"Testing neurophysiological markers related to fear-potentiated startle" (2018) Psychiatry Research
Testing neurophysiological markers related to fear-potentiated startle
(2018) Psychiatry Research, 267, pp. 195-200.
Seligowski, A.V.a b , Bondy, E.c , Singleton, P.a b , Orcutt, H.K.d , Ressler, K.J.a b , Auerbach, R.P.b e f
a Department of Psychiatry, Harvard Medical School, Boston, MA, United States
b McLean Hospital, Belmont, MA, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology, Northern Illinois University, DeKalb, IL, United States
e Department of Psychiatry, Columbia University, New York, NY, United States
f Division of Clinical Developmental Neuroscience, New York, NY, United States
Fear-potentiated startle (FPS) paradigms provide insight into fear learning mechanisms that contribute to impairment among individuals with posttraumatic stress symptoms (PTSS). Electrophysiology also has provided insight into these mechanisms through the examination of event-related potentials (ERPs) such as the P100 and LPP. It remains unclear, however, whether the P100 and LPP may be related to fear learning processes within the FPS paradigm. To this end, we tested differences in ERP amplitudes for conditioned stimuli associated (CS+) and not associated (CS-) with an aversive unconditioned stimulus (US) during fear acquisition. Participants included 54 female undergraduate students (mean age = 20.26). The FPS response was measured via electromyography of the orbicularis oculi muscle. EEG data were collected during the FPS paradigm. While the difference between CS+ and CS- P100 amplitude was not significant, LPP amplitudes were significantly enhanced following the CS+ relative to CS-. Furthermore, the LPP difference wave (CS+ minus CS-) was associated with FPS scores for the CS- during the later portion of fear acquisition. These findings suggest that conditioned stimuli may have altered emotional encoding (LPP) during the FPS paradigm. Thus, the LPP may be a promising neurophysiological marker that is related to fear learning processes. © 2018 Elsevier B.V.
Fear discrimination; Fear inhibition; Fear-potentiated startle; Late positive potential; P100
Document Type: Article
"Epilepsy treatment patterns among patients with tuberous sclerosis complex" (2018) Journal of the Neurological Sciences
Epilepsy treatment patterns among patients with tuberous sclerosis complex
(2018) Journal of the Neurological Sciences, 391, pp. 104-108.
Song, J.a , Swallow, E.a , Said, Q.b , Peeples, M.a , Meiselbach, M.a , Signorovitch, J.a , Kohrman, M.c , Korf, B.d , Krueger, D.e , Wong, M.f , Sparagana, S.g
a Analysis Group, Inc., 111 Huntington Ave, Floor 14, Boston, MA, United States
b Novartis Pharmaceuticals Corporation, 1 Health Plaza, East Hanover, NJ, United States
c Akron Children’s Hospital, 1 Perkins Square, Akron, OH, United States
d University of Alabama at Birmingham, 1720 2<sup>nd</sup> Ave S, Birmingham, AL, United States
e Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, United States
f Washington University in Saint Louis, 1 Brookings Dr, St. Louis, MO, United States
g Texas Scottish Rite Hospital for Children, 2222 Wellborn St, Dallas, TX, United States
Introduction: Tuberous sclerosis complex (TSC) is a rare congenital disorder often associated with epilepsy. However, real-world treatment patterns for epilepsy in patients with TSC are not yet well categorized. Methods: This study included patients with TSC and epilepsy from fifteen clinics in the United States and one in Belgium who were enrolled in the TSC Natural History Database (2006–2014). Patient demographics and epilepsy treatment patterns, including the use of anti-epileptic drugs (AEDs), epilepsy surgeries, and dietary therapies were assessed. Results: Of the 1328 patients with TSC in the database, 1110 (83.6%) were diagnosed with epilepsy. The median age of epilepsy diagnosis was 0.7 years. Of those who received treatment for epilepsy (92.3%), 99.5% were prescribed AEDs, 25.3% underwent surgery, 7.9% were prescribed special diets, and 1% were prescribed mammalian target of rapamycin (mTOR) inhibitors. Of the patients receiving AEDs, over half (64.5%) used ≥3 different AEDs, and 22.5% underwent surgical treatment following AED initiation. Of the patients who underwent surgery, 35.1% had subsequent surgery. Conclusion: The use of multiple AEDs and surgical interventions may indicate a need for new therapies to reduce the treatment burden among patients with TSC and epilepsy. © 2018
Anti-epileptic drugs; Epilepsy; Treatment patterns; Tuberous sclerosis complex; Tuberous Sclerosis Natural History Database
Document Type: Article
"Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data" (2018) Developmental Cognitive Neuroscience
Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data
(2018) Developmental Cognitive Neuroscience, 32, pp. 97-106. Cited 1 time.
