“Impact of fingolimod on clinical and magnetic resonance imaging outcomes in routine clinical practice: A retrospective analysis of the multiple sclerosis, clinical and MRI outcomes in the USA (MS-MRIUS) study” (2019) Multiple Sclerosis and Related Disorders
Impact of fingolimod on clinical and magnetic resonance imaging outcomes in routine clinical practice: A retrospective analysis of the multiple sclerosis, clinical and MRI outcomes in the USA (MS-MRIUS) study
(2019) Multiple Sclerosis and Related Disorders, 27, pp. 65-73.
Zivadinov, R.a b , Medin, J.c , Khan, N.d , Korn, J.R.e , Chitnis, T.f , Naismith, R.T.g , Alvarez, E.h , Dwyer, M.G.b , Bergsland, N.b , Carl, E.b , Silva, D.c , Weinstock-Guttman, B.i , MS-MRIUS Study Groupj
a Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, United States
b Center for Biomedical Imaging at Clinical Translational Science Institute, University at Buffalo, State University of New York, Buffalo, NY, United States
c Novartis Pharma AG, Basel, Switzerland
d IQVIA, Basel, Switzerland
e IQVIA, Burlington, MA, United States
f Partners Multiple Sclerosis Center, Brigham and Women’s Hospital, Boston, MA, United States
g Department of Neurology, Washington University, St. Louis, MO, United States
h Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
i Jacobs Multiple Sclerosis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New YorkNY, United States
Background: The effectiveness of fingolimod on clinical and magnetic resonance imaging (MRI) outcomes in patients with multiple sclerosis (MS) has been well established in trials and, to a lesser extent, in the real world. Objective: To evaluate clinical and MRI outcomes in patients with relapsing MS receiving fingolimod in US clinical practice. Methods: Clinical and MRI data from 590 patients initiating fingolimod treatment at 33 MS centers in the USA were retrospectively analyzed. Clinical data were obtained from medical records. MRI data were systematically quantified at a centralized imaging facility. Patients had an index (within 6 months before and 1 month after starting fingolimod) and post-index (9–24 months after starting fingolimod) MRI scan; 184 individuals had a pre-index scan (9–24 months before starting fingolimod). Results: In the index to post-index period, mean annualized relapse rates decreased from 0.36 to 0.13 and disability progression occurred in 18.5% of patients. Median T2, T1 and gadolinium-enhancing lesion volume changed by 1.15%, 2.36%, and –100% between the index and post-index scans, respectively, and median annualized percentage changes in brain volume and lateral ventricular volume were –0.32% and +0.66%, respectively. For patients with pre-index scans, MRI outcomes were unchanged or improved during treatment. Outcomes were generally comparable with those in fingolimod phase 3 trials. Conclusion: This real-world study highlights the effectiveness of fingolimod and the feasibility of quantifying clinical and MRI data collected from multiple centers during routine clinical practice on a group level using a systematic, quantitative methodology. © 2018
Brain atrophy; Clinical outcomes; Fingolimod; MRI outcomes; Real-world evidence; Relapsing multiple sclerosis
Document Type: Article
“External validation of the epidemiology-based mortality score in status epilepticus in an American intensive care population” (2018) Epilepsy Research
External validation of the epidemiology-based mortality score in status epilepticus in an American intensive care population
(2018) Epilepsy Research, 148, pp. 32-36.
Yechoor, N.a , Adeli, A.b , Hafeez, S.c
a Department of Neurology, Washington University in St. Louis School of Medicine, United States
b Department of Neurology, Ohio State University College of Medicine, United States
c Department of Neurosurgery, UT Health San Antonio Lozano School of Medicine, United States
Introduction: Although overall mortality of status epilepticus is high, baseline patient characteristics and co-morbidities may be helpful to predict outcomes and shape treatment decisions. Two previously published scoring systems exist to predict outcomes: the Status Epilepticus Severity Score (STESS) and the Epidemiology-based Mortality Score in Status Epilepticus (EMSE). However, a comparison of the two scores has not previously been completed in an American intensive care unit. We hypothesize that both scores will adequately predict the primary outcome of in-hospital death, but that the EMSE may more accurately predict functional outcomes, and significantly impact treatment decisions for both clinicians and families. Methods: We performed a retrospective analysis of all cases of status epilepticus admitted to the Neuro-Critical Care Unit (NCCU) at the Ohio State University Wexner Medical Center from 6/1/2014 – 8/31/2015. We collected data on age, comorbidities, EEG findings, and seizure history. The primary outcome measured was in-hospital death; secondary outcomes included length of stay in the NCCU, placement of a tracheostomy and/or a percutaneous endoscopic gastrostomy upon discharge, and discharge location were used as surrogate markers for outcome severity. A sensitivity and specificity analysis was carried out, in addition to a student’s t-test for a comparison of the two scores. ANOVA was completed to compare secondary outcomes Results: Forty-six patients were admitted to the NCCU for management of status epilepticus during June 2014 and January 2016, thirteen of which experienced in-hospital death. The median age of the sample was 60, with approximately half of the sample (52.63%) having 3 or more comorbidities. The sensitivity of both EMSE and STESS were very high (100% and 90% respectively); however, the specificities were very low (28.6% and 42.9% respectively). A student’s t-test between those who experienced in-hospital death and those who did not was only significant for EMSE at the p < 0.1 level (p = 0.055). Additionally, mean EMSE scores but not STESS scores, were significantly higher (p < 0.001) for those patients who were discharged to skilled nursing facilities or with hospice than compared to those who were discharged to home or to acute inpatient rehabilitation. Conclusions: The EMSE and STESS may be useful to predict outcomes of status epilepticus in populations with few comorbid conditions, but are less helpful when patients have multiple medical problems. Secondly, while neither score may be specific enough to differentiate for the primary outcome of death, their utility may be helpful to predict secondary outcomes that strongly affect clinical decisions. Based on these results, we believe a prospective trial of EMSE and STESS should be carried out to obtain more information on their utility, especially in American patients who may have more relevant comorbidities than in other countries. © 2018 Elsevier B.V.
Critical care; EMSE; Prognostication of status epilepticus; Seizures; Status epilepticus; STESS
Document Type: Article
“Understanding the use of diverted buprenorphine” (2018) Drug and Alcohol Dependence,
Understanding the use of diverted buprenorphine
(2018) Drug and Alcohol Dependence, 193, pp. 117-123.
Cicero, T.J.a , Ellis, M.S.a , Chilcoat, H.D.b c
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Indivior, Inc., Richmond, VA, United States
c Department of Mental Health, Johns Hopkins Bloomberg School of Mental Health, Baltimore, MD, United States
Background: Buprenorphine is approved in many countries for the treatment of opioid use disorder (OUD), but problems with diversion and abuse exist. There is a need to understand how and why patients use diverted buprenorphine, and whether barriers to access contribute to illicit use. Methods: Adults >18 years with DSM-IV criteria for substance use disorder and primarily using an opioid completed the online Survey of Key Informants’ Patients (SKIP) between August and September 2016. The survey included closed- and open-ended questions regarding reasons for buprenorphine use with and without a prescription, sources of buprenorphine, route of administration, and barriers to treatment. Results: Of 303 respondents, 175 (58%) reported a history of diverted buprenorphine use, 65 (37%) of whom reported never receiving a prescription. The most common reasons for illicit buprenorphine use were consistent with therapeutic use: to prevent withdrawal (79%), maintain abstinence (67%), or self-wean off drugs (53%). Approximately one-half (52%) reported using buprenorphine to get high or alter mood, but few (4%) indicated that it was their drug of choice. Among respondents who had used diverted buprenorphine, 33% reported that they had issues finding a doctor or obtaining buprenorphine on their own. Most (81%) of these participants indicated they would prefer using prescribed buprenorphine, if available. Conclusions: Although 58% of survey respondents reported a history of using diverted buprenorphine, the most frequently cited reasons for non-prescription use were consistent with therapeutic use. Diversion was partially driven by barriers to access, and an unmet need for OUD treatment persists. © 2018 The Authors
Barriers to treatment; Buprenorphine; Diversion; Opioid use disorder
Document Type: Article
Access Type: Open Access
“Spinal cord organogenesis model reveals role of Flk1+ cells in self-organization of neural progenitor cells into complex spinal cord tissue” (2018) Stem Cell Research
Spinal cord organogenesis model reveals role of Flk1+ cells in self-organization of neural progenitor cells into complex spinal cord tissue
(2018) Stem Cell Research, 33, pp. 156-165.
Pan, B.a b , Ao, H.e f , Liu, S.a , Xu, Y.d , McDonald, J.W.a b , Belegu, V.a b c
a International Center for Spinal Cord Injury, Hugo W. Moser Research Institute at Kennedy Krieger Inc, Baltimore, MD, United States
b Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
c Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
d Department of Neurology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
e Center for the Study of Nervous System Injury and the Restorative Treatment and Research Center, Washington University School of Medicine, St. Louis, MO 63108, United States
f Department of Anesthesiology, Chinese Academy of Medical Sciences and Peking Union Medical College Fuwai Hospital, Beijing, 100037, China
A platform for studying spinal cord organogenesis in vivo where embryonic stem cell (ESC)-derived neural progenitor cells (NPC) self-organize into spinal cord-like tissue after transplantation in subarachnoid space of the spinal cord has been described. We advance the applicability of this platform by imaging in vivo the formed graft through T2w magnetic resonance imaging (MRI). Furthermore, we used diffusion tensor imaging (DTI) to verify the stereotypical organization of the graft showing that it mimics the host spinal cord. Within the graft white matter (WM) we identified astrocytes that form glial limitans, myelinating oligodendrocytes, and myelinated axons with paranodes. Within the graft grey matter (GM) we identified cholinergic, glutamatergic, serotonergic and dopaminergic neurons. Furthermore, we demonstrate the presence of ESC-derived complex vasculature that includes the presence of blood brain barrier. In addition to the formation of mature spinal cord tissue, we describe factors that drive this process. Specifically, we identify Flk1+ cells as necessary for spinal cord formation, and synaptic connectivity with the host spinal cord and formation of host-graft chimeric vasculature as contributing factors. This model can be used to study spinal cord organogenesis, and as an in vivo drug discovery platform for screening potential therapeutic compounds and their toxicity. © 2018 The Authors
Embryonic stem cells; Flk1; Neural progenitor cells; Spinal cord organogenesis
Document Type: Article
Access Type: Open Access
“Hereditary Motor Neuropathies and Amyotrophic Lateral Sclerosis: a Molecular and Clinical Update” (2018) Current Neurology and Neuroscience Reports
Hereditary Motor Neuropathies and Amyotrophic Lateral Sclerosis: a Molecular and Clinical Update
(2018) Current Neurology and Neuroscience Reports, 18 (12), art. no. 93, .
