Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Neuronal evidence for good-based economic decisions under variable action costs” (2019) Nature Communications

Neuronal evidence for good-based economic decisions under variable action costs
(2019) Nature Communications, 10 (1), art. no. 393, . 

Cai, X.a b c d , Padoa-Schioppa, C.a e f

a Department of Neuroscience, Washington University in St Louis, St Louis, MO 63110, United States
b NYU Shanghai, 1555 Century Avenue, Shanghai, 200122, China
c Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Psychology and Cognitive Science, East China Normal University, Shanghai, 200062, China
d NYU-ECNU Institute of Brain and Cognitive Science at NYU Shanghai, 3663 Zhongshan Road North, Shanghai, 200062, China
e Department of Economics, Washington University in St Louis, St Louis, MO 63110, United States
f Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO 63110, United States

Abstract
Previous work showed that economic decisions can be made independently of spatial contingencies. However, when goods available for choice bear different action costs, the decision necessarily reflects aspects of the action. One possibility is that “stimulus values” are combined with the corresponding action costs in a motor representation, and decisions are then made in actions space. Alternatively, action costs could be integrated with other determinants of value in a non-spatial representation. If so, decisions under variable action costs could take place in goods space. Here, we recorded from orbitofrontal cortex while monkeys chose between different juices offered in variable amounts. We manipulated action costs by varying the saccade amplitude, and we dissociated in time and space offer presentation from action planning. Neurons encoding the binary choice outcome did so well before the presentation of saccade targets, indicating that decisions were made in goods space. © 2019, The Author(s).

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

“Opioid receptors inhibit the spinal AMPA receptor Ca2+ permeability that mediates latent pain sensitization” (2019) Experimental Neurology

Opioid receptors inhibit the spinal AMPA receptor Ca2+ permeability that mediates latent pain sensitization
(2019) Experimental Neurology, 314, pp. 58-66. 

Taylor, B.K.a b , Sinha, G.P.a b , Donahue, R.R.b , Grachen, C.M.a b , Morón, J.A.c , Doolen, S.a b

a Department of Anesthesiology, Pittsburgh Center for Pain Research, University of Pittsburgh School of Medicine, 200 Lothrop St., Pittsburgh, PA 15213, United States
b Department of Physiology, University of Kentucky School of Medicine, 800 Rose, St. Lexington, KY 40536-0298, United States
c Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, 600 South Euclid, St Louis, MO 63110, United States

Abstract
Acute inflammation induces sensitization of nociceptive neurons and triggers the accumulation of calcium permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in the dorsal horn of the spinal cord. This coincides with behavioral signs of acute inflammatory pain, but whether CP-AMPARs contribute to chronic pain remains unclear. To evaluate this question, we first constructed current-voltage (I–V) curves of C-fiber stimulus-evoked, AMPAR-mediated EPSCs in lamina II to test for inward rectification, a key characteristic of CP-AMPARs. We found that the intraplantar injection of complete Freund’s adjuvant (CFA) induced an inward rectification at 3 d that persisted to 21 d after injury. Furthermore, the CP- AMPAR antagonist IEM-1460 (50 μM) inhibited AMPAR-evoked Ca2+ transients 21d after injury but had no effect in uninflamed mice. We then used a model of long-lasting vulnerability for chronic pain that is determined by the balance between latent central sensitization (LCS) and mu opioid receptor constitutive activity (MORCA). When administered 21 d after the intraplantar injection of CFA, intrathecal administration of the MORCA inverse agonist naltrexone (NTX, 1 μg, i.t.) reinstated mechanical hypersensitivity, and superfusion of spinal cord slices with NTX (10 μM) increased the peak amplitude of AMPAR-evoked Ca2+ transients in lamina II neurons. The CP-AMPAR antagonist naspm (0–10 nmol, i.t.) inhibited these NTX-induced increases in mechanical hypersensitivity. NTX had no effect in uninflamed mice. Subsequent western blot analysis of the postsynaptic density membrane fraction from lumbar dorsal horn revealed that CFA increased GluA1 expression at 2 d and GluA4 expression at both 2 and 21 d post-injury, indicating that not just the GluA1 subunit, but also the GluA4 subunit, contributes to the expression of CP-AMPARs and synaptic strength during hyperalgesia. GluA2 expression increased at 21 d, an unexpected result that requires further study. We conclude that after tissue injury, dorsal horn AMPARs retain a Ca2+ permeability that underlies LCS. Because of their effectiveness in reducing naltrexone-induced reinstatement of hyperalgesia and potentiation of AMPAR-evoked Ca2+ signals, CP-AMPAR inhibitors are a promising class of agents for the treatment of chronic inflammatory pain. © 2019

Author Keywords
Ca2+ imaging;  Chronic pain;  Dorsal horn;  Inflammation;  Postsynaptic density;  Sensitization

Document Type: Article
Publication Stage: Final
Source: Scopus

“Inflammatory expression profile in peripheral blood mononuclear cells from patients with Nasu-Hakola Disease” (2019) Cytokine

Inflammatory expression profile in peripheral blood mononuclear cells from patients with Nasu-Hakola Disease
(2019) Cytokine, 116, pp. 115-119. 

Galimberti, D.a b , Fenoglio, C.a , Ghezzi, L.a b , Serpente, M.a , Arcaro, M.b , D’Anca, M.a , De Riz, M.b , Arighi, A.b , Fumagalli, G.G.b c , Pietroboni, A.M.b , Piccio, L.d , Scarpini, E.a b

a University of Milan, Centro Dino Ferrari, Milan, Italy
b Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Neurodegenerative Diseases Unit, Milan, Italy
c Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Homozygous mutations in Triggering Receptor Expressed on Myeloid cells 2 gene (TREM2) are one of the major causes of Nasu Hakola Disease (NHD). We analysed Peripheral Blood Mononuclear Cells (PBMC) profile of 164 inflammatory factors in patients with NHD carrying the TREM2 Q33X mutation as compared with heterozygous and wild type individuals. Several molecules related to bone formation and angiogenesis were altered in NHD compared to non-carriers: Bone Morphogenetic Protein (BMP)-1 mRNA levels were significantly increased in PBMC (2.32 fold-increase; P = 0.01), as were Transforming Growth Factor Beta (TGFB)3 levels (1.51 fold-increase; P = 0.02). Conversely, CXCL5 and Pro Platelet Basic Protein (PPBP) were strongly downregulated (−28.26, −9.85 fold-decrease over non-carriers, respectively, P = 0.01), as well as Platelet Factor 4 Variant 1 (PF4V1; −41.44, P = 0.03). Among other inflammatory factors evaluated, Interleukin (IL)-15 and Tumor Necrosis Factor Superfamily Member (TNFSF)4 mRNA levels were decreased in NHD as compared with non-carriers (−2.25 and −3.87 fold-decrease, P = 0.01 and 0.001, respectively). In heterozygous individuals, no significant differences were observed, apart from IL-15 mRNA levels, that were decreased at the same extent as NHD (−2.05 fold-decrease over non-carriers, P = 0.002). We identified a signature in PBMC from patients with NHD consisting of strongly decreased mRNA levels of CXCL5, PPBP, PF4V1, mildly decreased IL-15 and TNFSF4 and mildly increased BMP-1 and TGFB3. © 2019 Elsevier Ltd

Author Keywords
Chemokines;  Cytokines;  Expression;  Inflammation;  Nasu-Hakola Disease (NHD);  Peripheral Blood Mononuclear Cells (PBMC);  Triggering Receptor Expressed on Myeloid cells 2 (TREM2)

Document Type: Article
Publication Stage: Final
Source: Scopus

“Interreader Variability of Dynamic Contrast-enhanced MRI of Recurrent Glioblastoma: The Multicenter ACRIN 6677/RTOG 0625 Study” (2019) Radiology

Interreader Variability of Dynamic Contrast-enhanced MRI of Recurrent Glioblastoma: The Multicenter ACRIN 6677/RTOG 0625 Study
(2019) Radiology, 290 (2), pp. 467-476. 

Barboriak, D.P., Zhang, Z., Desai, P., Snyder, B.S., Safriel, Y., McKinstry, R.C., Bokstein, F., Sorensen, G., Gilbert, M.R., Boxerman, J.L.

