd Department of Pharmacy Services, Virginia Commonwealth University Health, Richmond, VA, United Statese Department of Psychiatry, Washington University at St. Louis School of Medicine, St. Louis, MO, United States
AbstractAnxiety and depression are common psychiatric conditions associated with significant morbidity and healthcare costs. Sleep is an evolutionarily conserved health state. Anxiety and depression have a bidirectional relationship with sleep. This study reports on the use of analysis of polysomnographic data using deep learning methods to detect the presence of anxiety and depression. Polysomnography data on 940 patients performed at an academic sleep center during the 3-year period from 01/01/2016 to 12/31/2018 were identified for analysis. The data were divided into 3 subgroups: 205 patients with Anxiety/Depression, 349 patients with no Anxiety/Depression, and 386 patients with likely Anxiety/Depression. The first two subgroups were used for training and testing of the deep learning algorithm, and the third subgroup was used for external validation of the resulting model. Hypnograms were constructed via automatic sleep staging, with the 12-channel PSG data being transformed into three-channel RGB (red, green, blue channels) images for analysis. Composite patient images were generated and utilized for training the Xception model, which provided a validation set accuracy of 0.9782 on the ninth training epoch. In the independent test set, the model achieved a high accuracy (0.9688), precision (0.9533), recall (0.9630), and F1-score (0.9581). Classification performance of most other mainstream deep learning models was comparable. These findings suggest that machine learning techniques have the potential to accurately detect the presence of anxiety and depression from analysis of sleep study data. Further studies are needed to explore the utility of these techniques in the field of psychiatry. © 2022
Author KeywordsAnxiety; Deep learning; Depression; Machine learning; Polysomnography
Funding detailsVirginia Commonwealth UniversityVCU
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Reliability and stability challenges in ABCD task fMRI data” (2022) NeuroImage
Reliability and stability challenges in ABCD task fMRI data(2022) NeuroImage, 252, art. no. 119046, .
Kennedy, J.T.a , Harms, M.P.a , Korucuoglu, O.a , Astafiev, S.V.a , Barch, D.M.a , Thompson, W.K.b , Bjork, J.M.c , Anokhin, A.P.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United Statesb Division of Biostatistics and Department of Radiology, Population Neuroscience and Genetics Lab, University of California, San Diego, United Statesc Department of Psychiatry, Virginia Commonwealth University, United States
AbstractTrait stability of measures is an essential requirement for individual differences research. Functional MRI has been increasingly used in studies that rely on the assumption of trait stability, such as attempts to relate task related brain activation to individual differences in behavior and psychopathology. However, recent research using adult samples has questioned the trait stability of task-fMRI measures, as assessed by test-retest correlations. To date, little is known about trait stability of task fMRI in children. Here, we examined within-session reliability and long-term stability of individual differences in task-fMRI measures using fMRI measures of brain activation provided by the adolescent brain cognitive development (ABCD) Study Release v4.0 as an individual’s average regional activity, using its tasks focused on reward processing, response inhibition, and working memory. We also evaluated the effects of factors potentially affecting reliability and stability. Reliability and stability (quantified as the ratio of non-scanner related stable variance to all variances) was poor in virtually all brain regions, with an average value of 0.088 and 0.072 for short term (within-session) reliability and long-term (between-session) stability, respectively, in regions of interest (ROIs) historically-recruited by the tasks. Only one reliability or stability value in ROIs exceeded the ‘poor’ cut-off of 0.4, and in fact rarely exceeded 0.2 (only 4.9%). Motion had a pronounced effect on estimated reliability/stability, with the lowest motion quartile of participants having a mean reliability/stability 2.5 times higher (albeit still ‘poor’) than the highest motion quartile. Poor reliability and stability of task-fMRI, particularly in children, diminishes potential utility of fMRI data due to a drastic reduction of effect sizes and, consequently, statistical power for the detection of brain-behavior associations. This essential issue urgently needs to be addressed through optimization of task design, scanning parameters, data acquisition protocols, preprocessing pipelines, and data denoising methods. © 2022
Funding detailsNational Institutes of HealthNIHR01HD083614, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA051016, U01DA051018, U01DA051037, U01DA051038, U01DA051039, U24DA041123, U24DA041147National Institute of Mental HealthNIMH
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Hypothiocyanous Acid Disrupts the Barrier Function of Brain Endothelial Cells” (2022) Antioxidants
Hypothiocyanous Acid Disrupts the Barrier Function of Brain Endothelial Cells(2022) Antioxidants, 11 (4), art. no. 608, .