Garcia-Santibanez, R.a , Burford, M.b , Bucelli, R.C.c
a Department of Neurology, Division of Neuromuscular Medicine, Emory University, Atlanta, GA, United States
b Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, United States
c Department of Neurology, Division of Neuromuscular Medicine, Washington University in St. Louis, 660 S Euclid Ave, Box 8111, St. Louis, MO 63110, United States
Purpose of Review: This article provides an overview of recent advancements in the fields of hereditary motor neuropathies and ALS. Recent Findings: There has been a robust growth in our knowledge and understanding of hereditary and degenerative motor neuronopathies/neuropathies over the last decade. Many breakthroughs in the field of hereditary motor neuropathies (HMN) have been associated with identification and characterization of the genes and molecular mechanisms underlying these disorders. Similar recent breakthroughs on the genetic and molecular underpinnings of the degenerative motor neuronopathy, amyotrophic lateral sclerosis (ALS), have been accompanied by advancements in biomarker research and the development and FDA approval of novel therapies. Summary: There is a reasonable hope that the marked and continued growth in our understanding of the molecular pathophysiology of the HMNs will translate into novel therapeutic approaches in the decade to come. Such breakthroughs have already begun in ALS, where novel biomarkers and treatment strategies have translated into a new FDA-approved therapy with a number of promising agents in development and/or in definitive phase 2/3 trials. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
Amyotrophic lateral sclerosis; Antisense oligonucleotides; C9orf72; Edaravone; Hereditary motor neuropathy; SOD1
Document Type: Review
“Internal cueing improves gait more than external cueing in healthy adults and people with Parkinson disease” (2018) Scientific Reports
Internal cueing improves gait more than external cueing in healthy adults and people with Parkinson disease
(2018) Scientific Reports, 8 (1), art. no. 15525, .
Harrison, E.C.a , Horin, A.P.a , Earhart, G.M.a b c
a Program in Physical Therapy, Washington University School of Medicine, St Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
Walking can be challenging for aging individuals and people with neurological disorders such as Parkinson disease (PD). Gait impairment characterized by reduced speed and higher variability destabilizes gait and increases the risk of falls. External auditory cueing provides an effective strategy to improve gait, as matching footfalls to rhythms typically increases gait speed and elicits larger steps, but the need to synchronize to an outside source often has a detrimental effect on gait variability. Internal cueing in the form of singing may provide an alternative to conventional gait therapy. In the present study, we compare the effects of internal and external cueing techniques on forward and backward walking for both people with PD and healthy controls. Results indicate that internal cueing was associated with improvements in gait velocity, cadence, and stride length in the backward direction, and reduced variability in both forward and backward walking. In comparison, external cueing was associated with minimal improvement in gait characteristics and a decline in gait stability. People with gait impairment due to aging or neurological decline may benefit more from internal cueing techniques such as singing as compared to external cueing techniques. © 2018, The Author(s).
Document Type: Article
Access Type: Open Access
“Thrombolysis is an Independent Risk Factor for Poor Outcome After Carotid Revascularization” (2018) Neurosurgery
Thrombolysis is an Independent Risk Factor for Poor Outcome After Carotid Revascularization
(2018) Neurosurgery, 83 (5), pp. 922-930.
Vellimana, A.K.a , Washington, C.W.a , Yarbrough, C.K.a , Pilgram, T.K.b , Hoh, B.L.c , Derdeyn, C.P.a b , Zipfel, G.J.a
a Department of Neurological Surgery, Washington University School of Medi-cine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, University of Florida, Gainesville, FL, United States
BACKGROUND: Thrombolysis is the standard of care for acute ischemic stroke patients presenting in the appropriate time window. Studies suggest that the risk of recurrent ischemia is lower if carotid revascularization is performed early after the index event. The safety of early carotid revascularization in this patient population is unclear.
OBJECTIVE: To evaluate the safety of carotid revascularization in patients who received thrombolysis for acute ischemic stroke.
METHODS: The Nationwide Inpatient Sample database was queried for patients admitted through the emergency room with a primary diagnosis of carotid stenosis and/or occlusion. Each patient was reviewed for administration of thrombolysis, carotid endarterectomy, (CEA) or carotid angioplasty and stenting (CAS). Primary endpoints were intracerebral hemorrhage (ICH), postprocedural stroke (PPS), poor outcome, and in-hospital mortality. Potential risk factors were examined using univariate and multivariate analyses.
RESULTS: A total of 310 257 patients were analyzed. Patients who received tissue plasminogen activator (tPA) and underwent either CEA or CAS had a significantly higher risk of developing an ICH or PPS than patients who underwent either CEA or CAS without tPA administration. The increased risk of ICH or PPS in tPA-treated patients who underwent carotid revascularization diminished with time, and became similar to patients who underwent carotid revascularization without tPA administration by 7 d after thrombolysis. Patients who received tPA and underwent CEA or CAS also had higher odds of poor outcome and in-hospital mortality.
CONCLUSION: Thrombolysis is a strong risk factor for ICH, PPS, poor outcome, and in-hospital mortality in patients with carotid stenosis/occlusion who undergo carotid revascularization. The increased risk of ICH or PPS due to tPA declines with time after thrombolysis. Delaying carotid revascularization in these patients may therefore be appropriate. This delay, however, will expose these patients to the risk of recurrent stroke. Future studies are needed to determine the relative risks of these 2 adverse events.
Document Type: Article
“Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy” (2018) Pain
Neuropathic pain clinical trials: factors associated with decreases in estimated drug efficacy
(2018) Pain, 159 (11), pp. 2339-2346.
Finnerup, N.B.a b , Haroutounian, S.c , Baron, R.d , Dworkin, R.H.e f g , Gilron, I.h , Haanpaa, M.i , Jensen, T.S.a b , Kamerman, P.R.j k , McNicol, E.l m , Moore, A.n , Raja, S.N.o , Andersen, N.T.p , Sena, E.S.q , Smith, B.H.r , Rice, A.S.C.s , Attal, N.t
a Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
b Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
c Division of Clinical and Translational Research, Department of Anesthesiology, Pain Center, Washington University in St. Louis School of Medicine, St Louis, MO, United States
d Division of Neurological Pain Research and Therapy, Department of Neurology, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany
e Departments of Anesthesiology and Perioperative Medicine, Japan
f Neurology, Australia
g Psychiatry, University of Rochester School of Medicine and Dentistry, Rochester, NY, United States
h Department of Anesthesiology and Perioperative Medicine, Queen’s University and Kingston General Hospital, Kingston, ON, Canada
i Ilmarinen Mutual Insurance Company, Helsinki, Finland
j Brain Function Research Group, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
k School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin University, Perth, Australia
l Departments of Pharmacy and
m Anesthesiology and Perioperative Medicine, Tufts University School of Medicine, Tufts Medical Center, Boston MA, United States
n Nuffield Division of Anaesthetics, Nuffield Department of Clinical Neurosciences, Pain Research, University of Oxford, The Churchill, Oxford, United Kingdom
o Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
p NT Section for Biostatistics, Department of Public Health, Aarhus University, Aarhus, Denmark
q Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
r Division of Population Health Sciences, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom
s Pain Research, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
t INSERM U-987, Centre d’Evaluation et de Traitement de la Douleur, Hôpital Ambroise Paré, Assistance Publique Hôpitaux de Paris, Boulogne-Billancourt, France
Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here, we analyze time-dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction, correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes, and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses.
Document Type: Article
“BOLD Activity During Correct-Answer Feedback in Cued Recall Predicts Subsequent Retrieval Performance: An fMRI Investigation Using a Partial Trial Design” (2018) Cerebral cortex
BOLD Activity During Correct-Answer Feedback in Cued Recall Predicts Subsequent Retrieval Performance: An fMRI Investigation Using a Partial Trial Design
(2018) Cerebral cortex (New York, N.Y. : 1991), 28 (11), pp. 4008-4022.
Gilmore, A.W.a , Nelson, S.M.b c d , Naaz, F.e , Shaffer, R.A.a , McDermott, K.B.a f
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
c Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
d Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
e Department of Psychological and Brain Sciences, University of Louisville, Louisville, KY, United States
f Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
Receiving correct answer feedback following a retrieval attempt has proven to be a highly effective means of learning new information, yet the mechanisms behind its efficacy remain poorly understood. Here, fMRI was used to examine how BOLD activity measured during a period of feedback could predict subsequent memory (SM) performance on a final test. Twenty-five human subjects studied pairs of associated words, and were then asked to covertly recall target words in response to provided cues. Correct answer feedback was provided immediately after covert retrieval attempts. A partial trial design enabled separate modeling of activity related to retrieval and to feedback processing. During initial study, typical SM effects were observed across the whole brain. During feedback following a failed recall attempt, activity in only a subset of these regions predicted final test performance. These regions fell within the default mode network (DMN) and demonstrated negative SM effects, such that greater deactivation was associated with successful recall. No “task-positive” regions demonstrated SM effects in this contrast. The obtained results are consistent with a growing literature that associates DMN deactivation with successful learning in multiple task contexts, likely reflecting differences in the allocation of attentional resources during encoding.
Document Type: Article
“Postoperative Brain Function: Toward a Better Understanding and the American Society of Anesthesiologists Perioperative Brain Health Initiative” (2018) Anesthesiology
Postoperative Brain Function: Toward a Better Understanding and the American Society of Anesthesiologists Perioperative Brain Health Initiative
(2018) Anesthesiology, 129 (5), pp. 861-863.
Cole, D.J., Kharasch, E.D.
From the Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California (D.J.C.) the Department of Anesthesiology and the Department of Biochemistry and Molecular Biophysics, Washington University in St. Louis, St. Louis, Missouri, and Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University in St. Louis, St. Louis, Missouri (E.D.K.)
Document Type: Article
“Language delay aggregates in toddler siblings of children with autism spectrum disorder” (2018) Journal of Neurodevelopmental Disorders
Language delay aggregates in toddler siblings of children with autism spectrum disorder
(2018) Journal of Neurodevelopmental Disorders, 10 (1), art. no. 29, .