From the Department of Radiology, Duke University Medical Center, 2301 Erwin Rd, Durham, NC 27710 (D.P.B.); Department of Biostatistics and Center for Statistical Sciences, Brown University, Providence, RI (Z.Z.); Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, Tex (P.D.); Center for Statistical Sciences, Brown University School of Public Health, Providence, RI (B.S.S.); Pharmascan Clinical Trials and Radiology Associates of Clearwater, University of South Florida, Clearwater, Fla (Y.S.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (R.C.M.); Neuro-Oncology Service, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (F.B.); A.A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass (G.S.); Siemens Healthcare, Malvern, Pa (G.S.); Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Tex (M.R.G.); and Department of Diagnostic Imaging, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, RI (J.L.B.)

Abstract
Purpose To evaluate factors contributing to interreader variation (IRV) in parameters measured at dynamic contrast material-enhanced (DCE) MRI in patients with glioblastoma who were participating in a multicenter trial. Materials and Methods A total of 18 patients (mean age, 57 years ± 13 [standard deviation]; 10 men) who volunteered for the advanced imaging arm of ACRIN 6677, a substudy of the RTOG 0625 clinical trial for recurrent glioblastoma treatment, underwent analyzable DCE MRI at one of four centers. The 78 imaging studies were analyzed centrally to derive the volume transfer constant (Ktrans) for gadolinium between blood plasma and tissue extravascular extracellular space, fractional volume of the extracellular extravascular space (ve), and initial area under the gadolinium concentration curve (IAUGC). Two independently trained teams consisting of a neuroradiologist and a technologist segmented the enhancing tumor on three-dimensional spoiled gradient-recalled acquisition in the steady-state images. Mean and median parameter values in the enhancing tumor were extracted after registering segmentations to parameter maps. The effect of imaging time relative to treatment, map quality, imager magnet and sequence, average tumor volume, and reader variability in tumor volume on IRV was studied by using intraclass correlation coefficients (ICCs) and linear mixed models. Results Mean interreader variations (± standard deviation) (difference as a percentage of the mean) for mean and median IAUGC, mean and median Ktrans, and median ve were 18% ± 24, 17% ± 23, 27% ± 34, 16% ± 27, and 27% ± 34, respectively. ICCs for these metrics ranged from 0.90 to 1.0 for baseline and from 0.48 to 0.76 for posttreatment examinations. Variability in reader-derived tumor volume was significantly related to IRV for all parameters. Conclusion Differences in reader tumor segmentations are a significant source of interreader variation for all dynamic contrast-enhanced MRI parameters. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Wolf in this issue.

Document Type: Article
Publication Stage: Final
Source: Scopus

“What methods of scoring young children’s spelling best predict later spelling performance?” (2019) Journal of Research in Reading

What methods of scoring young children’s spelling best predict later spelling performance?
(2019) Journal of Research in Reading, 42 (1), pp. 80-96. 

Treiman, R.a , Kessler, B.a , Caravolas, M.b

a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b School of Psychology, Bangor University, Bangor, United Kingdom

Abstract
Background: Children’s spellings are often scored as correct or incorrect, but other measures may be better predictors of later spelling performance. Method: We examined seven measures of spelling in Reception Year and Year 1 (5–6 years old) as predictors of performance on a standardised spelling test in Year 2 (age 7). Results: Correctness was the best predictor of later spelling by the middle of Year 1, and it significantly outperformed a binary measure of phonological plausibility at the end of Reception Year. Nonbinary measures based on Levenshtein distance were significant predictors of later spelling in the middle of Reception Year and in children who produced no correct spellings. Some widely used scales performed less well with children who did not yet produce any correct spellings. Conclusions: Nonbinary measures of spelling performance can predict later spelling performance but for a more restricted period than anticipated based on many theories. Copyright © 2018 UKLA

Document Type: Article
Publication Stage: Final
Source: Scopus

“Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review” (2019) Pain

Structural, functional, and symptom relations in painful distal symmetric polyneuropathies: a systematic review
(2019) Pain, 160 (2), pp. 286-297. Cited 1 time.

Karlsson, P.a b , Hincker, A.M.c , Jensen, T.S.a , Freeman, R.d , Haroutounian, S.c e

a Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
b Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Aarhus, Denmark
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
d Center for Autonomic and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center, Boston, MA, United States
e Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The diagnosis of distal symmetric polyneuropathies (DSPs) relies on the presenting symptomatology and neurological sensory examination, supported by objectively quantified structural and functional changes in sensory nerves. Although these separate components have important diagnostic utility, the associations between the structural vs the symptomatic and functional findings in painful DSP are still unclear. It is assumed that delineation of the correlations, or lack of such, between structure, clinical presentation, and function will contribute to a better understanding and treatment of DSP. This systematic review assessed small fiber morphology in patients with different types of painful DSP, and compared it with symptoms, signs, and nerve fiber function. Overall, 111 papers met the inclusion criteria for the systematic review. The results indicate that epidermal nerve fiber loss, in isolation, is not a useful indicator of painful symptoms or their severity in DSP. Intraepidermal nerve fiber density correlated reasonably well with neuropathy scores on tools assessing signs and symptoms (such as the Michigan Neuropathy Screening Instrument and the Total Neuropathy Score), but less so with symptom measures only. Among various psychophysical sensory measures, warmth detection and heat pain thresholds correlated best with intraepidermal nerve fiber density, particularly when assessed at the same anatomical site. The observed sources of heterogeneity, and the lack of associations between structural and functional measures in several studies are discussed. A framework is proposed for uniform assessment of nerve fiber parameters for investigating clinically relevant mechanisms of neuropathic pain in DSP.

Document Type: Article
Publication Stage: Final
Source: Scopus

“MANAGEMENT OF NEOVASCULAR OCULAR HISTOPLASMOSIS: Past and Present” (2019) Retina (Philadelphia, Pa.)

MANAGEMENT OF NEOVASCULAR OCULAR HISTOPLASMOSIS: Past and Present
(2019) Retina (Philadelphia, Pa.), 39 (2), pp. 226-234. 

Blinder, K.J.

The Retina Institute, St. Louis, Missouri; and Ophthalmology and Visual Sciences, Washington University, St. Louis, Missouri

Abstract
PURPOSE: To review the wide variety of treatment modalities available for choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome. METHODS: A literature search was performed to review the multitude of studies conducted to investigate the efficacy and safety of treatment modalities available for choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome. RESULTS: Each treatment modality is reviewed, with the studies summarized and presented to support or refute the method of treatment. Two case reports are presented to demonstrate the treatment regimens. CONCLUSION: This is a comprehensive review of the treatment modalities available to address choroidal neovascularization secondary to the presumed ocular histoplasmosis syndrome. Investigators will continue to strive toward higher efficacy and safety with future innovations in the field.

Document Type: Article
Publication Stage: Final
Source: Scopus

“A wireless closed-loop system for optogenetic peripheral neuromodulation” (2019) Nature

A wireless closed-loop system for optogenetic peripheral neuromodulation
(2019) Nature, 565 (7739), pp. 361-365. 