van Leeuwen, E.a , Hampton, M.B.a , Smyth, L.C.D.a b
a Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago, Christchurch, 8011, New Zealandb Center for Brain Immunology and Glia, Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, United States
AbstractInflammation is a common feature of neurological diseases. During neuroinflammation, neutrophils are recruited to the brain vasculature, where myeloperoxidase can produce hypochlorous acid and the less well-studied oxidant hypothiocyanous acid (HOSCN). In this study, we exposed primary brain endothelial cells (BECs) to HOSCN and observed a rapid loss of transendothelial electrical resistance (TEER) at sublethal concentrations. Decreased barrier function was associated with a loss of tight junctions at cellular contacts and a concomitant loss of dynamic microtubules. Both tight junction and cytoskeletal disruptions were visible within 30 min of exposure, whereas significant loss of TEER took more than 1 h. The removal of the HOSCN after 30 min prevented subsequent barrier dysfunction. These results indicate that BECs are sensitive to HOSCN, resulting in the eventual loss of barrier function. We hypothesise that this mechanism may be relevant in neutrophil transmigration, with HOSCN facilitating blood–brain barrier opening at the sites of egress. Furthermore, this mechanism may be a way through which neutrophils, residing in the vasculature, can influence neuroinflammation in diseases. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Author KeywordsBlood–brain barrier; Brain endothelial cells; Cytoskeleton; Hypothiocyanous acid; Myeloperoxidase; Oxidative stress; Tight junctions
Funding detailsUniversity of OtagoHealth Research Council of New ZealandHRC15/479Neurological Foundation of New Zealand1846WF
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Steroid hormone signaling activates thermal nociception during Drosophila peripheral nervous system development” (2022) eLife
Steroid hormone signaling activates thermal nociception during Drosophila peripheral nervous system development(2022) eLife, 11, art. no. e76464, .
Jaszczak, J.S.a b , Devault, L.a c , Jan, L.Y.a b , Jan, Y.N.a b
a Department of Physiology, Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United Statesb Howard Hughes Medical Institute, Chevy Chase, United Statesc Department of Developmental Biology, Washington University Medical School, Saint Louis, United States
AbstractSensory neurons enable animals to detect environmental changes and avoid harm. An intriguing open question concerns how the various attributes of sensory neurons arise in devel-opment. Drosophila melanogaster larvae undergo a behavioral transition by robustly activating a thermal nociceptive escape behavior during the second half of larval development (third instar). The Class IV dendritic arborization (C4da) neurons are multimodal sensors which tile the body wall of Drosophila larvae and detect nociceptive temperature, light, and mechanical force. In contrast to the increase in nociceptive behavior in the third instar, we find that ultraviolet light-induced Ca2+ activity in C4da neurons decreases during the same period of larval development. Loss of ecdysone receptor has previously been shown to reduce nociception in third instar larvae. We find that ligand-dependent activation of ecdysone signaling is sufficient to promote nociceptive responses in second instar larvae and suppress expression of subdued (encoding a TMEM16 channel). Reduction of subdued expression in second instar C4da neurons not only increases thermal nociception but also decreases the response to ultraviolet light. Thus, steroid hormone signaling suppresses subdued expression to facilitate the sensory switch of C4da neurons. This regulation of a developmental sensory switch through steroid hormone regulation of channel expression raises the possibility that ion channel homeostasis is a key target for tuning the development of sensory modalities. © Jaszczak et al.
Funding detailsNational Institutes of HealthNIHP40OD018537National Institute of General Medical SciencesNIGMSF32GM130019National Institute of Neurological Disorders and StrokeNINDSR35NS097227
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Reduced neural activity but improved coding in rodent higher-order visual cortex during locomotion” (2022) Nature Communications
Reduced neural activity but improved coding in rodent higher-order visual cortex during locomotion(2022) Nature Communications, 13 (1), p. 1676.
Christensen, A.J.a , Pillow, J.W.b
a Department of Neuroscience, Washington University, St. Louis, MO, USA. pillow@princeton.edub Princeton Neuroscience Institute & Department of Psychology, Princeton University, Princeton, United States
AbstractRunning profoundly alters stimulus-response properties in mouse primary visual cortex (V1), but its effect in higher-order visual cortex is under-explored. Here we systematically investigate how visual responses vary with locomotive state across six visual areas and three cortical layers using a massive dataset from the Allen Brain Institute. Although previous work has shown running speed to be positively correlated with neural activity in V1, here we show that the sign of correlations between speed and neural activity varies across extra-striate cortex, and is even negative in anterior extra-striate cortex. Nevertheless, across all visual cortices, neural responses can be decoded more accurately during running than during stationary periods. We show that this effect is not attributable to changes in population activity structure, and propose that it instead arises from an increase in reliability of single-neuron responses during locomotion. © 2022. The Author(s).