Marrus, N.a , Hall, L.P.b , Paterson, S.J.c , Elison, J.T.d , Wolff, J.J.e , Swanson, M.R.f , Parish-Morris, J.g , Eggebrecht, A.T.h , Pruett, J.R.a , Hazlett, H.C.f , Zwaigenbaum, L.i , Dager, S.j , Estes, A.M.k , Schultz, R.T.g , Botteron, K.N.a , Piven, J.f , Constantino, J.N.a , Piven, J.l , Hazlett, H.C.l , Chappell, C.l , Dager, S.l , Estes, A.l , Shaw, D.l , Botteron, K.l , McKinstry, R.l , Constantino, J.l , Pruett, J.l , Schultz, R.T.l , Paterson, S.l , Zwaigenbaum, L.l , Elison, J.l , Evans, A.C.l , Collins, D.L.l , Pike, G.B.l , Fonov, V.l , Kostopoulos, P.l , Das, S.l , Gerig, G.l , Styner, M.l , Gu, H.l
a Department of Psychiatry, Washington University, School of Medicine, 660 S. Euclid Ave, Box 8504, St Louis, MO 63110, United States
b Department of Psychology, St. Jude Children’s Research Hospital, Mail Stop 740, 262 Danny Thomas Place, Memphis, TN 38105, United States
c Department of Psychology, Temple University, 1801 N. Broad St, Philadelphia, PA 19122, United States
d Institute of Child Development, University of Minnesota, 51 East River Parkway, Minneapolis, MN 55455, United States
e Department of Educational Psychology, University of Minnesota, 56 East River Road, Minneapolis, MN 55455, United States
f Department of Psychiatry, University of North Carolina at Chapel Hill, 101 Manning Dr, Chapel Hill, NC 27514, United States
g Children’s Hospital of Philadelphia, University of Pennsylvania, Civic Center Blvd, Philadelphia, PA 19104, United States
h Mallinckrodt Institute of Radiology, Washington University, School of Medicine, 660 S. Euclid Ave, St Louis, MO 63110, United States
i Department of Pediatrics, University of Alberta, 1E1 Walter Mackenzie Health Sciences Centre (WMC), 8440 112 St NW, Edmonton, AB T6G 2B7, Canada
j Department of Radiology, University of Washington, Seattle, 1410 NE Campus Parkway, Seattle, WA 98195, United States
k Department of Speech and Hearing Sciences, University of Washington, Seattle, 1701 NE Columbia Rd, Seattle, WA 98195-7920, United States
Background: Language delay is extremely common in children with autism spectrum disorder (ASD), yet it is unclear whether measurable variation in early language is associated with genetic liability for ASD. Assessment of language development in unaffected siblings of children with ASD can inform whether decreased early language ability aggregates with inherited risk for ASD and serves as an ASD endophenotype. Methods: We implemented two approaches: (1) a meta-analysis of studies comparing language delay, a categorical indicator of language function, and language scores, a continuous metric, in unaffected toddlers at high and low familial risk for ASD, and (2) a parallel analysis of 350 unaffected 24-month-olds in the Infant Brain Imaging Study (IBIS), a prospective study of infants at high and low familial risk for ASD. An advantage of the former was its detection of group differences from pooled data across unique samples; an advantage of the latter was its sensitivity in quantifying early manifestations of language delay while accounting for covariates within a single large sample. Results: Meta-analysis showed that high-risk siblings without ASD (HR-noASD) were three to four times more likely to exhibit language delay versus low-risk siblings without ASD (LR-noASD) and had lower mean receptive and expressive language scores. Analyses of IBIS data corroborated that language delay, specifically receptive language delay, was more frequent in the HR-noASD (n = 235) versus LR-noASD group (n = 115). IBIS language scores were continuously and unimodally distributed, with a pathological shift towards decreased language function in HR-noASD siblings. The elevated inherited risk for ASD was associated with lower receptive and expressive language scores when controlling for sociodemographic factors. For receptive but not expressive language, the effect of risk group remained significant even when controlling for nonverbal cognition. Conclusions: Greater frequency of language delay and a lower distribution of language scores in high-risk, unaffected toddler-aged siblings support decreased early language ability as an endophenotype for ASD, with a more pronounced effect for receptive versus expressive language. Further characterization of language development is warranted to refine genetic investigations of ASD and to elucidate factors influencing the progression of core autistic traits and related symptoms. © 2018 The Author(s).
Autism spectrum disorder; Development; Endophenotype; Infant sibling; Language
Document Type: Article
Access Type: Open Access
“Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein e isoform-specific mechanism” (2018) Molecular Neurodegeneration
Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein e isoform-specific mechanism
(2018) Molecular Neurodegeneration, 13 (1), art. no. 57, .
Ma, Q.a b , Zhao, Z.a , Sagare, A.P.a , Wu, Y.a , Wang, M.a , Owens, N.C.a , Verghese, P.B.c , Herz, J.d e f , Holtzman, D.M.g , Zlokovic, B.V.a
a Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, United States
b Lawrence D. Longo, MD Center for Neonatal Biology, Division of Pharmacology, Department of Basic Sciences, Loma Linda University, School of Medicine, Loma Linda, CA 92350, United States
c C2N Diagnostics, LLC, Saint Louis, MO 63110, United States
d Department of Molecular Genetics, University of Texas, Southwestern Medical Center, Dallas, TX, United States
e Department of Neuroscience, University of Texas, Southwestern Medical Center, Dallas, TX, United States
f Department of Neurology and Neurotherapeutics, Center for Translational Neurodegeneration Research, University of Texas, Southwestern Medical Center, Dallas, TX, United States
g Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, School of Medicine, Saint Louis, MO 63110, United States
Background: Clearance at the blood-brain barrier (BBB) plays an important role in removal of Alzheimer’s amyloid-β (Aβ) toxin from brain both in humans and animal models. Apolipoprotein E (apoE), the major genetic risk factor for AD, disrupts Aβ clearance at the BBB. The cellular and molecular mechanisms, however, still remain unclear, particularly whether the BBB-associated brain capillary pericytes can contribute to removal of aggregated Aβ from brain capillaries, and whether removal of Aβ aggregates by pericytes requires apoE, and if so, is Aβ clearance on pericytes apoE isoform-specific. Methods: We performed immunostaining for Aβ and pericyte biomarkers on brain capillaries (< 6 μm in diameter) on tissue sections derived from AD patients and age-matched controls, and APP Swe/0 mice and littermate controls. Human Cy3-Aβ42 uptake by pericytes was studied on freshly isolated brain slices from control mice, pericyte LRP1-deficient mice (Lrp lox/lox ;Cspg4-Cre) and littermate controls. Clearance of aggregated Aβ42 by mouse pericytes was studied on multi-spot glass slides under different experimental conditions including pharmacologic and/or genetic inhibition of the low density lipoprotein receptor related protein 1 (LRP1), an apoE receptor, and/or silencing mouse endogenous Apoe in the presence and absence of human astrocyte-derived lipidated apoE3 or apoE4. Student’s t-test and one-way ANOVA followed by Bonferroni’s post-hoc test were used for statistical analysis. Results: First, we found that 35% and 60% of brain capillary pericytes accumulate Aβ in AD patients and 8.5-month-old APP Sw/0 mice, respectively, compared to negligible uptake in controls. Cy3-Aβ42 species were abundantly taken up by pericytes on cultured mouse brain slices via LRP1, as shown by both pharmacologic and genetic inhibition of LRP1 in pericytes. Mouse pericytes vigorously cleared aggregated Cy3-Aβ42 from multi-spot glass slides via LRP1, which was inhibited by pharmacologic and/or genetic knockdown of mouse endogenous apoE. Human astrocyte-derived lipidated apoE3, but not apoE4, normalized Aβ42 clearance by mouse pericytes with silenced mouse apoE. Conclusions: Our data suggest that BBB-associated pericytes clear Aβ aggregates via an LRP1/apoE isoform-specific mechanism. These data support the role of LRP1/apoE interactions on pericytes as a potential therapeutic target for controlling Aβ clearance in AD. © 2018 The Author(s).
Amyloid-β clearance; Apolipoprotein E; Blood-brain barrier (BBB); Low-density lipoprotein receptor-related protein 1 (LRP1); Pericyte
Document Type: Article
Access Type: Open Access
“Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow” (2018) Blood
Silent infarcts in sickle cell disease occur in the border zone region and are associated with low cerebral blood flow
(2018) Blood, 132 (16), pp. 1714-1723. Cited 1 time.
Ford, A.L.a , Ragan, D.K.a , Fellah, S.a , Binkley, M.M.a , Fields, M.E.b , Guilliams, K.P.a b , An, H.c , Jordan, L.C.d , McKinstry, R.C.c , Lee, J.-M.a c , DeBaun, M.R.d
a Department of Neurology, Washington University School of Medicine, 600 South Euclid Ave, Saint Louis, MO 63110, United States
b Department of Pediatrics, United States
c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Vanderbilt University, Nashville, TN, United States
Silent cerebral infarcts (SCIs) are associated with cognitive impairment in sickle cell anemia (SCA). SCI risk factors include low hemoglobin and elevated systolic blood pressure; however, mechanisms underlying their development are unclear. Using the largest prospective study evaluating SCIs in pediatric SCA, we identified brain regions with increased SCI density. We tested the hypothesis that infarct density is greatest within regions in which cerebral blood flow is lowest, further restricting cerebral oxygen delivery in the setting of chronic anemia. Neuroradiology and neurology committees reached a consensus of SCIs in 286 children in the Silent Infarct Transfusion (SIT) Trial. Each infarct was outlined and coregistered to a brain atlas to create an infarct density map. To evaluate cerebral blood flow as a function of infarct density, pseudocontinuous arterial spin labeling was performed in an independent pediatric SCA cohort. Blood flow maps were aligned to the SIT Trial infarct density map. Mean blood flow within low, moderate, and high infarct density regions from the SIT Trial were compared. Logistic regression evaluated clinical and imaging predictors of overt stroke at 3-year follow-up. The SIT Trial infarct density map revealed increased SCI density in the deep white matter of the frontal and parietal lobes. A relatively small region, measuring 5.6% of brain volume, encompassed SCIs from 90% of children. Cerebral blood flow was lowest in the region of highest infarct density (P < .001). Baseline infarct volume and reticulocyte count predicted overt stroke. In pediatric SCA, SCIs are symmetrically located in the deep white matter where minimum cerebral blood flow occurs. (Blood. 2018;132(16):1714-1723). © 2018 by The American Society of Hematology.