Mickle, A.D.a b , Won, S.M.c , Noh, K.N.c , Yoon, J.d , Meacham, K.W.a b , Xue, Y.e f g , McIlvried, L.A.a b , Copits, B.A.a b , Samineni, V.K.a b , Crawford, K.E.h , Kim, D.H.d , Srivastava, P.a b , Kim, B.H.d g i j , Min, S.d , Shiuan, Y.a b , Yun, Y.d , Payne, M.A.b k , Zhang, J.l , Jang, H.d , Li, Y.l , Lai, H.H.a b k , Huang, Y.e f g , Park, S.-I.m , Gereau, R.W., IVa b , Rogers, J.A.d f g i j n o p

a Washington University Pain Center and Department of Anesthesiology, Washington University, St Louis, MO, United States
b Washington University School of Medicine, St Louis, MO, United States
c Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
d Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL, United States
e Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL, United States
f Mechanical Engineering, Northwestern University, Evanston, IL, United States
g Materials Science and Engineering, Northwestern University, Evanston, IL, United States
h Department of Materials Science and Engineering, University of Central Florida, Orlando, FL, United States
i Simpson Querrey Institute, Northwestern University, Chicago, IL, United States
j Center for Bio-integrated Electronics, Northwestern University, Evanston, IL, United States
k Washington University Department of Surgery – Division of Urologic Surgery, St Louis, MO, United States
l Institute of Solid Mechanics, Beihang University (BUAA), Beijing, China
m Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX, United States
n Department of Biomedical Engineering, Northwestern University, Evanston, IL, United States
o Department of Chemistry, Northwestern University, Evanston, IL, United States
p Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States

Abstract
The fast-growing field of bioelectronic medicine aims to develop engineered systems that can relieve clinical conditions by stimulating the peripheral nervous system1–5. This type of technology relies largely on electrical stimulation to provide neuromodulation of organ function or pain. One example is sacral nerve stimulation to treat overactive bladder, urinary incontinence and interstitial cystitis (also known as bladder pain syndrome)4,6,7. Conventional, continuous stimulation protocols, however, can cause discomfort and pain, particularly when treating symptoms that can be intermittent (for example, sudden urinary urgency)8. Direct physical coupling of electrodes to the nerve can lead to injury and inflammation9–11. Furthermore, typical therapeutic stimulators target large nerve bundles that innervate multiple structures, resulting in a lack of organ specificity. Here we introduce a miniaturized bio-optoelectronic implant that avoids these limitations by using (1) an optical stimulation interface that exploits microscale inorganic light-emitting diodes to activate opsins; (2) a soft, high-precision biophysical sensor system that allows continuous measurements of organ function; and (3) a control module and data analytics approach that enables coordinated, closed-loop operation of the system to eliminate pathological behaviours as they occur in real-time. In the example reported here, a soft strain gauge yields real-time information on bladder function in a rat model. Data algorithms identify pathological behaviour, and automated, closed-loop optogenetic neuromodulation of bladder sensory afferents normalizes bladder function. This all-optical scheme for neuromodulation offers chronic stability and the potential to stimulate specific cell types. © 2019, Springer Nature Limited.

Document Type: Letter
Publication Stage: Final
Source: Scopus

“Early postoperative actigraphy poorly predicts hypoactive delirium” (2019) Journal of Clinical Sleep Medicine

Early postoperative actigraphy poorly predicts hypoactive delirium
(2019) Journal of Clinical Sleep Medicine, 15 (1), pp. 79-87. 

Maybrier, H.R.a d , Ryan King, C.a , Crawford, A.E.a , Mickle, A.M.a , Emmert, D.A.a b , Wildes, T.S.a , Avidan, M.S.a b , Palanca, B.J.A.a c

a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Study Objectives: Delirium is a postoperative complication accompanied by disturbances in attention, cognition, arousal, and psychomotor activity. Wrist actigraphy has been advocated to study inactivity and inferred sleep patterns during delirium. We hypothesized that altered patterns of motor activity or immobility, reflective of disordered sleep and wakefulness patterns, would serve as predictive markers of hypoactive postoperative delirium. Methods: Eighty-four elderly surgical patients were classified into three groups based on the timing of hypoactive delirium following surgery: intact with no delirium throughout postoperative days (POD) 0–5 (n = 51), delirium during POD 0–1 (n = 24), and delirium during POD 2–5 (n = 13). Delirium was detected on daily Confusion Assessment Method evaluations and chart review. Actigraphy measures were calculated from accelerometry signals acquired on the first postoperative day (POD 0, 16:00–23:00) and night (POD 0, 23:00–POD 1, 06:00). Results: Actigraphy metrics showed substantial interpatient variability. Among the three patient groups, only those without delirium showed greater movement during the day compared to night and also fewer minutes of night immobility (P = .03 and P = .02, Wilcoxon rank-sum tests). These patients were poorly discriminated from those with delirium during either POD 0–1 or POD 2–5, using differences in day and night activity (C-statistic, 95% confidence interval [CI]: 0.66 [0.53–0.79] and C-statistic, 95% CI: 0.71 [0.55–0.87], respectively). Inclusion of low-frequency signals improved performance of immobility measures without affecting those based on activity. Cognitively intact patients during POD 0–5 were distinguished from those with delirium during POD 0–1, based on differences in the number of day and night immobile minutes (C-statistic 0.65, 95% CI: [0.53–0.78]). Actigraphy metrics with the strongest association to delirium incidence were not reliably correlated with an increased risk during POD 0–5, when accounting for patient age, sex, intensive care unit admission, and Charlson Comorbidity Index (adjusted odds ratio of 1.7, 95% CI: [1.0–3.0], P = .09, likelihood ratio test). Conclusions: Early postoperative wrist actigraphy metrics that serve as markers of sleep and wakefulness offer limited capacity as sole predictors or markers of hypoactive delirium. © 2019 American Academy of Sleep Medicine.All Rights Reserved.

Author Keywords
Actigraphy;  Anesthesia;  Arousal;  Postoperative delirium;  Sleep;  Surgery

Document Type: Article
Publication Stage: Final
Source: Scopus

“Self-transcendence in mountaineering and BASE Jumping” (2019) Frontiers in Psychology

Self-transcendence in mountaineering and BASE Jumping
(2019) Frontiers in Psychology, 9 (JAN), art. no. 2686, . 

Monasterio, E.a b , Robert Cloninger, C.c

a Canterbury District Health Board Regional Forensic Service, Christchurch, New Zealand
b Psychological Medicine, Christchurch School of Medicine, University of Otago, Christchurch, New Zealand
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The “extreme sports” of mountaineering and BASE Jumping are growing in popularity and are associated with significant risk of injury and death. In recent years there have also been increasing numbers of reports of reckless disregard and selfishness in the pursuit of mountaineering goals, including severe environmental degradation. Extant research has focused predominantly on personality variables that contribute to engagement, participation, and stress responsivity in these extreme sports. The Temperament and Character Inventory (TCI) provides a comprehensive account of personality traits, measuring seven dimensions of personality that are moderately heritable and associated with distinct brain networks and psychological characteristics. One of these traits is Self-Transcendence, which is associated with spiritual ideas and experiences, such as searching for something elevated and greater than one’s individual self. High Self-Transcendence can motivate people to act altruistically even if that requires personal sacrifices and hardship. This article draws on the extant research literature, which has consistently found that despite substantial heterogeneity in their individual personality profiles, mountaineers, and BASE jumpers are adventurous in temperament and highly self-controlled and organized in character. Between 75 and 85% of the character configurations observed in these populations are associated with low Self-Transcendence. The purpose of this paper is to consider the role of Self-Transcendence and its effect on individual personality profiles of extreme athletes, in particular in moderating potentially self- destructive, and regressive ethical and moral behaviors in mountaineering and BASE jumping. © 2019 Monasterio and Cloninger.

Author Keywords
BASE jumping;  Character;  Elite performance;  Mountaineering;  Personality;  Self-transcendence;  Temperament

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

“Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease” (2019) Nature Medicine

Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer’s disease
(2019) Nature Medicine, . Article in Press. 