Document Type: ArticlePublication Stage: FinalSource: Scopus
“The Dual Mechanisms of Cognitive Control dataset, a theoretically-guided within-subject task fMRI battery” (2022) Scientific Data
The Dual Mechanisms of Cognitive Control dataset, a theoretically-guided within-subject task fMRI battery(2022) Scientific Data, 9 (1), p. 114.
Etzel, J.A.a , Brough, R.E.a , Freund, M.C.a , Kizhner, A.a b , Lin, Y.a , Singh, M.F.a c d e , Tang, R.a , Tay, A.a , Wang, A.a d , Braver, T.S.a c f
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, United Statesb Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, United Statesc Department of Neuroscience, Washington University in St. Louis, St. Louis, United Statesd Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, United Statese Center for Molecular and Behavioral Neuroscience, Rutgers University, Piscataway, United Statesf Department of Radiology, Washington University in St. Louis, St. Louis, United States
AbstractCognitive control is a critical higher mental function, which is subject to considerable individual variation, and is impaired in a range of mental health disorders. We describe here the initial release of Dual Mechanisms of Cognitive Control (DMCC) project data, the DMCC55B dataset, with 55 healthy unrelated young adult participants. Each participant performed four well-established cognitive control tasks (AX-CPT, Cued Task-Switching, Sternberg Working Memory, and Stroop) while undergoing functional MRI scanning. The dataset includes a range of state and trait self-report questionnaires, as well as behavioural tasks assessing individual differences in cognitive ability. The DMCC project is on-going and features additional components (e.g., related participants, manipulations of cognitive control mode, resting state fMRI, longitudinal testing) that will be publicly released following study completion. This DMCC55B subset is released early with the aim of encouraging wider use and greater benefit to the scientific community. The DMCC55B dataset is suitable for benchmarking and methods exploration, as well as analyses of task performance and individual differences. © 2022. The Author(s).
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Differential Sphingosine-1-Phosphate Receptor-1 Protein Expression in the Dorsolateral Prefrontal Cortex Between Schizophrenia Type 1 and Type 2” (2022) Frontiers in Psychiatry
Differential Sphingosine-1-Phosphate Receptor-1 Protein Expression in the Dorsolateral Prefrontal Cortex Between Schizophrenia Type 1 and Type 2(2022) Frontiers in Psychiatry, 13, art. no. 827981, .
Chand, G.B.a , Jiang, H.a , Miller, J.P.b , Rhodes, C.H.c , Tu, Z.a , Wong, D.F.a d
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United Statesb Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United Statesc NeuroDex Inc, Natick, MA, United Statesd Department of Psychiatry, Neuroscience, and Neurology, Washington University School of Medicine, St. Louis, MO, United States
AbstractUnderstanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia. Recent in vitro findings of messenger ribonucleic acid (mRNA) gene expression on postmortem dorsolateral prefrontal cortex (DLPFC) showed that schizophrenia has two subtypes, those with a relatively normal DLPFC transcriptome (Type 1) and those with differentially expressed genes (Type 2). Sphingosine-1-phosphate receptor-1 (S1PR1) is one of the genes that was highly upregulated in Type 2 compared to Type 1 and controls. The impact of that finding is limited because it only can be confirmed through analysis of autopsy tissue, and the clinical characteristics such as symptoms severity or illness duration except for cause of death was not available from that Medical Examiner based autopsy study. However, S1PR1 has great potential because it is a target gene that can be accessed via positron emission tomography (PET) in vivo using specific radioligands (starting with [11C]CS1P1) successfully developed at our center in human brain imaging. As a preliminary study to validate this PET target in schizophrenia, S1PR1 protein expression was assessed by receptor autoradiography (ARG) using [3H]CS1P1 and immunohistochemistry (IHC) in the DLPFC from patients with schizophrenia classified as Type 1 or Type 2 based on their DLPFC transcriptomes and from controls. Our analyses demonstrate that ARG S1PR1 protein expression is significantly higher in Type 2 compared to Type 1 (p < 0.05) and controls (p < 0.05), which was consistent with previous mRNA S1PR1. These findings support the possibility that PET S1PR1 can be used as a future imaging biomarker to distinguish these subgroups of schizophrenic patients during life with obvious implications for both patient management and the design of clinical trials to validate novel pharmacologic therapies. Copyright © 2022 Chand, Jiang, Miller, Rhodes, Tu and Wong.