Document Type: Article
“Understanding the Association Between Negative Symptoms and Performance on Effort-Based Decision-Making Tasks: The Importance of Defeatist Performance Beliefs” (2018) Schizophrenia bulletin
Understanding the Association Between Negative Symptoms and Performance on Effort-Based Decision-Making Tasks: The Importance of Defeatist Performance Beliefs
(2018) Schizophrenia bulletin, 44 (6), pp. 1217-1226.
Reddy, L.F.a b , Horan, W.P.a b , Barch, D.M.c , Buchanan, R.W.d , Gold, J.M.d , Marder, S.R.a b , Wynn, J.K.a b , Young, J.e f , Green, M.F.a b
a Department of Veterans Affairs VISN 22 Mental Illness Research, Education, Clinical Center, Los Angeles, CA, United States
b UCLA Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, Los Angeles, CA, United States
c Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, MO
d Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States
e Department of Psychiatry, University of California, San Diego, United States
f Research Service, VA San Diego Healthcare System, San Diego, CA, United States
Effort-based decision-making paradigms are increasingly utilized to gain insight into the nature of motivation deficits. Research has shown associations between effort-based decision making and experiential negative symptoms; however, the associations are not consistent. The current study had two primary goals. First, we aimed to replicate previous findings of a deficit in effort-based decision making among individuals with schizophrenia on a test of cognitive effort. Second, in a large sample combined from the current and a previous study, we sought to examine the association between negative symptoms and effort by including the related construct of defeatist beliefs. The results replicated previous findings of impaired cognitive effort-based decision making in schizophrenia. Defeatist beliefs significantly moderated the association between negative symptoms and effort-based decision making such that there was a strong association between high negative symptoms and deficits in effort-based decision making, but only among participants with high levels of defeatist beliefs. Thus, our findings suggest the relationship between negative symptoms and effort performance may be understood by taking into account the role of defeatist beliefs, and finding that might explain discrepancies in previous studies.
Document Type: Article
“HSP90 is a chaperone for DLK and is required for axon injury signaling” (2018) Proceedings of the National Academy of Sciences of the United States of America
HSP90 is a chaperone for DLK and is required for axon injury signaling
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (42), pp. E9899-E9908.
Karney-Grobe, S.a , Russo, A.a , Frey, E.a , Milbrandt, J.b c , DiAntonio, A.a c
a Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO 63110, United States
b Department of Genetics, Washington University, School of Medicine, St. Louis, MO 63110, United States
c Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States
Peripheral nerve injury induces a robust proregenerative program that drives axon regeneration. While many regeneration-associated genes are known, the mechanisms by which injury activates them are less well-understood. To identify such mechanisms, we performed a loss-of-function pharmacological screen in cultured adult mouse sensory neurons for proteins required to activate this program. Well-characterized inhibitors were present as injury signaling was induced but were removed before axon outgrowth to identify molecules that block induction of the program. Of 480 compounds, 35 prevented injury-induced neurite regrowth. The top hits were inhibitors to heat shock protein 90 (HSP90), a chaperone with no known role in axon injury. HSP90 inhibition blocks injury-induced activation of the proregenerative transcription factor cJun and several regeneration-associated genes. These phenotypes mimic loss of the proregenerative kinase, dual leucine zipper kinase (DLK), a critical neuronal stress sensor that drives axon degeneration, axon regeneration, and cell death. HSP90 is an atypical chaperone that promotes the stability of signaling molecules. HSP90 and DLK show two hallmarks of HSP90-client relationships: (i) HSP90 binds DLK, and (ii) HSP90 inhibition leads to rapid degradation of existing DLK protein. Moreover, HSP90 is required for DLK stability in vivo, where HSP90 inhibitor reduces DLK protein in the sciatic nerve. This phenomenon is evolutionarily conserved in Drosophila. Genetic knockdown of Drosophila HSP90, Hsp83, decreases levels of Drosophila DLK, Wallenda, and blocks Wallenda-dependent synaptic terminal overgrowth and injury signaling. Our findings support the hypothesis that HSP90 chaperones DLK and is required for DLK functions, including proregenerative axon injury signaling. © 2018 National Academy of Sciences. All Rights Reserved.
Axon regeneration; DLK; Highwire ligase; HSP90; Injury signaling
Document Type: Article
“Medical cannabis, synthetic marijuana extracts, and obstructive sleep apnea” (2018) Journal of Clinical Sleep Medicine
Medical cannabis, synthetic marijuana extracts, and obstructive sleep apnea
(2018) Journal of Clinical Sleep Medicine, 14 (10), pp. 1815-1816.
Ramar, K.a , Kirsch, D.B.b , Carden, K.A.c , Rosen, I.M.d , Malhotra, R.K.e
a Division of Pulmonary and Critical Care Medicine, Center for Sleep Medicine, Mayo Clinic, Rochester, MN, United States
b Carolinas Healthcare Medical Group Sleep Services, Charlotte, NC, United States
c Saint Thomas Medical Partners – Sleep Specialists, Nashville, TN, United States
d Division of Sleep Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Washington University Sleep Center, St. Louis, MO, United States
Document Type: Letter
“Neurosteroids in pain management: A new perspective on an old player” (2018) Frontiers in Pharmacology
Neurosteroids in pain management: A new perspective on an old player
(2018) Frontiers in Pharmacology, 9 (OCT), art. no. 1127, .
Joksimovic, S.L.a , Covey, D.F.b c , Jevtovic-Todorovic, V.a , Todorovic, S.M.a d
a Department of Anesthesiology, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
b Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Taylor Family Institute for Innovative Psychiatric Research, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Neuroscience Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, United States
Since the discovery of the nervous system’s ability to produce steroid hormones, numerous studies have demonstrated their importance in modulating neuronal excitability. These central effects are mostly mediated through different ligand-gated receptor systems such as GABAA and NMDA, as well as voltage-dependent Ca2+ or K+ channels. Because these targets are also implicated in transmission of sensory information, it is not surprising that numerous studies have shown the analgesic properties of neurosteroids in various pain models. Physiological (nociceptive) pain has protective value for an organism by promoting survival in life-threatening conditions. However, more prolonged pain that results from dysfunction of nerves (neuropathic pain), and persists even after tissue injury has resolved, is one of the main reasons that patients seek medical attention. This review will focus mostly on the analgesic perspective of neurosteroids and their synthetic 5α and 5β analogs in nociceptive and neuropathic pain conditions. © 2007 – 2018 Frontiers Media S.A. All Rights Reserved.
Analgesic (activity); Chronic pain; Neurosteroid analogs; Neurosteroids; T-channel (CaV3); T-channel calcium channel blockers
Document Type: Review
Access Type: Open Access
“Strengthening mental health and research training in Sub-Saharan Africa (SMART Africa): Uganda study protocol” (2018) Trials
Strengthening mental health and research training in Sub-Saharan Africa (SMART Africa): Uganda study protocol
(2018) Trials, 19 (1), art. no. 423, .
Ssewamala, F.M.a , Sensoy Bahar, O.a , McKay, M.M.a , Hoagwood, K.b , Huang, K.-Y.b , Pringle, B.c
a Brown School, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
b School of Medicine, New York University, Department of Child and Adolescent Psychiatry, 550 First Avenue, New York, NY 10016, United States
c National Institute of Mental Health, 6001 Executive Boulevard, Bethesda, MD 20892, United States
Background: Children in Sub-Saharan Africa (SSA) comprise half of the total regional population, yet existing mental health services are severely under-equipped to meet their needs. Although effective interventions for the treatment of disruptive behavioral disorders (DBDs) in youth have been tested in high-poverty and high-stress communities in developed countries, and are relevant for widespread dissemination in low- and middle-income countries (LMICs), most of these evidence-based practices (EBPs) have not been utilized in SSA, a region heavily impacted by poverty, diseases including HIV/AIDS, and violence. Thus, this paper presents a protocol for a scale-up longitudinal experimental study that uses a mixed-methods, hybrid type II, effectiveness implementation design to test the effectiveness of an EBP, called Multiple Family Group (MFG) aimed at improving child behavioral challenges in Uganda while concurrently examining the multi-level factors that influence uptake, implementation, sustainment, and youth outcomes. Methods: The MFG intervention will be implemented and tested via a longitudinal experimental study conducted across 30 public primary schools located in both semi-urban and rural communities. The schools will be randomly assigned to three study conditions (n = 10 per study condition): (1) MFG delivered by trained family peers; (2) MFG delivered by community health workers; or; (3) comparison: usual care comprising mental health care support materials, bolstered with school support materials. A total of 3000 children (ages 8 to 13 years; grades 2 to 7) and their caregivers (N = 3000 dyads); 60 parent peers, and 60 community health workers will be recruited. Each study condition will comprise of 1000 child-caregiver dyads. Data will be collected at baseline, 8 and 16 weeks, and 6-month follow-up. Discussion: This project is the first to test the effectiveness of the MFG intervention while concurrently examining multi-level factors that influence overall implementation of a family-based intervention provided in schools and aimed at reaching the large child population with mental health service needs in Uganda. Moreover, the study draws upon an EBP that has already been tested for delivery by parent peers and community facilitators, and hence will take advantage of the advancing science behind task-shifting. If successful, the project has great potential to address global child mental health needs. Trial registration: ClinicalTrials.gov, ID: NCT03081195. Registered on 16 March 2017. © 2018 The Author(s).
Child mental health services; Evidence-based practice; Implementation science; Multiple family group interventions
Document Type: Article
Access Type: Open Access
“Mechanistic insights into MicroRNA-induced neuronal reprogramming of human adult fibroblasts” (2018) Frontiers in Neuroscience
Mechanistic insights into MicroRNA-induced neuronal reprogramming of human adult fibroblasts
(2018) Frontiers in Neuroscience, 12 (AUG), art. no. 522, .
Lu, Y.-L.a b , Yoo, A.S.a
a Department of Developmental Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Program in Developmental, Regenerative and Stem Cell Biology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
The use of transcriptional factors as cell fate regulators are often the primary focus in the direct reprogramming of somatic cells into neurons. However, in human adult fibroblasts, deriving functionally mature neurons with high efficiency requires additional neurogenic factors such as microRNAs (miRNAs) to evoke a neuronal state permissive to transcription factors to exert their reprogramming activities. As such, increasing evidence suggests brain-enriched miRNAs, miR-9/9* and miR-124, as potent neurogenic molecules through simultaneously targeting of anti-neurogenic effectors while allowing additional transcription factors to generate specific subtypes of human neurons. In this review, we will focus on methods that utilize neuronal miRNAs and provide mechanistic insights by which neuronal miRNAs, in synergism with brain-region specific transcription factors, drive the conversion of human fibroblasts into clinically relevant subtypes of neurons. Furthermore, we will provide insights into the age signature of directly converted neurons and how the converted human neurons can be utilized to model late-onset neurodegenerative disorders. © 2018 Lu and Yoo.