Preische, O.a b , Schultz, S.A.c , Apel, A.a b , Kuhle, J.d , Kaeser, S.A.a b , Barro, C.d , Gräber, S.a , Kuder-Buletta, E.a , LaFougere, C.a , Laske, C.a b , Vöglein, J.e f , Levin, J.e f , Masters, C.L.g , Martins, R.h i , Schofield, P.R.j k , Rossor, M.N.l , Graff-Radford, N.R.m , Salloway, S.n , Ghetti, B.o , Ringman, J.M.p , Noble, J.M.q , Chhatwal, J.r , Goate, A.M.s , Benzinger, T.L.S.c , Morris, J.C.c , Bateman, R.J.c , Wang, G.c , Fagan, A.M.c , McDade, E.M.c , Gordon, B.A.c , Jucker, M.a b , Allegri, R.t , Amtashar, F.u , Bateman, R.u , Benzinger, T.u , Berman, S.v , Bodge, C.w , Brandon, S.u , Brooks, W.x , Buck, J.y , Buckles, V.u , Chea, S.z , Chhatwal, J.aa , Chrem, P.t , Chui, H.ab , Cinco, J.ac , Clifford, J.z , Cruchaga, C.u , D’Mello, M.x , Donahue, T.u , Douglas, J.ac , Edigo, N.t , Erekin-Taner, N.z , Fagan, A.u , Farlow, M.y , Farrar, A.u , Feldman, H.ad , Flynn, G.u , Fox, N.ac , Franklin, E.u , Fujii, H.ae , Gant, C.u , Gardener, S.af , Ghetti, B.y , Goate, A.ag , Goldman, J.ah , Gordon, B.u , Graff-Radford, N.z , Gray, J.u , Gurney, J.u , Hassenstab, J.u , Hirohara, M.ai , Holtzman, D.u , Hornbeck, R.u , DiBari, S.H.aj , Ikeuchi, T.ak , Ikonomovic, S.v , Jerome, G.u , Jucker, M.al , Karch, C.u , Kasuga, K.ak , Kawarabayashi, T.ai , Klunk, W.v , Koeppe, R.am , Kuder-Buletta, E.al , Laske, C.al , Lee, J.-H.an , Levin, J.aj , Marcus, D.u , Martins, R.af , Mason, N.S.ao , Masters, C.ap , Maue-Dreyfus, D.u , McDade, E.u , Montoya, L.ab , Mori, H.ae , Morris, J.u , Nagamatsu, A.aq , Neimeyer, K.ah , Noble, J.ah , Norton, J.u , Perrin, R.u , Raichle, M.u , Ringman, J.ab , Roh, J.H.an , Salloway, S.w , Schofield, P.x , Shimada, H.ae , Shiroto, T.ai , Shoji, M.ai , Sigurdson, W.u , Sohrabi, H.af , Sparks, P.aa , Suzuki, K.aq , Swisher, L.u , Taddei, K.af , Wang, J.ag , Wang, P.u , Weiner, M.ar , Wolfsberger, M.u , Xiong, C.u , Xu, X.u , Dominantly Inherited Alzheimer Networkas

a German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
b Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
c Department of Neurology, Department of Radiology, and Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland
e German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
f Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
g Neurodegeneration Division, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia
h School of Medical Health and Sciences, Edith Cowan University, Joondalup, WA, Australia
i Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australia
j Neuroscience Research Australia, Randwick, NSW, Australia
k School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
l Dementia Research Centre, Department of Neurodegeneration, Queen Square Institute of Neurology, University College London, London, United Kingdom
m Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, United States
n Warren Alpert Medical School of Brown University, Providence, RI, United States
o Indiana Alzheimer Disease Center and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
p Department of Neurology, Keck School of Medicine at USC, Los Angeles, CA, United States
q Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Department of Neurology, Columbia University Medical Center, New York, NY, United States
r Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
s Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
t FLENI Institute of Neurological Research (Fundacion para la Lucha contra las Enfermedades Neurologicas de la Infancia), Buenos Aries, Argentina
u Washington University School of Medicine, St. Louis, MO, United States
v University of Pittsburgh, Pittsburgh, PA, United States
w Brown University-Butler Hospital, Providence, RI, United States
x Neuroscience Research Australia, Sydney, NSW, Australia
y Indiana University, Bloomington, IN, United States
z Mayo Clinic Jacksonville, Jacksonville, FL, United States
aa Brigham and Women’s Hospital–Massachusetts General Hospital, Boston, MA, United States
ab University of Southern California, Los Angeles, CA, United States
ac University College London, London, United Kingdom
ad University of California San Diego, San Diego, CA, United States
ae Osaka City University, Osaka, Japan
af Edith Cowan University, Perth, WA, Australia
ag Icahn School of Medicine at Mount Sinai, New York, NY, United States
ah Columbia University, New York, NY, United States
ai Hirosaki University, Aomori, Japan
aj German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
ak Niigata University, Niigata, Japan
al German Center for Neurodegnerative Diseases (DZNE), Tubingen, Germany
am University of Michigan, Ann Arbor, MI, United States
an Asan Medical Center, Seoul, South Korea
ao University of Pittsburgh Medical Center, Pittsburgh, PA, United States
ap University of Melbourne, Melbourne, VIC, Australia
aq Tokyo University, Tokyo, Japan
ar University of California San Francisco, San Francisco, CA, United States

Abstract
Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer’s disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini–Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer’s disease, which supports its potential utility as a clinically useful biomarker. © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

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

“Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use” (2019) Biological Psychiatry

Exome Chip Meta-analysis Fine Maps Causal Variants and Elucidates the Genetic Architecture of Rare Coding Variants in Smoking and Alcohol Use
(2019) Biological Psychiatry, . Article in Press. 

Brazel, D.M.a b , Jiang, Y.c , Hughey, J.M.c , Turcot, V.e f , Zhan, X.g , Gong, J.h , Batini, C.k , Weissenkampen, J.D.c , Liu, M.o , Surendran, P.ao , Young, R.ao , Barnes, D.R.l ao , Nielsen, S.F.ao , Rasheed, A.ao , Samuel, M.ao , Zhao, W.s ao , Kontto, J.ao , Perola, M.ao , Caslake, M.ao , de Craen, A.J.M.ao , Trompet, S.ao , Uria-Nickelsen, M.ao , Malarstig, A.ao , Reily, D.F.ao , Hoek, M.ao , Vogt, T.ao , Jukema, J.W.ao , Sattar, N.ao , Ford, I.ao , Packard, C.J.ao , Alam, D.S.ao , Majumder, A.A.S.ao , Di Angelantonio, E.ao , Chowdhury, R.ao , Amouyel, P.ao , Arveiler, D.ao , Blankenberg, S.ao , Ferrières, J.ao , Kee, F.ao , Kuulasmaa, K.ao , Müller-Nurasyid, M.ao , Veronesi, G.ao , Virtamo, J.ao , EPIC-CVD Consortiumao , Frossard, P.ao , Nordestgaard, B.G.ao , Saleheen, D.ao , Danesh, J.ao , Butterworth, A.S.ao , Howson, J.M.M.l ao , Erzurumluoglu, A.M.k ap , Jackson, V.E.ap , Melbourne, C.A.k ap , Varga, T.V.ap , Warren, H.R.ap , Tragante, V.ap , Tachmazidou, I.ap , Harris, S.E.ap , Evangelou, E.ap , Marten, J.ap , Zhang, W.ap , Altmaier, E.ap , Luan, J.ap , Langenberg, C.ap , Scott, R.A.ap , Yaghootkar, H.ap , Stirrups, K.ap , Kanoni, S.ap , Marouli, E.ap , Karpe, F.ap , Dominiczak, A.F.ap , Sever, P.ap , Poulter, N.ap , Rolandsson, O.ap , Baumbach, C.ap , Afaq, S.ap , Chambers, J.C.ap , Kooner, J.S.ap , Wareham, N.J.ap , Renström, F.ap , Hallmans, G.ap , Marioni, R.E.ap , Corley, J.ap , Starr, J.M.ap , Verweij, N.ap , de Boer, R.A.ap , van der Meer, P.ap , Yavas, E.ap , Vaartjes, I.ap , Bots, M.L.ap , Asselbergs, F.W.ap , Grabe, H.J.ap , Völzke, H.ap , Nauck, M.ap , Weiss, S.ap , Pharoah, P.D.P.ap , Dunning, A.M.ap , Dennis, J.G.ap , Thompson, D.J.ap , Michailidou, K.ap , Easton, D.F.ap , Antoniou, A.C.ap , Tyrrell, J.ap , Mihailov, E.ap , Samani, N.J.ap , Zhou, K.ap , Neville, M.J.ap , Metspalu, A.ap , Palmer, C.N.A.ap , Hall, I.P.ap , Strachan, D.P.ap , Deary, I.J.ap , Frayling, T.M.ap , Hayward, C.ap , van der Harst, P.ap , Zeggini, E.ap , Understanding Society Scientific Groupap , Munroe, P.B.ap , Jansson, J.-H.ap , Franks, P.W.ap , Deloukas, P.ap , Caulfield, M.J.ap , Wain, L.V.ap , Tobin, M.D.k ap , Bertelsen, S.p , Chou, Y.-L.ah , Faul, J.D.r , Haessler, J.h , Hammerschlag, A.R.u , Hsu, C.y , Kapoor, M.p , Lai, D.aa , Le, N.ab , de Leeuw, C.A.u , Loukola, A.ac ad , Mangino, M.m n , Pistis, G.af , Qaiser, B.ac ad , Rohde, R.ag , Shao, Y.ag , Stringham, H.t , Wetherill, L.aa , Agrawal, A.ah , Bierut, L.ah , Chen, C.h i j , Eaton, C.B.aj , Goate, A.p , Haiman, C.y , Heath, A.ah , Iacono, W.G.o , Martin, N.G.ak , Polderman, T.J.u , Reiner, A.h i , Rice, J.ah ai , Schlessinger, D.al , Scholte, H.S.w x , Smith, J.A.s , Tardif, J.-C.e f , Tindle, H.A.am , van der Leij, A.R.w x , Boehnke, M.t , Chang-Claude, J.an , Cucca, F.af , David, S.P.z , Foroud, T.aa , Kardia, S.L.R.s , Kooperberg, C.h , Laakso, M.ae , Lettre, G.e f , Madden, P.ah , McGue, M.o , North, K.ag , Posthuma, D.u v , Spector, T.m , Stram, D.y , Weir, D.R.r , Kaprio, J.ac ad , Abecasis, G.R.q t , Liu, D.J.d , Vrieze, S.o , CHD Exome+ Consortiumaq , Consortium for Genetics of Smoking Behaviouraq

a Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
b Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, United States
c Department of Public Health Sciences, Penn State College of Medicine, Hershey, PA, United States
d Institute of Personalized Medicine, Penn State College of Medicine, Hershey, PA, United States
e Department of Medicine, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
f Montreal Heart Institute, Montreal, Quebec, Canada
g Department of Clinical Science, Center for Genetics of Host Defense, University of Texas Southwestern, Dallas, TX, United States
h Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
i Department of Epidemiology, Head and Neck Surgery Center, University of Washington, Seattle, WA, United States
j Department of Otolaryngology, Head and Neck Surgery Center, University of Washington, Seattle, WA, United States
k Department of Health Sciences, University of Leicester, Leicester, United Kingdom
l Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
m Department of Twin Research and Genetic Epidemiology, King’s College London, London, United Kingdom
n National Institute for Health Research Biomedical Research Centre at Guy’s and St Thomas’ Foundation Trust, London, United Kingdom
o Department of Psychology, University of Minnesota, Minneapolis, MN, United States
p Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
q Regeneron Pharmaceuticals, Tarrytown, NY, United States
r Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
s Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States
t Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, United States
u Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, University of Amsterdam, Amsterdam, Netherlands
v Department of Clinical Genetics, VU University Medical Centre, University of Amsterdam, Amsterdam, Netherlands
w Department of Psychology, University of Amsterdam, Amsterdam, Netherlands
x Amsterdam Brain and Cognition, University of Amsterdam, Amsterdam, Netherlands
y Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
z Department of Medicine, Stanford University, Stanford, CA, United States
aa Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, India
ab Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, United States
ac Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
ad Department of Public Health, University of Helsinki, Helsinki, Finland
ae Department of Internal Medicine, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
af Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy
ag Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
ah Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
ai Department of Mathematics, Washington University in St. Louis, St. Louis, MO, United States
aj Department of Family Medicine, Brown University, Providence, RI, United States
ak Queensland Institute for Medical Research, Brisbane, Australia
al National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
am Department of Medicine, Vanderbilt University, Nashville, TN, United States
an Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany

Abstract
Background: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. Methods: We analyzed 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. Results: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. Conclusions: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior. © 2018 Society of Biological Psychiatry

Author Keywords
Alcohol;  Behavioral genetics;  GWAS;  Heritability;  Nicotine;  Tobacco

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

“Transradial approach for flow diversion treatment of cerebral aneurysms: A multicenter study” (2019) Journal of NeuroInterventional Surgery

Transradial approach for flow diversion treatment of cerebral aneurysms: A multicenter study
(2019) Journal of NeuroInterventional Surgery, . Article in Press. 

Chen, S.H.a , Snelling, B.M.b , Shah, S.S.a , Sur, S.a , Brunet, M.C.a , Starke, R.M.a c , Yavagal, D.R.a d , Osbun, J.W.e , Peterson, E.C.a

a Department of Neurological Surgery, University of Miami, School of Medicine, Miami, FL 33136, United States
b Marcus Neuroscience Institute, Boca Raton Regional Hospital, Boca Raton, FL, United States
c Department of Radiology, University of Miami, School of Medicine, Miami, FL, United States
d Department of Neurology, University of Miami, Miami, FL, United States
e Department of Neurological Surgery, Washington University, School of Medicine, Saint Louis, MO, United States

Abstract
Background: The transradial approach (TRA) to endovascular procedures decreases access site morbidity and mortality in comparison with the traditional transfemoral technique (TFA). Despite its improved safety profile, there is a concern that TRA is less favorable for neurointerventional procedures that require large coaxial systems to manage the small tortuous cerebral vessels. Objective: To report our experience with TRA for flow diverter placement for treatment of unruptured cerebral aneurysms. Methods: We performed a retrospective review of prospective institutional databases at two high-volume centers to identify 49 patients who underwent flow diversion for aneurysm treatment via primary TRA between November 2016 and November 2018. Patient demographics, procedural techniques, and clinical data were recorded. Results: Of the 49 patients, 39 underwent successful flow diversion placement by TRA. Ten patients were converted to TFA after attempted TRA. There were no procedural complications. Reasons for failure included tortuosity in eight patients and severe radial artery spasm in two. Conclusions: In the largest reported series to date of flow diverter deployment via TRA for aneurysm treatment, we demonstrate the technical feasibility and safety of the method. The most common reason for failure of TRA was an acute angle of left common carotid artery origin or left internal carotid artery tortuosity. Overall, our data suggest that increasing adoption of TRA is merited given its apparent equivalence to the current TFA technique and its documented reduction in access site complications. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
aneurysm;  flow diverter;  intervention;  technique

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

“Biomarker and Genomic Risk Factors for Liver Function Test Abnormality in Hazardous Drinkers” (2019) Alcoholism: Clinical and Experimental Research

Biomarker and Genomic Risk Factors for Liver Function Test Abnormality in Hazardous Drinkers
(2019) Alcoholism: Clinical and Experimental Research, . Article in Press. 

Whitfield, J.B.a , Zhu, G.a , Madden, P.A.F.b , Montgomery, G.W.c , Heath, A.C.b , Martin, N.G.a

a QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD, Australia

Abstract
Background: Alcohol dependence and long-term excessive alcohol use may cause liver damage, but only some patients develop cirrhosis. Similarly, high alcohol intake without evident liver disease often but not always produces abnormal enzymatic liver function tests (LFTs), particularly gamma-glutamyl transferase (GGT). We postulate that the factors predisposing to cirrhosis in alcoholics and to liver enzyme abnormality in drinkers are similar, and that biochemical LFTs could therefore be useful as markers of risk of alcoholic liver disease in excessive drinkers. Methods: Data from participants in twin and twin-family studies on alcohol use and dependence were used to identify 1,003 people who had reported excessive alcohol intake (28 drinks or more per week). A total of 962 of these provided blood for biochemical tests at the same time. Body mass index (BMI) and biomarkers of metabolic syndrome, inflammation, and iron stores were used in logistic regression with abnormality in serum GGT, alanine aminotransferase (ALT), or aspartate aminotransferase (AST) as outcomes. We conducted genome-wide association analyses for GGT, ALT, and AST separately in the group reporting excessive alcohol intake (N = 951) and a low-intake group reporting 14 drinks or fewer per week (N = 8,716), and compared results. Results: Abnormal GGT and ALT among excessive drinkers were associated with higher BMI, triglycerides, insulin, uric acid, C-reactive protein, ferritin, and transferrin saturation; and with lower high-density-lipoprotein cholesterol. Abnormal AST was associated with triglycerides, ferritin, and transferrin saturation. ALT was significantly associated with variants at reported genetic loci for alcoholic liver disease (PNPLA3, rs738409, p = 0.0076; TM6SF2, rs10401969, p = 0.0076; HSD17B13, rs10433879, p = 0.0024). Conclusions: Known risk factors for alcoholic cirrhosis including obesity and markers of metabolic syndrome, iron overload and inflammation are associated with liver enzyme abnormality in excessive drinkers. © 2018 by the Research Society on Alcoholism

Author Keywords
Alanine Aminotransferase;  Alcohol;  Aspartate Aminotransferase;  Cirrhosis;  Gamma-Glutamyl Transferase

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

“Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging” (2019) Developmental Medicine and Child Neurology

Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging
(2019) Developmental Medicine and Child Neurology, . Article in Press. 