Uban, K.A.a , Horton, M.K.b , Jacobus, J.c , Heyser, C.d , Thompson, W.K.e , Tapert, S.F.c , Madden, P.A.F.f , Sowell, E.R.a , the Adolescent Brain Cognitive Development Studyg
a Department of Pediatrics, Keck School of Medicine, University of Southern California, Children’s Hospital Los Angeles, Los Angeles, CA, United States
b Icahn School of Medicine at Mount Sinai, Department of Environmental Medicine and Public Health, New York, NY, United States
c Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
d School of Medicine, University of California San Diego, La Jolla, CA, United States
e Department of Family Medicine and Public Health, Division of Biostatistics, University of California San Diego, La Jolla, CA, United States
f Washington University, School of Medicine, Department of Psychiatry, St. Louis, MO, United States
Biospecimen collection in the Adolescent Brain Cognitive Development (ABCD) study – of hair samples, shed deciduous (baby) teeth, and body fluids – will serve dual functions of screening for study eligibility, and providing measures of biological processes thought to predict or correlate with key study outcomes on brain and cognitive development. Biosamples are being collected annually to screen for recency of drug use prior to the neuroimaging or cognitive testing visit, and to store for the following future studies: (1) on the effects of exposure to illicit and recreational drugs (including alcohol and nicotine); (2) of pubertal hormones on brain and cognitive developmental trajectories; (3) on the contribution of genomics and epigenomics to child and adolescent development and behavioral outcomes; and (4) with pre- and post-natal exposure to environmental neurotoxicants and drugs of abuse measured from novel tooth analyses. The present manuscript describes the rationales for inclusion and selection of the specific biospecimens, methodological considerations for each measure, future plans for assessment of biospecimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations. © 2018
ABCD study; Biospecimens; Environmental exposures; Genetics; Gonadal hormones; Substance use
Document Type: Review
Access Type: Open Access
"Intraoperative electroencephalogram suppression at lower volatile anaesthetic concentrations predicts postoperative delirium occurring in the intensive care unit" (2018) British Journal of Anaesthesia
Intraoperative electroencephalogram suppression at lower volatile anaesthetic concentrations predicts postoperative delirium occurring in the intensive care unit
(2018) British Journal of Anaesthesia, 121 (1), pp. 241-248. Cited 1 time.
Fritz, B.A., Maybrier, H.R., Avidan, M.S.
Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Background: Postoperative delirium is a common complication associated with increased morbidity and mortality. A recently-reported association between intraoperative electroencephalogram suppression and postoperative delirium might be mediated in some patients by a heightened sensitivity to volatile anaesthetics. Methods: This retrospective cohort study included 618 elective surgery patients with planned intensive care unit admission, who also received intraoperative electroencephalogram monitoring and had delirium assessments documented in the medical record. Sensitivity to volatile anaesthetics was assessed using a mixed effects model predicting the likelihood of electroencephalogram suppression at each time point based on the current end-tidal anaesthetic concentration. Patients with a random intercept above the population median (electroencephalogram suppression at lower anaesthetic concentrations) were classified as having heightened sensitivity to volatile anaesthetics. Delirium was defined as a positive Confusion Assessment Method for the Intensive Care Unit assessment anytime in the first five postoperative days. Results: Postoperative delirium was observed in 162 of 618 patients (26%). Patients who experienced electroencephalogram suppression at lower volatile anaesthetic concentrations had a higher incidence of postoperative delirium [109/309 (35%)] than other patients [53/309 (17%)] [unadjusted odds ratio 2.63; 95% confidence interval (CI), 1.81–3.84, P<0.001]. This association remained significant after adjusting for patient characteristics, surgical variables, and duration of electroencephalogram suppression (adjusted odds ratio 2.13; 95% CI 1.24–3.65, P=0.006). Conclusions: These data support the hypothesis that patients with electroencephalogram suppression at lower volatile anaesthetic concentrations have an increased incidence of postoperative delirium. Such patients appear to exhibit a phenotype of anaesthetic sensitivity, which might predispose them to adverse cognitive outcomes. © 2017 British Journal of Anaesthesia
anaesthesia; brain waves/drug effects; delirium/aetiology; electroencephalography/instrumentation
Document Type: Article
"Neuroimmune disorders of the central nervous system in children in the molecular era" (2018) Nature Reviews Neurology
Neuroimmune disorders of the central nervous system in children in the molecular era
(2018) Nature Reviews Neurology, pp. 1-13. Article in Press.