Chromatin; Disease modeling; Human neurons; MicroRNA; Neurogenesis; Neuronal conversion; Reprogramming
Document Type: Short Survey
Access Type: Open Access
“Assessing calvarial vault constriction associated with helmet therapy in deformational plagiocephaly” (2018) Journal of Neurosurgery: Pediatrics
Assessing calvarial vault constriction associated with helmet therapy in deformational plagiocephaly
(2018) Journal of Neurosurgery: Pediatrics, 22 (2), pp. 113-119.
Peterson, E.C.a , Patel, K.B.a , Skolnick, G.B.a , Pfeifauf, K.D.a , Davidson, K.N.b , Smyth, M.D.c , Naidoo, S.D.a
a Department of Surgery, Division of Plastic and Reconstructive Surgery, Washington University School of Medicine in, St. Louis, MO, United States
b Boston College, Chestnut Hill, MA, United States
c Departments of Surgery and Neurosurgery, Division of Pediatric Neurosurgery, Washington University School of Medicine in, St. Louis, MO, United States
OBJECTIVE Deformational plagiocephaly and/or brachycephaly (DPB) is a cranial flattening frequently treated in pediatric craniofacial centers. The standard of care for DPB involves patient positioning or helmet therapy. Orthotic therapy successfully reduces cranial asymmetry, but there is concern over whether the orthotics have the potential to restrict cranial growth. Previous research addressing helmet safety was limited by lack of volume measurements and serial data. The purpose of this study was to directly compare head growth data in patients with DPB between those who underwent helmet therapy and those who received repositioning therapy. METHODS This retrospective cohort study analyzed pre- and posttherapy 3D photographs of 57 patients with DPB who had helmet therapy and a control group of 57 patients with DPB who underwent repositioning therapy. The authors determined the change in cranial vault volume and cranial circumference between each patient’s photographs using 3D photogrammetry. They also computed a cubic volume calculated by multiplying anterior-posterior diameter, biparietal diameter, and height. Linear regressions were used to quantify effects of age and therapy type on these quantities. RESULTS A comparison of the following variables between the two groups yielded nonsignificant results: age at the beginning (p = 0.861) and end (p = 0.539) of therapy, therapy duration (p = 0.161), and the ratio of males to females (p = 0.689). There was no significant difference between patients who underwent helmeting versus positioning therapy with respect to change in either volume calculation or head circumference z-score (p ≥ 0.545). Pretherapy photograph age was a significant predictor of cranial growth (p ≤ 0.001), but therapy type was not predictive of the change in the study measurements (p ≤ 0.210). CONCLUSIONS The authors found no evidence that helmet therapy was associated with cranial constriction in the study population of patients with DPB. These results strengthen previous research supporting helmet safety and should allow health care providers and families to choose the appropriate therapy without concern for potential negative effects on cranial growth. © AANS 2018.
Cranial constriction; Craniofacial; Deformational plagiocephaly; Helmet therapy
Document Type: Article
“What Research Tells Us About Reading Instruction” (2018) Psychological science in the public interest : a journal of the American Psychological Society
What Research Tells Us About Reading Instruction
(2018) Psychological science in the public interest : a journal of the American Psychological Society, 19 (1), pp. 1-4.
Department of Psychological and Brain Sciences, Washington University in St. Louis
Document Type: Article
“The frontoparietal network: Function, electrophysiology, and importance of individual precision mapping” (2018) Dialogues in Clinical Neuroscience
The frontoparietal network: Function, electrophysiology, and importance of individual precision mapping
(2018) Dialogues in Clinical Neuroscience, 20 (2), pp. 133-141.
Marek, S.a , Dosenbach, N.F.b c
a Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
b Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
The frontoparietal network is critical for our ability to coordinate behavior in a rapid, accurate, and flexible goal-driven manner. In this review, we outline support for the framing of the frontoparietal network as a distinct control network, in part functioning to flexibly interact with and alter other functional brain networks. This network coordination likely occurs in a 4 Hz to13 Hz rhythm, both during resting state and task state. Precision mapping of individual human brains has revealed that the functional topography of the frontoparietal network is variable between individuals, underscoring the notion that group-Average studies of the frontoparietal network may be obscuring important typical and atypical features. Many forms of psychopathology implicate the frontoparietal network, such as schizophrenia and attention-deficit/hyperactivity disorder. Given the interindividual variability in frontoparietal network organization, clinical studies will likely benefit greatly from acquiring more individual subject data to accurately characterize resting-state networks compromised in psychopathology. © 2018, AICH – Servier Group.
cognitive control; Cognitive flexibility; Frontoparietal; Intraparietal sulcus; Lateral prefrontal cortex; Psychopathology
Document Type: Review
“Protein production is an early biomarker for RNA-targeted therapies” (2018) Annals of Clinical and Translational Neurology
Protein production is an early biomarker for RNA-targeted therapies
(2018) Annals of Clinical and Translational Neurology, . Article in Press.
Self, W.K.a , Schoch, K.M.a , Alex, J.a , Barthélemy, N.a , Bollinger, J.G.a , Sato, C.a , Cole, T.b , Kordasiewicz, H.B.b , Swayze, E.b , Bateman, R.J.a , Miller, T.M.a
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Ionis Pharmaceuticals, Carlsbad, CA, United States
Objectives: Clinical trials for progressive neurodegenerative disorders such as Alzheimer’s Disease and Amyotrophic Lateral Sclerosis have been hindered due to the absence of effective pharmacodynamics markers to assay target engagement. We tested whether measurements of new protein production would be a viable pharmacodynamics tool for RNA-targeted therapies. Methods: Transgenic animal models expressing human proteins implicated in neurodegenerative disorders – microtubule-associated protein tau (hTau) or superoxide dismutase-1 (hSOD1) – were treated with antisense oligonucleotides (ASOs) delivered to the central nervous system to target these human mRNA transcripts. Simultaneously, animals were administered 13C6-leucine via drinking water to measure new protein synthesis after ASO treatment. Measures of new protein synthesis and protein concentration were assayed at designated time points after ASO treatment using targeted proteomics. Results: ASO treatment lowered hTau mRNA and protein production (measured by 13C6-leucine-labeled hTau protein) earlier than total hTau protein concentration in transgenic mouse cortex. In the CSF of hSOD1 transgenic rats, ASO treatment lowered newly generated hSOD1 protein driven by decreases in newly synthesized hSOD1 protein, not overall protein concentration, 30 days after treatment. At later time points, decreases in newly generated protein were still observed after mRNA lowering reached a steady state after ASO treatment. Interpretation: Measures of newly generated protein show earlier pharmacodynamics changes for RNA-lowering therapeutics compared with total protein concentration. Early in ASO treatment, decreases in newly generated protein are driven by changes in newly synthesized protein. Measuring new protein production in CSF may be a promising early pharmacodynamics marker for RNA-targeted therapeutics. © 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
Document Type: Article in Press
Access Type: Open Access
“Impact of Connector Placement and Design on Bending Stiffness of Spinal Constructs” (2018) World Neurosurgery
Impact of Connector Placement and Design on Bending Stiffness of Spinal Constructs
(2018) World Neurosurgery, . Article in Press.
Godzik, J.a , Hool, N.b , Dalton, J.F.c , Whiting, A.C.a , Newcomb, A.G.U.S.b , Kelly, B.P.b , Crawford, N.R.b
a Department of Neurosurgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
b Spinal Biomechanics Laboratory, Department of Neurosurgery Research, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
c Washington University Medical School, St. Louis, MO, United States
Objective: To evaluate the stability of multiple rod–connector construct designs using a mechanical 4-point bending testing frame. Methods: A mechanical study was used to evaluate the bending stiffness of 3 connectors across 12 different configurations of rod–connector–rod constructs. Stability was evaluated in flexion–extension and lateral bending. Combinations of rods having 1 of 3 diameters (4.0 mm, 5.5 mm, and 6.0 mm) connected by 1 of 3 connector types (parallel open, snap-on, and hinged) were compared. Configurations with single connectors and with double connectors with variable spacing were also compared to simulate revision surgery conditions. Results: Constructs consisting of 4.0-mm rods connected to 4.0-mm rods were significantly less stiff as the total number of connectors used in a series exceeded 2. When single-connector configurations were compared, parallel open rod connectors demonstrated greater stiffness in flexion–extension than hinged open connectors, whereas hinged open connectors demonstrated greater stiffness in lateral bending. Using double connectors increased stiffness of 4.0- to 4.0-mm rod configurations in flexion–extension and lateral bending, 4.0- to 6.0-mm rod configurations in flexion–extension, and 5.5- to 6.0-mm rod configurations in lateral bending. Spacing the double connectors significantly improved lateral bending stiffness of 4.0- to 4.0-mm and 5.5- to 6.0-mm rod configurations. Conclusions: Our data indicate that the design, number, and placement of rod connectors have a significant impact on the bending stiffness of a surgical construct. Such mechanical data may influence construct design in primary and revision surgeries of the cervical spine and cervicothoracic junction. © 2018 Elsevier Inc.
Bending stiffness; Biomechanics; Cervical spine; Component testing; Instrumentation; Spinal fixation implant
Document Type: Article in Press
“Role of resting state MRI temporal latency in refractory pediatric extratemporal epilepsy lateralization” (2018) Journal of Magnetic Resonance Imaging
Role of resting state MRI temporal latency in refractory pediatric extratemporal epilepsy lateralization
(2018) Journal of Magnetic Resonance Imaging, . Article in Press.