Author Keywordsautoradiography; molecular imaging; neuroimaging; postmortem brain tissues; schizophrenia; sphingosine-1-phosphate receptor-1 (S1PR1)
Funding detailsNational Institute of Mental HealthNIMH
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Modification of Neurogenic Colonic Motor Behaviours by Chemogenetic Ablation of Calretinin Neurons” (2022) Frontiers in Cellular Neuroscience
Modification of Neurogenic Colonic Motor Behaviours by Chemogenetic Ablation of Calretinin Neurons(2022) Frontiers in Cellular Neuroscience, 16, art. no. 799717, .
Feng, J.a b , Hibberd, T.J.c , Luo, J.a , Yang, P.a , Xie, Z.a , Travis, L.c , Spencer, N.J.c , Hu, H.a
a Center for the Study of Itch and Sensory Disorders, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United Statesb Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, Chinac College of Medicine and Public Health, Centre for Neuroscience, Flinders University, Adelaide, SA, Australia
AbstractHow the enteric nervous system determines the pacing and propagation direction of neurogenic contractions along the colon remains largely unknown. We used a chemogenetic strategy to ablate enteric neurons expressing calretinin (CAL). Mice expressing human diphtheria toxin receptor (DTR) in CAL neurons were generated by crossing CAL-ires-Cre mice with Cre-dependent ROSA26-DTR mice. Immunohistochemical analysis revealed treatment with diphtheria toxin incurred a 42% reduction in counts of Hu-expressing colonic myenteric neurons (P = 0.036), and 57% loss of CAL neurons (comprising ∼25% of all Hu neurons; P = 0.004) compared to control. As proportions of Hu-expressing neurons, CAL neurons that contained nitric oxide synthase (NOS) were relatively spared (control: 15 ± 2%, CAL-DTR: 13 ± 1%; P = 0.145), while calretinin neurons lacking NOS were significantly reduced (control: 26 ± 2%, CAL-DTR: 18 ± 5%; P = 0.010). Colonic length and pellet sizes were significantly reduced without overt inflammation or changes in ganglionic density. Interestingly, colonic motor complexes (CMCs) persisted with increased frequency (mid-colon interval 111 ± 19 vs. 189 ± 24 s, CAL-DTR vs. control, respectively, P < 0.001), decreased contraction size (mid-colon AUC 26 ± 24 vs. 59 ± 13 gram/seconds, CAL-DTR vs. control, respectively, P < 0.001), and lacked preferential anterograde migration (P < 0.001). The functional effects of modest calretinin neuron ablation, particularly increased neurogenic motor activity frequencies, differ from models that incur general enteric neuron loss, and suggest calretinin neurons may contribute to pacing, force, and polarity of CMCs in the large bowel. Copyright © 2022 Feng, Hibberd, Luo, Yang, Xie, Travis, Spencer and Hu.
Author Keywordscolon; colonic motor complex; enteric nervous system; IPAN; large intestine; peristalsis; sensory neuron
Funding detailsNational Institutes of HealthNIHR01DK103901, R01GM101218National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK1156416, P30 DK052574Australian Research CouncilARC190103628
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Prevalence of parkinsonism and Parkinson disease in urban and rural populations from Latin America: A community based study” (2022) The Lancet Regional Health – Americas
Prevalence of parkinsonism and Parkinson disease in urban and rural populations from Latin America: A community based study(2022) The Lancet Regional Health – Americas, 7, art. no. 100136, .