Wells, E.a , Hacohen, Y.b c , Waldman, A.d , Tillema, J.M.e , Soldatos, A.f , Ances, B.g , Benseler, S.h , Bielekova, B.i , Dale, R.C.j , Dalmau, J.k l , Gaillard, W.a , Gorman, M.m , Greenberg, B.n , Hyslop, A.o , Pardo, C.A.p , Tasker, R.C.q , Yeh, E.A.r , Bar-Or, A.s , Pittock, S.e t , Vanderver, A.d , Banwell, B.d
a Center for Neuroscience and Behavioral Medicine, Children’s National Health System, Washington, DC, United States
b Department of Neuroinflammation, Queen Square MS Centre, UCL Institute of Neurology, London, United Kingdom
c Paediatric Neurology, Great Ormond Street Hospital, London, United Kingdom
d Department of Neurology and Pediatric Multiple Sclerosis Clinic, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
e Department of Neurology, Mayo Clinic, Rochester, MN, United States
f National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States
g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Section of Rheumatology, Department of Pediatrics, Alberta Children’s Hospital, Calgary, AB, Canada
i Neuroimmunological Diseases Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, United States
j Institute for Neuroscience and Muscle Research, Kids Research Institute at the Children’s Hospital at Westmead, University of Sydney, Westmead, NSW, Australia
k ICREA-IDIBAPS, Hospital Clínic, University of Barcelona, Barcelona, Spain
l Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
m Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
n Department of Neurology and Neurotherapeutics and Department of Pediatrics, University of Texas Southwestern, Dallas, TX, United States
o Department of Pediatric Neurology and Epilepsy, Miami Children’s Hospital, Miami, FL, United States
p Johns Hopkins Transverse Myelitis Center, Baltimore, MD, United States
q Department of Neurocritical Care, Boston Children’s Hospital, Boston, MA, United States
r Department of Paediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
s Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
t Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
Immune-mediated disorders of the CNS in children are a complex group of demyelinating, inflammatory, parainfectious and postinfectious disorders with heterogeneous pathobiological mechanisms and clinical manifestations, often associated with fundamental derangement in immune regulation. In this Review, we aim to provide an update on our knowledge of neuroimmune disorders and highlight areas of research that are priorities for improving clinical management. We outline the clinical features of neuroimmune disorders, the current approaches to their treatment and new approaches in development. We then consider the pathological features, including biomarkers, pathological mechanisms and genetics, and discuss the value of immune assays in clinical investigation and basic research. On the basis of current knowledge and techniques, we propose four research priorities: rigorous and consistent collection of core clinical data, cooperative investigation of treatments, development of biological assays and genetic studies. These priorities should help us to achieve the shared goal of precision medicine for neuroimmune disorders. However, multicentre research and the creation of clinical consortia for these rare disorders will be necessary, and we hope that this Review serves as a call to action that is timely given current exciting advances in neuroimmune therapeutics. © 2018 Macmillan Publishers Ltd., part of Springer Nature
Document Type: Article in Press
"Age-related changes in neural mechanisms of prospective memory" (2018) Cognitive, Affective and Behavioral Neuroscience
Age-related changes in neural mechanisms of prospective memory
(2018) Cognitive, Affective and Behavioral Neuroscience, pp. 1-18. Article in Press.
Lamichhane, B., McDaniel, M.A., Waldum, E.R., Braver, T.S.
Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
The capability to remember and execute intentions in the future – termed prospective memory (PM) – may be of special significance for older adults to enable successful completion of important activities of daily living. Despite the importance of this cognitive function, mixed findings have been obtained regarding age-related decline in PM, and, currently, there is limited understanding of potential contributing mechanisms. In the current study, older (N=41) and younger adults (N=47) underwent task-functional MRI during performance of PM conditions that encouraged either spontaneous retrieval (Focal) or sustained attentional monitoring (Non-focal) to detect PM targets. Older adults exhibited a reduction in PM-related sustained activity within the anterior prefrontal cortex (aPFC) and associated dorsal frontoparietal cognitive control network, due to an increase in non-specific sustained activation in (no-PM) control blocks (i.e., an age-related compensatory shift). Transient PM-trial specific activity was observed in both age groups within a ventral parietal memory network that included the precuneus. However, within a left posterior inferior parietal node of this network, transient PM-related activity was selectively reduced in older adults during the non-focal condition. These age differences in sustained and transient brain activity statistically mediated age-related declines in PM performance, and were potentially linked via age-related changes in functional connectivity between the aPFC and precuneus. Together, they support an account consistent with the Dual Mechanisms of Control framework, in which age-related PM declines are due to neural mechanisms that support proactive cognitive control processes, such as sustained attentional monitoring, while leaving reactive control mechanisms relatively spared. © 2018 Psychonomic Society, Inc.
Frontoparietal network; Parietal memory network; Proactive control; Prospective memory; Reactive control; Salience network; Sustained brain activity; Transient brain activity
Document Type: Article in Press
"Pulsed Hydrogen-Deuterium Exchange Illuminates the Aggregation Kinetics of α-Synuclein, the Causative Agent for Parkinson's Disease" (2018) ACS Chemical Neuroscience
Pulsed Hydrogen-Deuterium Exchange Illuminates the Aggregation Kinetics of α-Synuclein, the Causative Agent for Parkinson’s Disease
(2018) ACS Chemical Neuroscience, 9 (6), pp. 1469-1476.