Shah, M.N.a , Nguyen, R.D.a , Pao, L.P.a , Zhu, L.b , CreveCoeur, T.S.c , Mitra, A.d , Smyth, M.D.c
a Departments of Pediatric Surgery and Neurosurgery, McGovern Medical School at UTHealth, Houston, TX, United States
b Department of Internal Medicine, Clinical and Translational Sciences, McGovern Medical School at UTHealth, Houston, TX, United States
c Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States
Background: Pediatric epilepsy affects 0.5–1% of children, with 10–30% of these children refractory to medical anticonvulsant therapy and potentially requiring surgical intervention. Analysis of resting state functional MRI (rsMRI) signal temporal differences (latency) has been proposed to study the pathological cognitive processes. Purpose/Hypothesis: To quantitatively and qualitatively analyze the correlation of rsMRI signal latency to pediatric refractory extratemporal epilepsy seizure foci lateralization. Study Type: Retrospective review. Population: With Institutional Review Board approval, rsMRI and anatomical MRI scans were obtained from 38 registered pediatric epilepsy surgery patients from Washington University and 259 healthy control patients from the ADHD-200 dataset. Field Strength/Sequence: 3 T echo planar imaging (EPI) blood oxygenation level-dependent (BOLD) sequence. Assessment: The images were transformed to pediatric atlases in Talairach space. Preoperative voxelwise latency maps were generated with parabolic interpolation of the rsMRI signal lateness or earliness when compared with the global mean signal (GMS) using cross-covariance analysis. Statistical Tests: Latency z-score maps were created for each epilepsy patient by voxelwise calculation using healthy control mean and standard deviation maps. Voxelwise hypothesis testing was performed via multiple comparisons corrected (false discovery and familywise error rate) and uncorrected methods to determine significantly late and early voxels. Significantly late and/or early voxels were counted for the right and left hemisphere separately. The hemisphere with the greater proportion of significantly late and/or early voxels was hypothesized to contain the seizure focus. Preoperative rsMRI latency analysis hypotheses were compared with postoperative seizure foci lateralization determined by resection images. Results: Preoperative rsMRI latency analysis correctly identified seizure foci lateralization of 64–85% of postoperative epilepsy resections with the proposed methods. RsMRI latency lateralization analysis was 77–100% sensitive and 58–79% specific. In some patients, qualitative analysis yielded preoperative rsMRI latency patterns specific to procedure performed. Data Conclusion: Preoperative rsMRI signal latency of pediatric epilepsy patients was correlated with seizure foci lateralization. J. Magn. Reson. Imaging 2018. © 2018 International Society for Magnetic Resonance in Medicine
hemispherotomy; lesionectomy; resting state functional MRI; seizure foci; temporal latency
Document Type: Article in Press
“Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls – CORRIGENDUM” (2018) Psychological Medicine
Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls – CORRIGENDUM
(2018) Psychological Medicine, . Article in Press.
Pettersson, E.a , Lichtenstein, P.a , Larsson, H.a b , Song, J.a , Agrawal, A.c , Børglum, A.D.d e f , Bulik, C.M.a g , Daly, M.J.h i j , Davis, L.K.k , Demontis, D.d e f , Edenberg, H.J.l m , Grove, J.d e f n , Gelernter, J.o p q , Neale, B.M.h i j , Pardiñas, A.F.r , Stahl, E.s , Walters, J.T.R.t , Walters, R.h j , Sullivan, P.F.a t , Posthuma, D.u v , Polderman, T.J.C.u
a Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
b School of Medical Sciences, Örebro University, Örebro, Sweden
c Department of Psychiatry, Washington University in Saint Louis, School of Medicine, Saint Louis, MO, United States
d Department of Biomedicine, Aarhus University, Aarhus, Denmark
e IPSYCH, Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
f ISEQ, Centre for Integrative Sequencing, Aarhus University, Aarhus, Denmark
g University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
h Analytic and Translational Genetics Unit (ATGU), Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
i Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, United States
j Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA, United States
k Department of Medicine, Division of Genetic Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, United States
l Indiana University, School of Medicine, Biochemistry and Molecular Biology, Indianapolis, IN, United States
m Indiana University, School of Medicine, Medical and Molecular Genetics, Indianapolis, IN, United States
n BiRC-Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
o Yale University, School of Medicine, Genetics and Neurobiology, New Haven, CT, United States
p US Department of Veterans Affairs, Psychiatry, West Haven, CT, United States
q Yale University, School of Medicine, Psychiatry, New Haven, CT, United States
r Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
s Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, United States
t Department of Genetics and Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
u Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, Netherlands
v Department of Clinical Genetics, VU University Medical Center (VUMC), Amsterdam, Netherlands
Document Type: Article in Press
“Therapeutic potency of oncolytic virotherapy–induced cancer stem cells targeting in brain tumors, current status, and perspectives” (2018) Journal of Cellular Biochemistry
Therapeutic potency of oncolytic virotherapy–induced cancer stem cells targeting in brain tumors, current status, and perspectives
(2018) Journal of Cellular Biochemistry, . Article in Press.
Bahreyni, A.a b , Ghorbani, E.c , Fuji, H.d , Ryzhikov, M.e , Khazaei, M.f g , Erfani, M.h , Avan, A.g i , Hassanian, S.M.g j , Azadmanesh, K.k
a Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
b Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
c Department of Microbiology, Al-Zahra University, Tehran, Iran
d Department of Biochemistry, Payame-Noor University, Mashhad, Iran
e Division of Pulmonary and Critical Care Medicine, Washington University, School of Medicine, Saint Louis, MO, United States
f Department of Medical Physiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
g Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
h Department of Neurology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
i Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
j Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
k Virology Department, Pasteur Institute of Iran, Tehran, Iran
Brain tumors are the most common form of solid tumors in children and is presently a serious therapeutic challenge worldwide. Traditional treatment with chemotherapy and radiotherapy was shown to be unsuccessful in targeting brain tumor cancer stem cells (CSCs), leading to recurrent, treatment-resistant secondary malignancies. Oncolytic virotherapy (OV) is an effective antitumor therapeutic strategy which offers a novel, targeted approach for eradicating pediatric brain tumor CSCs by utilizing mechanisms of cell killing that differ from conventional therapies. A number of studies and some clinical trials have therefore investigated the effects of combined therapy of radiations or chemotherapies with oncolytic viruses which provide new insights regarding the effectiveness and improvement of treatment responses for brain cancer patients. This review summarizes the current knowledge of the therapeutic potency of OVs-induced CSCs targeting in the treatment of brain tumors for a better understanding and hence a better management of this disease. © 2018 Wiley Periodicals, Inc.
brain tumor; cancer stem cell (CSC); oncolytic virotherapy (OV)
Document Type: Article in Press
“High-affinity interactions and signal transduction between Aβ oligomers and TREM2” (2018) EMBO Molecular Medicine
High-affinity interactions and signal transduction between Aβ oligomers and TREM2
(2018) EMBO Molecular Medicine, art. no. e201809027, . Article in Press.
Lessard, C.B.a , Malnik, S.L.a , Zhou, Y.b , Ladd, T.B.a , Cruz, P.E.a , Ran, Y.a , Mahan, T.E.c , Chakrabaty, P.a d , Holtzman, D.M.c , Ulrich, J.D.c , Colonna, M.b , Golde, T.E.a d
a Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, FL, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Hope Center for Neurological Disorders, Knight ADRC, Washington University School of Medicine, St. Louis, MO, United States
d McKnight Brain Institute, University of Florida, Gainesville, FL, United States
Rare coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased risk for Alzheimer’s disease (AD), but how they confer this risk remains uncertain. We assessed binding of TREM2, AD-associated TREM2 variants to various forms of Aβ and APOE in multiple assays. TREM2 interacts directly with various forms of Aβ, with highest affinity interactions observed between TREM2 and soluble Aβ42 oligomers. High-affinity binding of TREM2 to Aβ oligomers is characterized by very slow dissociation. Pre-incubation with Aβ is shown to block the interaction of APOE. In cellular assays, AD-associated variants of TREM2 reduced the amount of Aβ42 internalized, and in NFAT assay, the R47H and R62H variants decreased NFAT signaling activity in response to Aβ42. These studies demonstrate i) a high-affinity interaction between TREM2 and Aβ oligomers that can block interaction with another TREM2 ligand and ii) that AD-associated TREM2 variants bind Aβ with equivalent affinity but show loss of function in terms of signaling and Aβ internalization. © 2018 The Authors. Published under the terms of the CC BY 4.0 license
Alzheimer’s disease; amyloid; APOE; innate immune response; TREM2
Document Type: Article in Press
Access Type: Open Access
“Blood exposure causes ventricular zone disruption and glial activation in vitro” (2018) Journal of Neuropathology and Experimental Neurology
Blood exposure causes ventricular zone disruption and glial activation in vitro
(2018) Journal of Neuropathology and Experimental Neurology, 77 (9), pp. 803-813.
Castaneyra-Ruiz, L.a , Morales, D.M.a , McAllister, J.P.a , Brody, S.L.b , Isaacs, A.M.c , Strahle, J.M.a d , Dahiya, S.M.e , Limbrick, D.D.a d
a Department of Neurological Surgery, Washington University, School of Medicine, St. Louis Children’s Hospital, Campus Box 8057, 660 South Euclid Ave, St. Louis, MO 63110, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MI, United States
c Department of Neuroscience, Washington University School of Medicine, St. Louis, MI, United States
d Department of Pediatrics, Washington University School of Medicine, St. Louis, MI, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MI, United States
Intraventricular hemorrhage (IVH) is the most common cause of pediatric hydrocephalus in North America but remains poorly understood. Cell junction-mediated ventricular zone (VZ) disruption and astrogliosis are associated with the pathogenesis of congenital, nonhemorrhagic hydrocephalus. Recently, our group demonstrated that VZ disruption is also present in preterm infants with IVH. On the basis of this observation, we hypothesized that blood triggers the loss of VZ cell junction integrity and related cytopathology. In order to test this hypothesis, we developed an in vitro model of IVH by applying syngeneic blood to cultured VZ cells obtained from newborn mice. Following blood treatment, cells were assayed for N-cadherindependent adherens junctions, ciliated ependymal cells, and markers of glial activation using immunohistochemistry and immunoblotting. After 24-48 hours of exposure to blood, VZ cell junctions were disrupted as determined by a significant reduction in N-cadherin expression (p<0.05). This was also associated with significant decrease in multiciliated cells and increase in glial fibrillary acid protein-expressing cells (p<0.05). These observations suggest that, in vitro, blood triggers VZ cell loss and glial activation in a pattern that mirrors the cytopathology of human IVH and supports the relevance of this in vitro model to define injury mechanisms. © 2018 American Association of Neuropathologists, Inc. All rights reserved.
Ependyma; Hydrocephalus; Intraventricular hemorrhage; N-cadherin; Ventricular zone
Document Type: Article
“Genetic Predisposition vs Individual-Specific Processes in the Association between Psychotic-like Experiences and Cannabis Use” (2018) JAMA Psychiatry
Genetic Predisposition vs Individual-Specific Processes in the Association between Psychotic-like Experiences and Cannabis Use
(2018) JAMA Psychiatry, . Article in Press.