Llibre-Guerra, J.J.a b , Prina, M.c , Sosa, A.L.d , Acosta, D.e , Jimenez-Velazquez, I.Z.f , Guerra, M.g , Salas, A.h , Llibre-Guerra, J.C.i , Valvuerdi, A.j , Peeters, G.k , Ziegemeier, E.a , Acosta, I.d , Tanner, C.l , Juncos, J.m , Llibre Rodriguez, J.J.n
a Department of Neurology, Washington University School of Medicine in St. Louis, United Statesb Department of Neurology, National Institute of Neurology and Neurosurgery, La Habana, Cubac Health Service and Population Research Department, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdomd Laboratory of the Dementias, National Institute of Neurology and Neurosurgery of Mexico, National Autonomous University of Mexico, Mexico City, Mexicoe Universidad Nacional Pedro Henriquez Ureña (UNPHU), Internal Medicine Department, Geriatric Section, Santo Domingo, Dominican Republicf Internal Medicine Department, Geriatrics Program, School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Ricog Instituto de la Memoria Depresion y Enfermedades de Riesgo IMEDER, Lima, Peruh Medicine Department, Caracas University Hospital, Faculty of Medicine, Universidad Central de Venezuela, Caracas, Venezuelai Department of Neurology, Hospital del Mar, Barcelona, Spainj Medical University of Matanzas, Matanzas, Cubak Radboud Institute of Health Sciences, Radboud University Medical Centre, Nijmegen, Netherlandsl Department of Neurology, Weill Institute for Neurosciences, University of San Francisco, California, United Statesm Department of Neurology, Emory University School of Medicine.n Facultad de Medicina Finlay-Albarran, Medical University of Havana, Havana, Cuba
AbstractBackground: Age and gender specific prevalence rates for parkinsonism and Parkinson’s disease (PD) are important to guide research, clinical practice, and public health planning; however, prevalence estimates in Latin America (LatAm) are limited. We aimed to estimate the prevalence of parkinsonism and PD and examine related risk factors in a cohort of elderly individuals from Latin America (LatAm). Methods: Data from 11,613 adults (65+ years) who participated in a baseline assessment of the 10/66 study and lived in six LatAm countries were analyzed to estimate parkinsonism and PD prevalence. Crude and age-adjusted prevalence were determined by sex and country. Diagnosis of PD was established using the UK Parkinson’s Disease Society Brain Bank’s clinical criteria. Findings: In this cohort, the prevalence of parkinsonism was 8.0% (95% CI 7.6%–8.5%), and the prevalence of PD was 2.0% (95% CI 1.7%–2.3%). PD prevalence increased with age from 1.0 to 3.5 (65–69vs. 80 years or older, p < 0.001). Age-adjusted prevalence rates were lower for women than for men. No significant differences were found across countries, except for lower prevalence in urban areas of Peru. PD was positively associated with depression (adjusted prevalence ratio [aPR] 2.06, 95% CI 1.40–3.01, I2 = 56.0%), dementia (aPR 1.57, 95% CI 1.07- 2.32, I2 = 0.0%) and educational level (aPR 1.14, 95% CI 1.01– 1.29, I2 = 58.6%). Interpretation: The reported prevalence of PD in LatAm is similar to reports from high-income countries (HIC). A significant proportion of cases with PD did not have a previous diagnosis, nor did they seek any medical or neurological attention. These findings underscore the need to improve public health programs for populations currently undergoing rapid demographic aging and epidemiological transition. Funding: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. © 2021 The Author(s)
Author KeywordsLatin America; Parkinson’s disease; Parkinsonism; Prevalence; Risk factors
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Hold that pose: capturing cervical dystonia’s head deviation severity from video” (2022) Annals of Clinical and Translational Neurology
Hold that pose: capturing cervical dystonia’s head deviation severity from video(2022) Annals of Clinical and Translational Neurology, .