Illes-Toth, E., Rempel, D.L., Gross, M.L.
Department of Chemistry, Washington University in St. Louis, St. Louis, MI, United States
α-Synuclein (aS) forms toxic intermediates ranging from small oligomers and protofibrils to large amyloid fibrils. Understanding the time course of aS fibril formation and the role played by its regions is critical for therapeutic intervention. Here, we used pulsed hydrogen-deuterium exchange and mass spectrometry (HDX-MS) for the first time to probe kinetic intermediates of the full aS aggregation in vitro, achieving kinetic snapshots containing spatially resolved protein information about critical stages. Monitoring the resultant mass shifts shows distinct binomial abundances for two main exchange profiles: one that represents a fast-exchanging, solvent-accessible species and another with a more protected nature. We show using a series of proteolytic peptides from the full protein that self-association is most pronounced in the non-amyloid-β-component region and less so for either terminus. The N-terminus, however, shows a minor protected population at mid- and late times, whereas the C-terminus shows predominantly unimodal HDX, indicating that these regions are devoid of any large conformational rearrangements. Focusing on the hydrophobic core, we confirmed and modeled the different isotopic distributions and calculated their relative fractions to discern their individual contributions. The data fitting reports respective t1/2 values, which are nearly identical and do not depend on location. We followed the aggregation by complementary transmission electron microscopy to observe the morphology of aggregates and circular dichroism to assess changes in secondary structure. Our results provide a detailed picture of aS aggregation in vitro and demonstrate that HDX-MS offers unique spatially resolved, coexisting kinetic intermediates in solution. This new platform is suitable for testing promising inhibitors of aS aggregation. © 2018 American Chemical Society.
aggregation kinetics; amyloids; bimodal HDX profiles; kinetic modeling; mass spectrometry; Pulsed hydrogen-deuterium exchange
Document Type: Article
"High-content screen for modifiers of Niemann-Pick type C disease in patient cells" (2018) Human Molecular Genetics
High-content screen for modifiers of Niemann-Pick type C disease in patient cells
(2018) Human Molecular Genetics, 27 (12), pp. 2101-2112.
Pugach, E.K.a , Feltes, M.b , Kaufman, R.J.c , Ory, D.S.b , Bang, A.G.a
a Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
b Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, United States
c Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
Niemann-Pick type C (NPC) disease is a rare lysosomal storage disease caused primarily by mutations in NPC1. NPC1 encodes the lysosomal cholesterol transport protein NPC1. The most common NPC1 mutation is a missense mutation (NPC1I1061T) that causes misfolding and rapid degradation of mutant protein in the endoplasmic reticulum. Cholesterol accumulates in enlarged lysosomes as a result of decreased levels of lysosomal NPC1I1061T protein in patient cells. There is currently no cure or FDA-approved treatment for patients. We sought to identify novel compounds that decrease lysosomal cholesterol storage in NPC1I1061T/I1061T patient fibroblasts using a high-content screen with the cholesterol dye, filipin and the lysosomal marker, LAMP1. A total of 3532 compounds were screened, including 2013 FDA-approved drugs, 327 kinase inhibitors and 760 serum metabolites. Twenty-three hits were identified that decreased both filipin and LAMP1 signals. The majority of hits (16/21) were histone deacetylase (HDAC) inhibitors, a previously described class of modifiers of NPC cholesterol storage. Of the remaining hits, the antimicrobial compound, alexidine dihydrochloride had the most potent lysosomal cholesterol-reducing activity. Subsequent analyses showed that alexidine specifically increased levels of NPC1 transcript and mature protein in both control and NPC patient cells. Although unsuitable for systemic therapy, alexidine represents a unique tool compound for further NPC studies and as a potent inducer of NPC1. Together, these findings confirm the utility of high-content imagebased compound screens of NPC1 patient cells and support extending the approach into larger compound collections. © The Author(s) 2018.
Document Type: Article
"Joint Design of Training and Hardware Towards Efficient and Accuracy-Scalable Neural Network Inference" (2018) IEEE Journal on Emerging and Selected Topics in Circuits and Systems
Joint Design of Training and Hardware Towards Efficient and Accuracy-Scalable Neural Network Inference
(2018) IEEE Journal on Emerging and Selected Topics in Circuits and Systems, . Article in Press.
He, X.a , Lu, W.b , Yan, G.c , Zhang, X.a
a Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, 63130 USA.
b State Key Laboratory of Computer Architecture, Institute of Computing Technology, Chinese Academy of Sciences and University of Chinese Academy of Sciences, Beijing, China.
c State Key Laboratory of Computer Architecture, Institute of Computing Technology, Chinese Academy of Sciences.