Karcher, N.R.a , Barch, D.M.a b , Demers, C.H.b , Baranger, D.A.A.b , Heath, A.C.a , Lynskey, M.T.c , Agrawal, A.a
a Department of Psychiatry, Washington University, School of Medicine, St Louis, MO, United States
b Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
c Addictions Department, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, United Kingdom
Importance: Previous research indicates that cannabis use is associated with psychotic-like experiences (PLEs). However, it is unclear whether this association results from predispositional (ie, shared genetic) factors or individual-specific factors (eg, causal processes, such as cannabis use leading to PLEs). Objectives: To estimate genetic and environmental correlations between cannabis use and PLEs, and to examine PLEs in twin and nontwin sibling pairs discordant for exposure to cannabis use to disentangle predispositional from individual-specific effects. Design, Setting, and Participants: In this cross-sectional analysis, diagnostic interviews and self-reported data were collected from 2 separate population-based samples of twin and nontwin sibling pairs. Data from the Human Connectome Project were collected between August 10, 2012, and September 29, 2015, and data from the Australian Twin Registry Cohort 3 (ATR3) were collected between August 1, 2005, and August 31, 2010. Data were analyzed between August 17, 2017, and July 6, 2018. The study included data from 1188 Human Connectome Project participants and 3486 ATR3 participants, totaling 4674 participants. Main Outcomes and Measures: Three cannabis-involvement variables were examined: frequent use (ie, ≥100 times), a DSM-IV lifetime cannabis use disorder diagnosis, and current cannabis use. Genetic and environmental correlations between cannabis involvement and PLEs were estimated. Generalized linear mixed models examined PLE differences in twin and nontwin sibling pairs discordant for cannabis use. Results: Among the 4674 participants, the mean (SD) age was 30.5 (3.2) years, and 2923 (62.5%) were female. Data on race/ethnicity were not included as a covariate owing to lack of variability within the ATR3 sample; among the 1188 participants in the Human Connectome Project, 875 (73.7%) were white. Psychotic-like experiences were associated with frequent cannabis use (β = 0.11; 95% CI, 0.08-0.14), cannabis use disorder (β = 0.13; 95% CI, 0.09-0.16), and current cannabis use (β = 0.07; 95% CI, 0.04-0.10) even after adjustment for covariates. Correlated genetic factors explained between 69.2% and 84.1% of this observed association. Within discordant pairs of twins/siblings (Npairs, 308-324), Psychotic-like experiences were more common in cannabis-exposed individuals compared with their relative who used cannabis to a lesser degree (β ≥.23, P <.05; eg, frequent and infrequent cannabis-using relatives significantly differed, z = -5.41; P <.001). Conclusions and Relevance: Despite the strong contribution of shared genetic factors, frequent and problem cannabis use also appears to be associated with PLEs via person-specific pathways. This study’s findings suggest that policy discussions surrounding legalization should consider the influence of escalations in cannabis use on traitlike indices of vulnerability, such as PLEs, which could contribute to pervasive psychological and interpersonal burden. © 2018 American Medical Association. All rights reserved.
Document Type: Article in Press
“Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity mri alexander schaefer1” (2018) Cerebral Cortex
Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity mri alexander schaefer1
(2018) Cerebral Cortex, 28 (9), pp. 3095-3114. Cited 5 times.
Kong, R.a , Gordon, E.M.b , Laumann, T.O.c , Zuo, X.-N.d e , Holmes, A.J.f , Eickhoff, S.B.g h , Yeo, B.T.T.a i j
a Department of Electrical and Computer Engineering, ASTAR-NUS Clinical Imaging Research Centre, Singapore Institute for Neurotechnology and Memory Networks Program, National University of Singapore, Singapore, Singapore
b VISN 17, Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
c Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d CAS Key Laboratory of Behavioral Sciences, Institute of Psychology, Beijing, China
e University of Chinese Academy of Sciences, Beijing, China
f Yale University, New Haven, CT, United States
g Institute for Systems Neuroscience, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
h Institute of Neuroscience and Medicine, Brain and Behaviour (INM-7), Research Center Julich, Julich, Germany
i Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
j Centre for Cognitive Neuroscience, Duke-NUS Medical School, Singapore, Singapore
A central goal in systems neuroscience is the parcellation of the cerebral cortex into discrete neurobiological “atoms”. Restingstate functional magnetic resonance imaging (rs-fMRI) offers the possibility of in vivo human cortical parcellation. Almost all previous parcellations relied on 1 of 2 approaches. The local gradient approach detects abrupt transitions in functional connectivity patterns. These transitions potentially reflect cortical areal boundaries defined by histology or visuotopic fMRI. By contrast, the global similarity approach clusters similar functional connectivity patterns regardless of spatial proximity, resulting in parcels with homogeneous (similar) rs-fMRI signals. Here, we propose a gradient-weighted Markov RandomField (gwMRF) model integrating local gradient and global similarity approaches. Using task-fMRI and rs-fMRI across diverse acquisition protocols, we found gwMRF parcellations to be more homogeneous than 4 previously published parcellations. Furthermore, gwMRF parcellations agreed with the boundaries of certain cortical areas defined using histology and visuotopic fMRI. Some parcels captured subareal (somatotopic and visuotopic) features that likely reflect distinct computational units within known cortical areas. These results suggest that gwMRF parcellations reveal neurobiologically meaningful features of brain organization and are potentially useful for future applications requiring dimensionality reduction of voxel-wise fMRI data. Multiresolution parcellations generated from1489 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/ tree/master/stable-projects/brain-parcellation/Schaefer2018-LocalGlobal). © The Author 2017. Published by Oxford University Press. All rights reserved.
Brain parcellation; Brodmann areas; Cytoarchitecture; Resting-state functional connectivity; Retinotopy
Document Type: Article
“Local and Global Dynamics in Intrinsically Disordered Synuclein” (2018) Angewandte Chemie – International Edition
Local and Global Dynamics in Intrinsically Disordered Synuclein
(2018) Angewandte Chemie – International Edition, . Article in Press.
Rezaei-Ghaleh, N.a , Parigi, G.b , Soranno, A.c d , Holla, A.d , Becker, S.e , Schuler, B.d , Luchinat, C.b , Zweckstetter, M.a
a University Medical Center Göttingen &, German Center for Neurodegenerative Diseases (DZNE) &, MPI for Biophysical Chemistry, Von-Siebold-Strasse 3a, Göttingen, 37075, Germany
b Magnetic Resonance Center (CERM) &, Department of Chemistry “Ugo Schiff”, University of Florence, via Sacconi 6, Sesto Fiorentino, 50121, Italy
c Washington University in St. Louis, St. Louis, MO 63110, United States
d University of Zurich, Zurich, 8057, Switzerland
e Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, Göttingen, 37077, Germany
Intrinsically disordered proteins (IDPs) experience a diverse spectrum of motions that are difficult to characterize with a single experimental technique. Herein we combine high- and low-field nuclear spin relaxation, nanosecond fluorescence correlation spectroscopy (nsFCS), and long molecular dynamics simulations of alpha-synuclein, an IDP involved in Parkinson disease, to obtain a comprehensive picture of its conformational dynamics. The combined analysis shows that fast motions below 2 ns caused by local dihedral angle fluctuations and conformational sampling within and between Ramachandran substates decorrelate most of the backbone N−H orientational memory. However, slow motions with correlation times of up to ca. 13 ns from segmental dynamics are present throughout the alpha-synuclein chain, in particular in its C-terminal domain, and global chain reconfiguration occurs on a timescale of ca. 60 ns. Our study demonstrates a powerful strategy to determine residue-specific protein dynamics in IDPs at different time and length scales. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
intrinsically disordered proteins; NMR spectroscopy; protein dynamics
Document Type: Article in Press
“Asymmetric sensorineural hearing loss is a risk factor for late-onset hearing loss in pediatric cancer survivors following cisplatin treatment” (2018) Pediatric Blood and Cancer
Asymmetric sensorineural hearing loss is a risk factor for late-onset hearing loss in pediatric cancer survivors following cisplatin treatment
(2018) Pediatric Blood and Cancer, art. no. e27494, . Article in Press.
Robertson, M.S.a , Hayashi, S.S.b , Camet, M.L.c , Trinkaus, K.d , Henry, J.e , Hayashi, R.J.e f
a Davis Audiology, Greenville, SC, United States
b Audiology Division, St. Louis Children’s Hospital, St. Louis, MO, United States
c Program in Audiology and Communication Sciences, Washington University School of Medicine, St. Louis, MO, United States
d Biostatistics Shared Resource, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
e Division of Pediatric Hematology/Oncology, Department of Pediatrics Washington University School of Medicine, St. Louis, MO, United States
f St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
Background: Ototoxicity is a significant complication of cisplatin treatment. Hearing loss can be symmetric or asymmetric, and may decline after therapy. This study examined the risks of asymmetric and late-onset hearing loss (LOHL) in cisplatin-treated pediatric patients with cancer. Methods: A retrospective review of 993 patients’ medical and audiological charts from August 1990 to March 2015 was conducted using stringent criteria to characterize patients with asymmetric hearing loss (AHL) or LOHL. Audiologic data were reviewed for 248 patients that received cisplatin to assess cisplatin-induced sensorineural hearing loss and its associated risk factors. Results: Of the patients evaluable for AHL, 26% exhibited this finding. Of those evaluable for LOHL, 42% of the patients’ hearing worsened more than 6 months after therapy completion. Radiation and type of cancer diagnosis were major risk factors for both AHL and LOHL. Furthermore, LOHL was linked to age of diagnosis, noncranial radiation, and longer audiologic follow-up. AHL was strongly associated with LOHL—60% of patients with AHL also had LOHL. Logistic regression analysis revealed that patients with AHL (OR 6.3, 95% CI: 2.2-17.8, P = 0.0005) or those receiving radiation (OR 3.2, 95% CI: 1.2-8.6, P = 0.02) were at greatest risk for LOHL. Conclusion: Children receiving cisplatin therapy are at risk for developing AHL and LOHL. Those that have received radiation and/or with AHL are at increased risk for further hearing decline. Long-term monitoring of these patients is important for early intervention as hearing diminishes. © 2018 Wiley Periodicals, Inc.
asymmetric; cisplatin; hearing loss; late-onset; pediatric
Document Type: Article in Press
“The revised national Alzheimer’s coordinating center’s neuropathology form-available data and new analyses” (2018) Journal of Neuropathology and Experimental Neurology
The revised national Alzheimer’s coordinating center’s neuropathology form-available data and new analyses
(2018) Journal of Neuropathology and Experimental Neurology, 77 (8), pp. 717-726.