Zhang, Z.a , Cisneros, E.a , Lee, H.Y.a , Vu, J.P.a , Chen, Q.a , Benadof, C.N.a , Whitehill, J.b , Rouzbehani, R.a , Sy, D.T.a , Huang, J.S.c , Sejnowski, T.J.d , Jankovic, J.e , Factor, S.f , Goetz, C.G.g , Barbano, R.L.h , Perlmutter, J.S.i j , Jinnah, H.A.f k , Berman, B.D.l , Richardson, S.P.m n , Stebbins, G.T.g , Comella, C.L.g , Peterson, D.A.a d
a Institute for Neural Computation, University of California, San Diego, La Jolla, CA, United Statesb Department of Computer Science, Worcester Polytechnic Institute, Worcester, MA, United Statesc Department of Pediatrics, University of California, San Diego, La Jolla, CA, United Statesd Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, United Statese Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United Statesf Department of Neurology, Emory University School of Medicine, Atlanta, GA, United Statesg Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United Statesh Department of Neurology, University of Rochester, Rochester, NY, United Statesi Department of Neurology, Washington University School of Medicine, St. Louis, MO, United Statesj Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United Statesk Departments of Human Genetics, Emory University School of Medicine, Atlanta, GA, United Statesl Department of Neurology, Virginia Commonwealth University, Richmond, VA, United Statesm Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, United Statesn Neurology Service, New Mexico Veterans Affairs Health Care System, Albuquerque, NM, United States
AbstractObjective: Deviated head posture is a defining characteristic of cervical dystonia (CD). Head posture severity is typically quantified with clinical rating scales such as the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). Because clinical rating scales are inherently subjective, they are susceptible to variability that reduces their sensitivity as outcome measures. The variability could be circumvented with methods to measure CD head posture objectively. However, previously used objective methods require specialized equipment and have been limited to studies with a small number of cases. The objective of this study was to evaluate a novel software system—the Computational Motor Objective Rater (CMOR)—to quantify multi-axis directionality and severity of head posture in CD using only conventional video camera recordings. Methods: CMOR is based on computer vision and machine learning technology that captures 3D head angle from video. We used CMOR to quantify the axial patterns and severity of predominant head posture in a retrospective, cross-sectional study of 185 patients with isolated CD recruited from 10 sites in the Dystonia Coalition. Results: The predominant head posture involved more than one axis in 80.5% of patients and all three axes in 44.4%. CMOR’s metrics for head posture severity correlated with severity ratings from movement disorders neurologists using both the TWSTRS-2 and an adapted version of the Global Dystonia Rating Scale (rho = 0.59–0.68, all p <0.001). Conclusions: CMOR’s convergent validity with clinical rating scales and reliance upon only conventional video recordings supports its future potential for large scale multisite clinical trials. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding detailsW81XWH‐17‐1‐0393, W81XWH‐19‐1‐0146National Institutes of HealthNIHNational Institute of Neurological Disorders and StrokeNINDSU54 NS065701, U54 NS116025National Center for Advancing Translational SciencesNCATSU54 TR001456
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Return of the lesion: a meta-analysis of 1134 angiographically cured pediatric arteriovenous malformations” (2021) Journal of Neurosurgery: Pediatrics
Return of the lesion: a meta-analysis of 1134 angiographically cured pediatric arteriovenous malformations(2021) Journal of Neurosurgery: Pediatrics, 28 (6), pp. 677-684.
Lauzier, D.C.a d , Vellimana, A.K.a , Chatterjee, A.R.e , Osbun, J.W.e , Moran, C.J.a b , Zipfel, G.J.b c , Kansagra, A.P.a c
a Mallinckrodt Institute of Radiology, United Statesb Department of Neurological Surgery, United Statesc Department of Neurology, Washington University School of Medicine, St. Louis, MO, United Statesd Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
AbstractOBJECTIVE Brain arteriovenous malformations (AVMs) carry a risk of rupture and subsequent morbidity or mortality unless fully treated. AVMs in pediatric patients are known to occasionally recur after obliteration. The objective of this study was to characterize the risk of AVM recurrence following angiographically confirmed obliteration in children. METHODS Consecutive pediatric AVMs treated at a single center were identified from a prospective database. Patients with angiographically confirmed AVM obliteration following treatment were included in this study. Associations between AVM recurrence and patient or procedural factors were characterized using the two-tailed Fisher exact test or Mann-Whitney U-test. A literature search was conducted using PubMed, Scopus, Embase, and the Clarivate Web of Science with defined search criteria, and eligible studies were included alongside this study cohort in a meta-analysis. Rates of AVM recurrence following obliteration were pooled across studies with a random-effects model and reported with 95% confidence intervals (CIs). RESULTS Recurrence after angiographic confirmation of AVM obliteration was observed in 10.4% (7/67) of pediatric AVMs treated at the authors’ center. Patients with recurrent AVMs were significantly younger than those without recurrence (p = 0.002). In the meta-analysis, which included 1134 patients across 24 studies, the rate of recurrence was 4.8% (95% CI 3.0%–6.7%). The rate of AVM recurrence following radiosurgery was 0.7% (95% CI 0%–1.6%), which was significantly lower than the 8.5% rate (95% CI 5.0%–12.0%) following microsurgery. CONCLUSIONS Recurrence of obliterated brain AVMs is common in children. Recurrence is more common in young children and following microsurgery. ©AANS 2021, except where prohibited by US copyright law
Author Keywordsangiography; arteriovenous malformation; obliteration; recurrence; vascular disorders
Document Type: ArticlePublication Stage: FinalSource: Scopus