The intrinsic error tolerance of neural network (NN) presents opportunities for approximate computing techniques to improve the energy efficiency of NN inference. Conventional approximate computing focuses on exploiting the efficiencyaccuracy trade-off in existing pre-trained networks, which can lead to suboptimal solutions. In this paper, we first present AxTrain, a hardware-oriented training framework to facilitate approximate computing for NN inference. Specifically, AxTrain leverages the synergy between two orthogonal methods–one actively searches for a network parameters distribution with high error tolerance, and the other passively learns resilient weights by numerically incorporating the noise distributions of the approximate hardware in the forward pass during the training phase. Then we incorporate AxTrain framework in an accuracy-scalable NN accelerator designed for high energy efficiency. Experimental results from various datasets with different approximation strategies demonstrate AxTrain’s ability to obtain resilient neural network parameters for approximate computing and to improve system energy efficiency. And with AxTrain-guided NN models our proposed accuracy-scalable NN accelerator could achieve significantly higher energy efficiency with limited accuracy degradation under joint approximation techniques. IEEE
Approximate computing; Approximate computing; approximate multiplier; Artificial neural networks; Computational modeling; Energy efficient architecture; Hardware; Hardware-oriented training; Near threshold voltage; Neural network accelerator; Neurons; Sensitivity analysis; Training
Document Type: Article in Press
"Estimating the Economic Cost of Childhood Poverty in the United States" (2018) Social Work Research
Estimating the Economic Cost of Childhood Poverty in the United States
(2018) Social Work Research, 42 (2), pp. 73-83.
McLaughlin, M., Rank, M.R.
Herbert S. Hadley Professor of Social Welfare, George Warren Brown School of Social Work, Washington University, St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, MO, United States
Poverty has been an issue of ongoing concern for social work practitioners and researchers over the decades. The societal impact of poverty on a broad range of problems is widely acknowledged throughout the field. However, one vital piece of information regarding poverty has often been missing – its economic cost. This study presents new estimates into the annual costs of childhood poverty in the United States by updating earlier research and including previously unmeasured costs. Cost-measurement analysis indicates that the annual aggregate cost of U.S. child poverty is $1.0298 trillion, representing 5.4% of the gross domestic product. These costs are clustered around the loss of economic productivity, increased health and crime costs, and increased costs as a result of child homelessness and maltreatment. In addition, it is estimated that for every dollar spent on reducing childhood poverty, the country would save at least seven dollars with respect to the economic costs of poverty. The implications of these findings are discussed. © 2018 National Association of Social Workers.
capabilities perspective; childhood; economic costs; poverty; social work advocacy
Document Type: Article
"Using Community-Based Participatory Research to Develop a Series of Core Competency Trainings Within a Developmental Disability Program" (2018) Journal of Social Service Research
Using Community-Based Participatory Research to Develop a Series of Core Competency Trainings Within a Developmental Disability Program
(2018) Journal of Social Service Research, pp. 1-11. Article in Press.
Rahman, R.a , Kirkbride, G.b , Bauta, B.H.c , Jabbour, J.d , Maranaga, G.d
a Graduate School of Social Service, Fordham University, New York, USA
b Brown School of Social Work, Washington University in St. Louis, St. Louis, New York, USA
c Silver School of Social Work, New York University, New York, New York, USA
d Development Disabilities Program, Catholic Guardian Services, New York, New York, USA
The New York State Talent Development Consortium at the Office for People with Developmental Disabilities (OPWDD) mandated developmental disability programs to train and evaluate direct service providers (DSPs) on seven core competencies. Utilizing community-based participatory research (CPBR) – an approach where clients, providers, and researchers share their knowledge and experience to identify study areas, formulate research questions, and use results to improve practice – a needs assessment was conducted by a New York-based developmental disability program to inform a training curriculum. Six focus groups were conducted from a purposive sample of 14 DSPs, and 19 managers/supervisors. Staff identified skills that corresponded with six out of seven competencies. Staff recommended hands-on training on: appropriate communication to deal with individuals with severe disabilities; professionalism; person-centered care; and education on terminology in behavioral health plans, medication, and mental health illnesses. Empowering DSPs through CBPR allows for a training curriculum catered toward staff needs, which may be well-received and utilized. The CBPR process employed may be beneficial to other agencies within the intellectual and developmental disabilities field, particularly at a time when the demand for nonlicensure providers such as DSPs is increasing, and there is a need to train them to render quality and effective services. © 2018 Taylor & Francis Group, LLC
community-based participatory research; Core competencies; developmental disability programs; direct service providers
Document Type: Article in Press
"TRPV1 agonist, capsaicin, induces axon outgrowth after injury via Ca2+/PKA signaling" (2018) eNeuro
TRPV1 agonist, capsaicin, induces axon outgrowth after injury via Ca2+/PKA signaling
(2018) eNeuro, 5 (3), art. no. e0095-18.2018, .