Besser, L.M.a b , Kukull, W.A.a , Teylan, M.A.a , Bigio, E.H.c , Cairns, N.J.d , Kofler, J.K.e , Montine, T.J.f , Schneider, J.A.g , Nelson, P.T.h
a Department of Epidemiology, National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, United States
b Institute for Healthy Aging and Lifespan Studies, School of Urban and Regional Planning, Florida Atlantic University, 777 Glades Rd., Boca Raton, FL 33431, United States
c Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
d Department of Neurology, Washington University in St Louis, St. Louis, MO, United States
e Department of Pathology, University of Pittsburgh, Pittsburgh, PA, United States
f Department of Pathology, Stanford University, Stanford, CA, United States
g Department of Pathology, Rush University, Chicago, IL, United States
h Sanders-Brown Center on Aging, Division of Neuropathology, Department of Pathology, University of Kentucky, Lexington, KY, United States
Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer’s Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer’s Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer’s disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide. © 2018 American Association of Neuropathologists, Inc. All rights reserved.
Lewy; MRI; Primary age-related tauopathy (PART); Stroke; Subjective memory complaint (SMC); Tauopathy
Document Type: Article
“Predicting state transitions in brain dynamics through spectral difference of phase-space graphs” (2018) Journal of Computational Neuroscience
Predicting state transitions in brain dynamics through spectral difference of phase-space graphs
(2018) Journal of Computational Neuroscience, . Article in Press.
Luckett, P.a , Pavelescu, E.b , McDonald, T.c , Hively, L.d , Ochoa, J.e
a Department of Neurology, Washington University, St. Louis, MO, United States
b Department of Mathematics and Statistics, University of South Alabama, Mobile, AL 36688, United States
c School of Computing, University of South Alabama, Mobile, AL 36688, United States
d Oak Ridge National Laboratory (retired), Oak Ridge, TN 37830, United States
e Department of Neurology, University of South Alabama, Mobile, AL 36604, United States
Networks are naturally occurring phenomena that are studied across many disciplines. The topological features of a network can provide insight into the dynamics of a system as it evolves, and can be used to predict changes in state. The brain is a complex network whose temporal and spatial behavior can be measured using electroencephalography (EEG). This data can be reconstructed to form a family of graphs that represent the state of the brain over time, and the evolution of these graphs can be used to predict changes in brain states, such as the transition from preictal to ictal in patients with epilepsy. This research proposes objective indications of seizure onset observed from minimally invasive scalp EEG. The approach considers the brain as a complex nonlinear dynamical system whose state can be derived through time-delay embedding of the EEG data and characterized to determine change in brain dynamics related to the preictal state. This method targets phase-space graph spectra as biomarkers for seizure prediction, correlates historical degrees of change in spectra, and makes accurate prediction of seizure onset. A significant trend of normalized dissimilarity over time indicates a departure from the norm, and thus a change in state. Our methods show high sensitivity (90–100%) and specificity (90%) on 241 h of scalp EEG training data, and sensitivity and specificity of 70%–90% on test data. Moreover, the algorithm was capable of processing 12.7 min of data per second on an Intel Core i3 CPU in Matlab, showing that real-time analysis is viable. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.
Epilepsy; Graph spectra; Phase-space graph analysis; Seizure prediction
Document Type: Article in Press
“BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells” (2018) Brain
BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells
(2018) Brain, 141 (8), pp. 2299-2311.
Lessel, D.a , Gehbauer, C.b , Bramswig, N.C.c , Schluth-Bolard, C.d e , Venkataramanappa, S.f , van Gassen, K.L.I.g , Hempel, M.a , Haack, T.B.h i j , Baresic, A.k , Genetti, C.A.l m , Funari, M.F.A.n , Lessel, I.a , Kuhlmann, L.o , Simon, R.f , Liu, P.p , Denecke, J.q , Kuechler, A.c , De Kruijff, I.r , Shoukier, M.s , Lek, M.t u , Mullen, T.t u , Lüdecke, H.-J.c v , Lerario, A.M.w x , Kobbe, R.q , Krieger, T.y , Demeer, B.z , Lebrun, M.aa , Keren, B.ab , Nava, C.ab , Buratti, J.ab , Afenjar, A.ac , Shinawi, M.ad , Guillen Sacoto, M.J.ae , Gauthier, J.af , Hamdan, F.F.af , Laberge, A.-M.ag , Campeau, P.M.ah , Louie, R.J.ai , Cathey, S.S.ai , Prinz, I.o , Jorge, A.A.L.n x , Terhal, P.A.g , Lenhard, B.k aj , Wieczorek, D.c v , Strom, T.M.h i , Agrawal, P.B.l m , Britsch, S.f , Tolosa, E.b , Kubisch, C.a
a Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg, 20246, Germany
b Department of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
c Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
d Service de Génétique, Hospices Civils de Lyon, Lyon, France
e Lyon Neuroscience Research Center, Inserm U1028 – CNRS UMR5292 – UCBLyon1, GENDEV Team, Bron, France
f Institute of Molecular and Cellular Anatomy, Ulm University, Ulm, Germany
g Department of Genetics, University Medical Center Utrecht, Utrecht, Netherlands
h Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany
i Institute of Human Genetics, Technische Universität München, Munich, Germany
j Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
k Computational Regulatory Genomics Group, MRC London Institute of Medical Sciences, London, United Kingdom
l Divisions of Genetics and Genomics and Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, Boston, United States
m Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, United States
n Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
o Institute of Immunology, Hannover Medical School, Hannover, Germany
p Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
q Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany
r Department of Pediatrics, St. Antonius Hospital, Nieuwegein, Netherlands
s Pränatal-Medizin München, Munich, Germany
t Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, United States
u Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, United States
v Institute of Human Genetics, University Clinic, Heinrich-Heine University, Düsseldorf, Germany
w Unidade de Endocrinologia Genetica (LIM25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil
x Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, United States
y Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
z Unité de Génétique Clinique, CLAD Nord de France, CHU Amiens-Picardie, Amiens, France
aa Service de Génétique Clinique, Chromosomique et Moléculaire, CHU Hôpital Nord, Saint-Etienne, France
ab Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
ac Département de génétique médicale, Sorbonne Université, GRC n19, Pathologies Congénitales du Cervelet-LeucoDystrophies, AP-HP, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, Paris, F-75012, France
ad Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicin, St. Louis, MO, United States
ae GeneDx, Gaithersburg, MD, United States
af Molecular Diagnostic Laboratory, Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, Canada
ag Division of Medical Genetics and Research Center, CHU Sainte-Justine and Department of Pediatrics, Université de Montréal, Montreal, Canada
ah Department of Pediatrics, CHU Sainte-Justine and, University of Montreal, Montreal, Canada
ai Greenwood Genetic Center, Greenwood, SC, United States
aj Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes. © The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
BCL11B; Developmental delay; Intellectual disability; Neurodevelopment; Type 2 innate lymphoid cells
Document Type: Article
“Précis of talking to our selves: Reflection, ignorance, and agency” (2018) Behavioral and Brain Sciences
Précis of talking to our selves: Reflection, ignorance, and agency
(2018) Behavioral and Brain Sciences, 41, art. no. e36, .
Philosophy-Neuroscience-Psychology Program, Philosophy Department, Washington University in St. Louis, St. Louis, MO 63130, United States
Does it make sense for people to hold one another responsible for what they do, as happens in countless social interactions every day?One of the most unsettling lessons from recent psychological research is that people are routinely mistaken about the origins of their behavior. Yet philosophical orthodoxy holds that the exercise of morally responsible agency typically requires accurate self-awareness. If the orthodoxy is right, and the psychology is to be believed, people characteristically fail to meet the standards of morally responsible agency, and we are faced with the possibility of skepticism about agency. Unlike many philosophers, I accept the unsettling lesson from psychology. I insist, however, that we are not driven to skepticism. Instead, we should reject the requirement of accurate self-awareness for morally responsible agency. In Talking to Our Selves I develop a dialogic theory, where the exercise of morally responsible agency emerges through a collaborative conversational process by which human beings, although afflicted with a remarkable degree of self-ignorance are able to realize their values in their lives. © 2018 Cambridge University Press.
Agency; Character; Confabulation; Deliberation; Ethics; Morality; Psychology; Reasoning; Reflection; Responsibility; Selfknowledge; The self; Value
Document Type: Article
“Construct validity for the verbal associated pairs screen” (2018) Child Neuropsychology
Construct validity for the verbal associated pairs screen
(2018) Child Neuropsychology, . Article in Press.
Dodd, J.a b , Murphy, S.c , Doherty, M.d
a Department of Psychology, St. Louis Children’s Hospital, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychology, University of Missouri–St. Louis, St. Louis, MO, United States
d Department of Occupational Therapy, St. Louis Children’s Hospital, St. Louis, MO, United States
The present study introduces the Verbal Associated Pairs Screen (VAPS) as a new measure for assessing performance validity in pediatric populations. This study presents initial data on psychometric properties and establishes construct validity for the VAPS in a sample of 30 adolescent healthy controls and 206 youths with traumatic brain injury (TBI: moderate/severe, N = 30; mild, N = 176). The control group’s age (M = 14.93, SD = 1.8) was significantly higher than the moderate/severe TBI (M = 13.9, SD = 2.8), t(68.508) = −3.038, p = .003, and mild TBI (mTBI) groups (M = 14, SD = 2.8), t(54.147) = 2.038, p = .046. The TBI groups were administered the VAPS in accord with other established performance validity tests (PVTs) and well-established memory tests as part of routine clinical evaluations. The healthy control group was administered the VAPS only. VAPS score distributions for the control group were negatively skewed and highly kurtotic. VAPS scores from the moderate/severe TBI and control groups were indistinguishable for Trial 2 (U = 274, p < .01) and the Delay (U = 396, p = .218). In the mTBI group, convergent and divergent validity was established with other well-validated PVTs and memory tests, respectively. ROC curve analyses identified optimal cutoff scores for the VAPS Total Score, with acceptable sensitivity (55%) and excellent specificity (100%), as well as strong detectability (AUC = .829, 95% CI: 0.731–0.928, p < .001). Clinical applications, limitations, and directions for future research with the VAPS are discussed. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
brain injury; forensic; neuropsychology; Pediatric; performance validity
Document Type: Article in Press