Eby, N.S., Griffith, J.L., Gutmann, D.H., Morris, S.M.

Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Aim: To characterize the adaptive behavior profile of children with neurofibromatosis type 1 (NF1) and determine its relationship to neuropsychological functioning and non-neoplastic T2-weighted hyperintense brain lesions on brain magnetic resonance imaging (MRI). Method: In this cross-sectional study, we retrospectively reviewed neuropsychological reports from 104 children with NF1 (56 males, 48 females; mean age 10y 4mo; standard deviation [SD] 3y 4mo; range 3y 5mo–17y 6mo), and extracted data from a range of cognitive and behavioral measures, including the Adaptive Behavior Assessment System (ABAS). Brain MRI was retrospectively reviewed in 42 individuals. Results: Adaptive Behavior Assessment System scores were continuously distributed and pathologically shifted by 0.79 to 1.26SD across Conceptual, Social, and Practical domains, and 46.5% of individuals had a composite score in the borderline or impaired range. Impairment in adaptive functioning was correlated with deficits in executive function (r=–9.543, p<0.001), externalizing problems (r=−0.366, p<0.001), and attention (r=−9.467, p=0.001). Cluster analysis revealed three distinct phenotypic subgroups, one of which exhibited normal cognitive ability, but impaired adaptive functioning, with persistent deficits in executive function, behavioral problems, and attention-deficit/hyperactivity disorder symptomatology. There was no relationship between ABAS scores and the number or location of unidentified bright objects. Interpretation: Adaptive functioning deficits are common among children with NF1 and are associated with impairment in other cognitive/behavioral domains, independent of general cognitive ability. What this paper adds: Deficits in adaptive behavior are common in children with neurofibromatosis type 1 (NF1). Poor adaptive functioning is associated with impairments in executive function, externalizing behaviors, and attention, regardless of cognitive ability. The presence or location of unidentified bright objects do not predict adaptive behavior skills in children with NF1. © 2019 Mac Keith Press

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

“Obstructive sleep apnea treatment, slow wave activity, and amyloid-β” (2019) Annals of Neurology

Obstructive sleep apnea treatment, slow wave activity, and amyloid-β
(2019) Annals of Neurology, . Article in Press. 

Ju, Y.-E.S.a b , Zangrilli, M.A.a , Finn, M.B.a , Fagan, A.M.a b , Holtzman, D.M.a b

a Department of Neurology, Washington University, Saint Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University, Saint Louis, MO, United States

Abstract
Obstructive sleep apnea (OSA) increases risk of dementia, a relationship that may be mediated by amyloid-β (Aβ) and downstream Alzheimer disease pathology. We previously showed that OSA may impair Aβ clearance and affect the relationship between slow wave activity (SWA) and Aβ. In this study, SWA and CSF Aβ were measured in participants with OSA before and 1 to 4 months after treatment. OSA treatment increased SWA, and SWA was significantly correlated with lower Aβ after treatment. Greater improvement in OSA was associated with greater decreases in Aβ. We propose a model whereby OSA treatment may affect both Aβ release and clearance. Ann Neurol 2018. © 2018 American Neurological Association

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

“Dynamic changes of functional segregation and integration in vulnerability and resilience to schizophrenia” (2019) Human Brain Mapping

Dynamic changes of functional segregation and integration in vulnerability and resilience to schizophrenia
(2019) Human Brain Mapping, . Article in Press. 

Duan, J.a b , Xia, M.c d e , Womer, F.Y.f , Chang, M.b g , Yin, Z.a b , Zhou, Q.h , Zhu, Y.a b , Liu, Z.i , Jiang, X.b g , Wei, S.b g , Anthony O’Neill, F.j , He, Y.c d e , Tang, Y.a b , Wang, F.a b g

a Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
b Brain Function Research Section, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
c National Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China
d Beijing Key Laboratory of Brain Imaging and Connectomics, Beijing Normal University, Beijing, China
e IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
h Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wan Ping Nan Road, Shanghai, China
i School of Public Health, China Medical University, Shenyang, Liaoning, China
j Centre for Public Health, Queen’s University Belfast, Belfast, Northern Ireland, United Kingdom

Abstract
Schizophrenia (SZ) is a highly heritable disease with neurodevelopmental origins and significant functional brain network dysfunction. Functional network is heavily influenced by neurodevelopment processes and can be characterized by the degree of segregation and integration. This study examines functional segregation and integration in SZ and their first-degree relatives (high risk [HR]) to better understand the dynamic changes in vulnerability and resiliency, and disease markers. Resting-state functional magnetic resonance imaging data acquired from 137 SZ, 89 HR, and 210 healthy controls (HCs). Small-worldness σ was computed at voxel level to quantify balance between segregation and integration. Interregional functional associations were examined based on Euclidean distance between regions and reflect degree of segregation and integration. Distance strength maps were used to localize regions of altered distance-based functional connectivity. σ was significantly decreased in SZ compared to HC, with no differences in high risk (HR). In three-group comparison, significant differences were noted in short-range connectivity (primarily in the primary sensory, motor and their association cortices, and the thalamus) and medium/long-range connectivity (in the prefrontal cortices [PFCs]). Decreased short- and increased medium/long-range connectivity was found in SZ. Decreased short-range connectivity was seen in SZ and HR, while HR had decreased medium/long-range connectivity. We observed disrupted balance between segregation and integration in SZ, whereas relatively preserved in HR. Similarities and differences between SZ and HR, specific changes of SZ were found. These might reflect dynamic changes of segregation in primary cortices and integration in PFCs in vulnerability and resilience, and disease markers in SZ. © 2019 Wiley Periodicals, Inc.

Author Keywords
fMRI;  functional network;  genetic risk;  resilience;  schizophrenia;  vulnerability

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

“Parkinson’s disease and multiple system atrophy have distinct -synuclein seed characteristics” (2019) Journal of Biological Chemistry

Parkinson’s disease and multiple system atrophy have distinct -synuclein seed characteristics
(2019) Journal of Biological Chemistry, 294 (3), pp. 1045-1058. 

Yamasaki, T.R.a d , Holmes, B.B.b e , Furman, J.L.b f , Dhavale, D.D.b , Su, B.W.a , Song, E.-S.a , Cairns, N.J.b c , Kotzbauer, P.T.b , Diamond, M.I.f

a Department of Neurology, University of Kentucky, Lexington, KY 40536, United States
b Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
c Pathology and Immunology, Washington University in St. Louis, St. Louis, MO 63110, United States
d Dept. of Neurology, University of Kentucky, Ste. J401, 740 S. Limestone St., Lexington, KY, United States
e University of California, San Francisco, Dept. of Neurology, 505 Parnassus Ave., San Francisco, CA 94143, United States
f Center for Alzheimer’s and Neurodegenerative Diseases, Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States

Abstract
Parkinson’s disease (PD) and multiple system atrophy (MSA) are distinct clinical syndromes characterized by the pathological accumulation of -synuclein (-syn) protein fibrils in neurons and glial cells. These disorders and other neurodegenerative diseases may progress via prion-like mechanisms. The prion model of propagation predicts the existence of “strains” that link pathological aggregate structure and neuropathology. Prion strains are aggregated conformers that stably propagate in vivo and cause disease with defined incubation times and patterns of neuropathology. Indeed, tau prions have been well defined, and research suggests that both -syn and -amyloid may also form strains. However, there is a lack of studies characterizing PD-versus MSA-derived -syn strains or demonstrating stable propagation of these unique conformers between cells or animals. To fill this gap, we used an assay based on FRET that exploits a HEK293T “biosensor” cell line stably expressing -syn (A53T)-CFP/YFP fusion proteins to detect -syn seeds in brain extracts from PD and MSA patients. Both soluble and insoluble fractions of MSA extracts had robust seeding activity, whereas only the insoluble fractions of PD extracts displayed seeding activity. The morphology of MSA-seeded inclusions differed from PD-seeded inclusions. These differences persisted upon propagation of aggregation to second-generation biosensor cells. We conclude that PD and MSA feature -syn conformers with very distinct biochemical properties that can be transmitted to -syn monomers in a cell system. These findings are consistent with the idea that distinct -syn strains underlie PD and MSA and offer possible directions for synucleinopathy diagnosis. © 2019 Yamasaki et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial” (2019) Clinical Pharmacology and Therapeutics

Bioequivalence and Therapeutic Equivalence of Generic and Brand Bupropion in Adults With Major Depression: A Randomized Clinical Trial
(2019) Clinical Pharmacology and Therapeutics, . Article in Press. 