Frey, E.a , Karney-Grobe, S.a , Krolak, T.a , Milbrandt, J.b , DiAntonio, A.a
a Department of Developmental Biology, Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Genetics, Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO, United States
Preconditioning nerve injuries activate a pro-regenerative program that enhances axon regeneration for most classes of sensory neurons. However, nociceptive sensory neurons and central nervous system neurons regenerate poorly. In hopes of identifying novel mechanisms that promote regeneration, we screened for drugs that mimicked the preconditioning response and identified a nociceptive ligand that activates a preconditioninglike response to promote axon outgrowth. We show that activating the ion channel TRPV1 with capsaicin induces axon outgrowth of cultured dorsal root ganglion (DRG) sensory neurons, and that this effect is blocked in TRPV1 knockout neurons. Regeneration occurs only in NF200-negative nociceptive neurons, consistent with a cellautonomous mechanism. Moreover, we identify a signaling pathway in which TRPV1 activation leads to calcium influx and protein kinase A (PKA) activation to induce a preconditioning-like response. Finally, capsaicin administration to the mouse sciatic nerve activates a similar preconditioning-like response and induces enhanced axonal outgrowth, indicating that this pathway can be induced in vivo. These findings highlight the use of local ligands to induce regeneration and suggest that it may be possible to target selective neuronal populations for repair, including cell types that often fail to regenerate. © 2018 Frey et al.
Axon regeneration; Capsaicin; Neurite outgrowth; PKA; Preconditioning; TRPV1
Document Type: Article
"MicroRNAs Overcome Cell Fate Barrier by Reducing EZH2-Controlled REST Stability during Neuronal Conversion of Human Adult Fibroblasts" (2018) Developmental Cell
MicroRNAs Overcome Cell Fate Barrier by Reducing EZH2-Controlled REST Stability during Neuronal Conversion of Human Adult Fibroblasts
(2018) Developmental Cell, 46 (1), pp. 73-84.e7.
Lee, S.W.a , Oh, Y.M.b , Lu, Y.-L.a c , Kim, W.K.a , Yoo, A.S.a
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
c Program in Developmental, Regenerative and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO, United States
The ability to convert human somatic cells efficiently to neurons facilitates the utility of patient-derived neurons for studying neurological disorders. As such, ectopic expression of neuronal microRNAs (miRNAs), miR-9/9∗ and miR-124 (miR-9/9∗-124) in adult human fibroblasts has been found to evoke extensive reconfigurations of the chromatin and direct the fate conversion to neurons. However, how miR-9/9∗-124 break the cell fate barrier to activate the neuronal program remains to be defined. Here, we identified an anti-neurogenic function of EZH2 in fibroblasts that acts outside its role as a subunit of Polycomb Repressive Complex 2 to directly methylate and stabilize REST, a transcriptional repressor of neuronal genes. During neuronal conversion, miR-9/9∗-124 induced the repression of the EZH2-REST axis by downregulating USP14, accounting for the opening of chromatin regions harboring REST binding sites. Our findings underscore the interplay between miRNAs and protein stability cascade underlying the activation of neuronal program. © 2018 Elsevier Inc.
Ectopic expression of neuronal microRNAs miR-9/9∗ and miR-124 in adult human fibroblasts induces chromatin changes and fate conversion to neurons. Lee et al. uncover the regulatory basis, showing that the miRNAs trigger repression of EZH2 and disrupt its PRC2-independent role in methylating and stabilizing REST to form an anti-neurogenic barrier.
ACTL6b; BAF complex; chromatin remodeling complex; EZH2; microRNAs; neuronal reprogramming; protein modification; protein stability control; REST; USP14
Document Type: Article
"Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy" (2018) Neuromuscular Disorders
Homozygous recessive MYH2 mutation mimicking dominant MYH2 associated myopathy
(2018) Neuromuscular Disorders, . Article in Press.
Findlay, A.R.a , Harms, M.B.b , Pestronk, A.a , Weihl, C.C.a
a Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Columbia University, United States
Mutations in MYH2 that encodes myosin heavy chain IIa cause both dominant and recessively inherited myopathies. Patients with dominantly inherited MYH2 missense mutations present with ophthalmoplegia and progressive proximal limb weakness. Muscle biopsy reveals rimmed vacuoles and inclusions, prompting this entity to initially be described as hereditary inclusion body myopathy 3. In contrast, patients with recessive MYH2 mutations have early onset, non-progressive, diffuse weakness and ophthalmoplegia. Muscle biopsy reveals near or complete absence of type 2A fibers with no vacuole or inclusion pathology. We describe a patient with childhood onset ophthalmoplegia, progressive proximal muscle weakness beginning in adolescence, and muscle biopsy with myopathic changes and rimmed vacuoles. Although this patient’s disease course and histopathology is consistent with dominant MYH2 mutations, whole exome sequencing revealed a c.737 G>A p.Arg246Thr homozygous MYH2 variant. These findings expand the clinical and pathologic phenotype of recessive MYH2 myopathies. © 2018 Elsevier B.V.
Genetics; MYH2; Myosin heavy chain IIa; Myosinopathy
Document Type: Article in Press
"Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population" (2018) Neurobiology of Aging
Pooled-DNA target sequencing of Parkinson genes reveals novel phenotypic associations in Spanish population
(2018) Neurobiology of Aging, . Article in Press.
Diez-Fairen, M.a b c , Benitez, B.A.d , Ortega-Cubero, S.c e f , Lorenzo-Betancor, O.g , Cruchaga, C.h i , Lorenzo, E.c e , Samaranch, L.j , Carcel, M.a b , Obeso, J.A.c k l , Rodriguez-Oroz, M.C.c m , Aguilar, M.a b , Coria, F.n , Pastor, M.A.c o p , Pastor, P.a b c
a Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Terrassa, Barcelona, Spain
b Movement Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain
c Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain
d Department of Medicine, School of Medicine, Washington University, St. Louis, MO, United States
e Division of Neurosciences, Neurogenetics Laboratory, Center for Applied Medical Research, University of Navarra (CIMA), Pamplona, Spain
f Department of Neurology and Neurosurgery, Hospital Universitario de Burgos, Burgos, Spain
g Department of Neurology, Veterans Affairs Puget Sound Health Care System, University of Washington School of Medicine, Seattle, WA, United States
h Department of Neurology, University of Washington School of Medicine, St. Louis, MO, United States
i Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, United States
j Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
k Centre for Integrative Neurosciences AC (CINAC), Hospital HM Puerta del Sur, Fundación Hospitales de Madrid, Madrid, Spain
l CEU San Pablo University, Campus de Moncloa, Madrid, Spain
m Department of Neurology, University Hospital Donostia, Neuroscience Unit BioDonostia Research Institute, San Sebastian, Ikerbasque, Basque Foundation for Science, Bilbao, Spain
n Clinic for Nervous Disorders, Service of Neurology, Son Espases University Hospital, Palma de Mallorca, Spain
o Department of Neurology, Clínica Universidad de Navarra, University of Navarra School of Medicine, Pamplona, Spain
p Neuroimaging Laboratory, Division of Neurosciences, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Eighteen loci and several susceptibility genes have been related to Parkinson’s disease (PD). However, most studies focus on single genes in small PD series. Our aim was to establish the genetic background of a large Spanish PD sample. Pooled-DNA target sequencing of 7 major PD genes (SNCA, PARK2, PINK1, DJ-1, LRRK2, GBA, and MAPT) was performed in 562 PD cases. Forty-four variants were found among 114 individuals (20.28%, p<0.05). Among these variants, 30 were found in Mendelian genes (68.18%) and 14 in PD susceptibility genes (31.82%). Seven novel variants were identified. Interestingly, most variants were found in PARK2 and PINK1 genes, whereas SNCA and DJ-1 variants were rare. Validated variants were also genotyped in Spanish healthy controls (n = 597). Carriers of heterozygous PARK2 variants presented earlier disease onset and showed dementia more frequently. PD subjects carrying 2 variants at different genes (1.42%) had an earlier age of onset and a predominantly akinetic-rigid PD phenotype (55.6%, p < 0.05), suggesting that the accumulation of genetic risk variants could modify PD phenotype. © 2018 Elsevier Inc.
GBA; LRRK2; MAPT; PARK2; PINK1
Document Type: Article in Press
"NAD+ and sirtuins in retinal degenerative diseases: A look at future therapies" (2018) Progress in Retinal and Eye Research
NAD+ and sirtuins in retinal degenerative diseases: A look at future therapies
(2018) Progress in Retinal and Eye Research, . Article in Press.
Lin, J.B.a b , Apte, R.S.a b c d
a Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
c Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Retinal degenerative diseases are a major cause of morbidity in modern society because visual impairment significantly decreases the quality of life of patients. A significant challenge in treating retinal degenerative diseases is their genetic and phenotypic heterogeneity. However, despite this diversity, many of these diseases share a common endpoint involving death of light-sensitive photoreceptors. Identifying common pathogenic mechanisms that contribute to photoreceptor death in these diverse diseases may lead to a unifying therapy for multiple retinal diseases that would be highly innovative and address a great clinical need. Because the retina and photoreceptors, in particular, have immense metabolic and energetic requirements, many investigators have hypothesized that metabolic dysfunction may be a common link unifying various retinal degenerative diseases. Here, we discuss a new area of research examining the role of NAD+ and sirtuins in regulating retinal metabolism and in the pathogenesis of retinal degenerative diseases. Indeed, the results of numerous studies suggest that NAD+ intermediates or small molecules that modulate sirtuin function could enhance retinal metabolism, reduce photoreceptor death, and improve vision. Although further research is necessary to translate these findings to the bedside, they have strong potential to truly transform the standard of care for patients with retinal degenerative diseases. © 2018 Elsevier Ltd
Metabolism; Mitochondria; NAD+; Neurodegeneration; Retinal degeneration; Sirtuins
Document Type: Article in Press
"Special Section Guest Editorial: Functional Near Infrared Spectroscopy, Part 3" (2018) Neurophotonics
Special Section Guest Editorial: Functional Near Infrared Spectroscopy, Part 3
(2018) Neurophotonics, 5 (1), art. no. 011001, .