Kharasch, E.D.a , Neiner, A.b , Kraus, K.b , Blood, J.b , Stevens, A.c , Schweiger, J.c , Miller, J.P.d , Lenze, E.J.c

a Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States
b Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Controversy persists about bupropion XL 300 mg generic equivalence to brand product. A prospective, randomized, double-blinded crossover in 70 adults with major depression in stable remission taking any bupropion XL 300 mg tested bioequivalence and therapeutic equivalence of available XL 300 mg products. After a 4-week lead-in on patients’ existing bupropion, four 6-week phases evaluated brand and three generics. Patients were uninformed of switching. Drug overencapsulation ensured blinding. There were no differences between any generic and brand, or between generics, in peak plasma concentration (Cmax) and area under the plasma concentration-time curve over the 24-hour dosing interval (AUC0–24) for racemic bupropion or major metabolites. All generics met formal bioequivalence criteria for bupropion and metabolites. There were no differences between generics and brand, or between generics, in depression symptoms or side effects, assessed by every 3-week in-person interview and daily smartphone-based self-report. There were no differences in patients’ perceptions of bupropion products. Results show three bupropion XL 300 mg generic products are both bioequivalent and not therapeutically different from brand drug and each other. © 2018 American Society for Clinical Pharmacology and Therapeutics

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

“Child and parent reports of children’s depressive symptoms in relation to children’s weight loss response in family-based obesity treatment” (2019) Pediatric Obesity

Child and parent reports of children’s depressive symptoms in relation to children’s weight loss response in family-based obesity treatment
(2019) Pediatric Obesity, art. no. e12511, . Article in Press. 

Conlon, R.P.K.a , Hurst, K.T.b , Hayes, J.F.c , Balantekin, K.N.d , Stein, R.I.c , Saelens, B.E.e , Brown, M.L.f , Sheinbein, D.H.c , Welch, R.R.c , Perri, M.G.g , Schechtman, K.B.c , Epstein, L.H.d , Wilfley, D.E.c

a School of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
b National Center for Weight and Wellness, Washington, DC, United States
c School of Medicine, Washington University, St. Louis, MO, United States
d School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, United States
e Seattle Children’s Research Institute and the University of Washington, Seattle, WA, United States
f Center for Anxiety and Traumatic Stress Disorders, Massachusetts General Hospital, Boston, MA, United States
g College of Public Health and Health Professions, University of Florida, Gainesville, FL, United States

Abstract
Background: Studies of the association between children’s depressive symptoms and obesity treatment response show mixed results. Different measurement may contribute to the inconsistent findings, as children’s depressive symptoms are often based on parent-report about their child rather than child self-report. Objectives: We assessed both child- and parent-report of child depressive symptoms as predictors of children’s obesity treatment response. Methods: Children with overweight/obesity (body mass index [BMI] ≥ 85th percentile; N = 181) and their parents reported on children’s depressive symptoms prior to family-based behavioral weight loss treatment. Results: Child percent overweight reduction from baseline to post-treatment was not predicted by child self-reported depressive symptoms or parent-report of child symptoms (P > 0.80), but was significantly predicted by the interaction between child self-report and parent-report on child (β = 0.14, P = 0.05). In analyses using clinical cutoffs, amongst children with high self-reported symptoms, those whose parents reported low child depressive symptoms had greater reduction in percent overweight (t = 2.67, P = 0.008), whereas amongst children with low self-reported symptoms, parent ratings were not associated with treatment outcome. Conclusions: Including both child self-report and parent-report of child depressive symptoms may inform obesity care. Research is needed to examine differences amongst child and parent depressive symptom reports and strategies to address symptoms and optimize pediatric obesity treatment. © 2019 World Obesity Federation

Author Keywords
child;  depressive symptoms;  method;  obesity;  treatment

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

“Low-dose augmentation with buprenorphine increases emotional reactivity but not reward activity in treatment resistant mid- and late-life depression” (2019) NeuroImage: Clinical

Low-dose augmentation with buprenorphine increases emotional reactivity but not reward activity in treatment resistant mid- and late-life depression
(2019) NeuroImage: Clinical, 21, art. no. 101679, . 

Lin, C.a , Karim, H.T.b , Pecina, M.b , Aizenstein, H.J.b c , Lenze, E.J.d , Blumberger, D.M.e , Mulsant, B.H.e , Kharasch, E.D.f , Reynolds, C.F., IIIb , Karp, J.F.b

a Department of Psychiatry, Keelung Chang Chung Memorial Hospital, Keelung, Taiwan
b Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
c Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
e Centre for Addiction and Mental Health, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
f Department of Anesthesiology, The Center for Clinical Pharmacology, St. Louis College of Pharmacy, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Buprenorphine is currently being studied for treatment-resistant depression because of its rapid effect, relative safety, and unique pharmacodynamics. To understand the neural impact of buprenorphine in depression, we examined acute limbic and reward circuit changes during an intervention with low-dose buprenorphine augmentation pharmacotherapy. Mid and late-life adults with major depression (N = 31) who did not completely respond to an adequate trial of venlafaxine were randomized to augmentation with low-dose buprenorphine or matching placebo. We investigated early neural changes using functional magnetic resonance imaging (fMRI) from pre-randomization to 3 weeks using both an emotional reactivity task and a gambling task. We tested if: 1) there were significant neural changes acutely per intervention group, and 2) if acute neural changes were associated with depressive symptom change over 8 weeks using both the total score and the dysphoria subscale of the Montgomery Asberg Depression Rating Scale. Participants in both the buprenorphine and placebo groups showed similar changes in depressive symptoms. Neither the emotional reactivity nor gambling task resulted in significant neural activation changes from pre-randomization to 3-weeks. In both groups, increases in rostral anterior cingulate (rACC) and ventromedial prefrontal cortex (vmPFC) activation during the emotional reactivity task were associated with overall symptom improvement. In the buprenorphine but not the placebo group, increased activation in left anterior insula (aINS) and bilateral middle frontal gyrus (MFG) was associated with improvement on the dysphoria subscale. Activation changes in the reward task were not associated with buprenorphine. This is the first study to show an association between acute neural changes during emotion reactivity and changes in depression severity with buprenorphine treatment. © 2019 The Authors

Author Keywords
Buprenorphine;  Clinical trial;  fMRI;  Geriatric;  Placebo;  Treatment-resistant depression

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

“How central is central poststroke pain? The role of afferent input in poststroke neuropathic pain: a prospective, open-label pilot study” (2018) Pain

How central is central poststroke pain? The role of afferent input in poststroke neuropathic pain: a prospective, open-label pilot study
(2018) Pain, 159 (7), pp. 1317-1324. 

Haroutounian, S.a b , Ford, A.L.c , Frey, K.a , Nikolajsen, L.d e , Finnerup, N.B.d f , Neiner, A.a , Kharasch, E.D.b g , Karlsson, P.d , Bottros, M.M.a b

a Division of Clinical and Translational Research, Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Washington University Pain Center, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Department of Clinical Medicine, Danish Pain Research Center, Aarhus University, Aarhus, Denmark
e Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark
f Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
g Center for Clinical Pharmacology, St. Louis College of Pharmacy, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Central poststroke pain (CPSP) is a neuropathic pain disorder, the underlying mechanisms of which are not well understood. It has been suggested that stroke-associated loss of inhibitory neurons in the spinothalamic tract causes disinhibition of thalamic neurons, which autonomously generate ectopic nociceptive action potentials responsible for the pain experience. We hypothesized that CPSP is a result of misinterpretation of afferent sensory input by the sensitized neurons within the brain, rather than generated spontaneously by the damaged central nervous system (CNS) neurons. To test this hypothesis, we prospectively recruited 8 patients with definite CPSP affecting at least 1 extremity. In an open-label intervention, an ultrasound-guided peripheral nerve block with lidocaine was performed to block afferent sensory input from a painful extremity. Spontaneous and evoked pain, neuropathic pain descriptors, and lidocaine plasma concentrations were measured. The blockade of peripheral sensory input resulted in complete abolition of pain in 7 of the 8 subjects within 30 minutes (the primary outcome measure of the study), and >50% pain relief in the remaining participant. Median (interquartile range) spontaneous pain intensity changed from 6.5 (4.3-7.0) at baseline to 0 (0-0) after the block (P = 0.008). All mechanical/thermal hypersensitivity was abolished by the nerve block. The results suggest that it is unlikely that CPSP is autonomously generated within the CNS. Rather, this pain is dependent on afferent input from the painful region in the periphery, and may be mediated by misinterpretation of peripheral sensory input by sensitized neurons in the CNS.