Gervain, J.a , Culver, J.P.b
a UMR 8242 CNRS-Paris Descartes, Laboratoire Psychologie de la Perception, 45 rue des Saints-Pères, Paris, France
b Washington University, School of Medicine, Department of Radiology, Campus Box 8225, 4525 Scott Avenue, St. Louis, MO, United States
Document Type: Editorial
"Using Correlative Properties of Neighboring Pixels to Enhance Contrast-to-Noise Ratio of Abnormal Hippocampus in Patients With Intractable Epilepsy and Mesial Temporal Sclerosis" (2018) Academic Radiology
Using Correlative Properties of Neighboring Pixels to Enhance Contrast-to-Noise Ratio of Abnormal Hippocampus in Patients With Intractable Epilepsy and Mesial Temporal Sclerosis
(2018) Academic Radiology, . Article in Press.
Parsons, M.S., Sharma, A., Hildebolt, C.
Mallinckrodt Institute of Radiology, Washington University School of Medicine, Campus Box 8131, 510 S Kingshighway Blvd, St. Louis, MO, United States
Rationale and Objectives: To test whether an image-processing algorithm can aid in visualization of mesial temporal sclerosis on magnetic resonance imaging by selectively increasing contrast-to-noise ratio (CNR) between abnormal hippocampus and normal brain. Materials and Methods: In this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study, baseline coronal fluid-attenuated inversion recovery images of 18 adults (10 females, eight males; mean age 41.2 years) with proven mesial temporal sclerosis were processed using a custom algorithm to produce corresponding enhanced images. Average (Hmean) and maximum (Hmax) CNR for abnormal hippocampus were calculated relative to normal ipsilateral white matter. CNR values for normal gray matter (GM) were similarly calculated using ipsilateral cingulate gyrus as the internal control. To evaluate effect of image processing on visual conspicuity of hippocampal signal alteration, a neuroradiologist masked to the side of hippocampal abnormality rated signal intensity (SI) of hippocampi on baseline and enhanced images using a five-point scale (definitely abnormal to definitely normal). Differences in Hmean, Hmax, GM, and SI ratings for abnormal hippocampi on baseline and enhanced images were assessed for statistical significance. Results: Both Hmean and Hmax were significantly higher in enhanced images as compared to baseline images (p < 0.0001 for both). There was no significant difference in the GM between baseline and enhanced images (p = 0.9375). SI ratings showed a more confident identification of abnormality on enhanced images (p = 0.0001). Conclusion: Image-processing resulted in increased CNR of abnormal hippocampus without affecting the CNR of normal gray matter. This selective increase in conspicuity of abnormal hippocampus was associated with more confident identification of hippocampal signal alteration. © 2018 Academic Radiology
Document Type: Article in Press
"Identification, Management, and Transition of Care for Patients With Opioid Use Disorder in the Emergency Department" (2018) Annals of Emergency Medicine
Identification, Management, and Transition of Care for Patients With Opioid Use Disorder in the Emergency Department
(2018) Annals of Emergency Medicine, . Article in Press.
Duber, H.C.a , Barata, I.A.b , Cioè-Peña, E.b , Liang, S.Y.c , Ketcham, E.d , Macias-Konstantopoulos, W.e , Ryan, S.A.f , Stavros, M.g , Whiteside, L.K.a
a Department of Emergency Medicine, University of Washington School of Medicine, Seattle, WA, United States
b Department of Emergency Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, United States
c Divisions of Emergency Medicine and Infectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
d San Juan Regional Medical Center, Farmington, NM, United States
e Department of Emergency Medicine, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
f Department of Emergency Medicine, University of Cincinnati, and BrightView, Cincinnati, OH, United States
g Department of Emergency Medicine, Florida State University, Tallahassee, FL, United States
Because of a soaring number of opioid-related deaths during the past decade, opioid use disorder has become a prominent issue in both the scientific literature and lay press. Although most of the focus within the emergency medicine community has been on opioid prescribing—specifically, on reducing the incidence of opioid prescribing and examining alternative pain treatment—interest is heightening in identifying and managing patients with opioid use disorder in an effective and evidence-based manner. In this clinical review article, we examine current strategies for identifying patients with opioid use disorder, the treatment of patients with acute opioid withdrawal syndrome, approaches to medication-assisted therapy, and the transition of patients with opioid use disorder from the emergency department to outpatient services. © 2018 American College of Emergency Physicians
Document Type: Article in Press