Document Type: Article
Publication Stage: Final
Source: Scopus

“In vivo (18F)-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease” (2018) Neurology

In vivo [18F]-AV-1451 tau-PET imaging in sporadic Creutzfeldt-Jakob disease
(2018) Neurology, 90 (10), pp. e896-e906. Cited 2 times.

Day, G.S., Gordon, B.A., Perrin, R.J., Cairns, N.J., Beaumont, H., Schwetye, K., Ferguson, C., Sinha, N., Bucelli, R., Musiek, E.S., Ghoshal, N., Ponisio, M.R., Vincent, B., Mishra, S., Jackson, K., Morris, J.C., Benzinger, T.L.S., Ances, B.M.

From The Charles F. and Joanne Knight Alzheimer Disease Research Center (G.S.D., B.A.G., R.J.P., N.J.C., H.B., E.S.M., N.G., J.C.M., T.L.S.B., B.M.A.), Department of Neurology (G.S.D., R.B., E.S.M., N.G., J.C.M., B.M.A.), Mallinckrodt Institute of Radiology (B.A.G., H.B., M.R.P., B.V., S.M., K.J., T.L.S.B., B.M.A.), and Department of Pathology (R.J.P., N.J.C., K.S., C.F., N.S., J.C.M.), Washington University School of Medicine (G.S.D., B.A.G., R.J.P., N.J.C., H.B., K.S., C.F., N.S., R.B., E.S.M., N.G., M.R.P., B.V., S.M., K.J., J.C.M., T.L.S.B., B.M.A.), St. Louis, MO

Abstract
OBJECTIVE: To determine whether specific patterns of [18F]-AV-1451 tau-PET retention are observed in patients with autopsy-proven sporadic Creutzfeldt-Jakob disease (CJD). METHODS: In vivo [18F]-AV-1451 PET neuroimaging was performed in 5 patients with sporadic CJD (median age, 66 years [63-74]), and results were compared to cognitively normal (CN) persons (n = 44; median age, 68 years [63-74]) and to participants with very mild Alzheimer disease (AD) dementia (n = 8; median age, 77 years [63-90]). Autopsy was completed in all patients with CJD, confirming the clinical diagnosis and permitting characterization of AD neuropathologic change (ADNC). RESULTS: All patients with CJD presented with rapidly progressive dementia, typical magnetic resonance brain imaging changes, and elevated CSF total tau (median = 6,519; range = 1,528-13,240 pg/mL). Death occurred within 9 months of symptom onset, with a median 1 month (0.2-3.3) interval from [18F]-AV-1451 PET to autopsy. No unique pattern of [18F]-AV-1451 retention was observed on visual inspection. Summary standardized uptake value ratios in patients with CJD (1.17, 1.08-1.36) were indistinguishable from CN persons (1.14, 0.84-1.54; p = 0.6), and well below those of participants with AD (2.23, 1.60-3.04; p ≤ 0.01). [18F]-AV-1451 retention in patients with CJD and CN persons was similar in brain areas frequently affected in AD and CJD. Neuropathologic analysis confirmed the clinical diagnosis in all patients with CJD. Four patients with CJD also had low-level ADNC (A1B1C0); one patient had intermediate-level ADNC (A2B2C1/2). CONCLUSION: Increased [18F]-AV-1451 retention was not observed in patients with rapidly progressive dementia due to sporadic CJD. The [18F]-AV-1451 PET tracer maintains good specificity for paired helical tau filaments associated with AD dementia. © 2018 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Volume Estimation Through Mental Simulation” (2018) Psychological Science

Volume Estimation Through Mental Simulation
(2018) Psychological Science, . Article in Press. 

Perfecto, H.a , Donnelly, K.b , Critcher, C.R.b

a Olin Business School, Washington University in St. Louis, United States
b Haas School of Business, University of California, Berkeley, United States

Abstract
Although mental simulation underlies many day-to-day judgments, we identified a new domain influenced by simulation: volume estimation. Previous research has identified various ways in which volume estimates are biased but typically has not presented a psychological process by which such judgments are made. Our simulation-informs-perception account proposes that people often estimate a container’s size by simulating filling it. First, this produces an orientation effect: The same container is judged larger when right side up than when upside down because of the greater ease of imagining filling an upright container. Second, we identified a cavern effect: Imagining pouring water through a narrow opening toward a relatively wide base produces a sense that the container is cavernous and large (compared with identically sized, wide-topped, narrow-based containers). By testing for and demonstrating the importance of simulation to these effects, we showed how complex perceptual judgments can be distorted by higher level cognitive influences even when they are necessarily informed by modularly processed perceptual input. © The Author(s) 2018.

Author Keywords
judgment;  metacognitive ease;  open data;  open materials;  perception;  simulation;  volume estimation

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

“Acquisition of Early Developmental Milestones and Need for Special Education Services in Pediatric Multiple Sclerosis” (2018) Journal of Child Neurology

Acquisition of Early Developmental Milestones and Need for Special Education Services in Pediatric Multiple Sclerosis
(2018) Journal of Child Neurology, . Article in Press. 

Aaen, G.a , Waltz, M.b , Vargas, W.c , Makhani, N.d , Ness, J.e , Harris, Y.e , Casper, T.C.b , Benson, L.f , Candee, M.b , Chitnis, T.g , Gorman, M.f , Graves, J.h , Greenberg, B.i , Lotze, T.j , Mar, S.k , Tillema, J.-M.l , Rensel, M.m , Rodriguez, M.l , Rose, J.b , Rubin, J.n , Schreiner, T.o , Waldman, A.p , Weinstock-Guttman, B.q , Belman, A.r , Waubant, E.h , Krupp, L.s

a Pediatric Multiple Sclerosis Center at Loma, Linda University Children’s Hospital, Loma Linda, CA, United States
b Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
c Pediatric Multiple Sclerosis Program, Columbia University Medical Center, New York, NY, United States
d Pediatric Multiple Sclerosis Program, Yale MS and Neuroimmunology Center, New Haven, CT, United States
e Center for Pediatric-Onset Demyelinating Disease at the Children’s Hospital of Alabama, Birmingham, AL, United States
f Pediatric Multiple Sclerosis and Related Disorders Program at Boston Children’s Hospital, Boston, MA, United States
g Partners Pediatric Multiple Sclerosis Center, Massachusetts General Hospital for Children, Boston, MA, United States
h Neurology, University of California, San Francisco, CA, United States
i University of Texas Southwestern, Dallas, TX, United States
j The Blue Bird Circle Clinic for Multiple Sclerosis, Texas Children’s Hospital, Houston, TX, United States
k Washington University Pediatric Multiple Sclerosis, Demyelinating Disease Center, St. Louis, MO, United States
l Mayo Clinic Pediatric Multiple Sclerosis Center, Rochester, MN, United States
m Cleveland Clinic, Cleveland, OH, United States
n Lurie Children’s Hospital, Chicago, IL, United States
o Rocky Mountain Multiple Sclerosis Center, University of Colorado at Denver, Aurora, CO, United States
p The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
q Pediatric Multiple Sclerosis Center of the Jacobs Neurological Institute, Buffalo, NY, United States
r Stony Brook University, Stony Brook, NY, United States
s Pediatric Multiple Sclerosis Center at, New York University Langone Medical Center, New York, NY, United States

Abstract
Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan (P =.002), reading assistance (P =.0003), and math assistance (P =.001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls. © The Author(s) 2018.

Author Keywords
cognitive impairment;  developmental milestones;  multiple sclerosis;  pediatric

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