Alt Text
Office of Neuroscience Research > Resources and Facilities > WUSTL Neuroscience Publications for the week > Weekly Neuroscience Publications - Archives > Neuroscience Publications Archive - September 2016

Neuroscience Publications Archive - September 2016

 September 30, 2016


Garcia, K.E.a , Okamoto, R.J.b , Bayly, P.V.a b , Taber, L.A.a b
Contraction and stress-dependent growth shape the forebrain of the early chicken embryo
(2017) Journal of the Mechanical Behavior of Biomedical Materials, 65, pp. 383-397. 

DOI: 10.1016/j.jmbbm.2016.08.010

a Department of Biomedical Engineering, Washington University, 1 Brookings Drive, Saint Louis, MO, United States
b Department of Mechanical Engineering and Material Science, Washington University, 1 Brookings Drive, Saint Louis, MO, United States

During early vertebrate development, local constrictions, or sulci, form to divide the forebrain into the diencephalon, telencephalon, and optic vesicles. These partitions are maintained and exaggerated as the brain tube inflates, grows, and bends. Combining quantitative experiments on chick embryos with computational modeling, we investigated the biophysical mechanisms that drive these changes in brain shape. Chemical perturbations of contractility indicated that actomyosin contraction plays a major role in the creation of initial constrictions (Hamburger–Hamilton stages HH11–12), and fluorescent staining revealed that F-actin is circumferentially aligned at all constrictions. A finite element model based on these findings shows that the observed shape changes are consistent with circumferential contraction in these regions. To explain why sulci continue to deepen as the forebrain expands (HH12–20), we speculate that growth depends on wall stress. This idea was examined by including stress-dependent growth in a model with cerebrospinal fluid pressure and bending (cephalic flexure). The results given by the model agree with observed morphological changes that occur in the brain tube under normal and reduced eCSF pressure, quantitative measurements of relative sulcal depth versus time, and previously published patterns of cell proliferation. Taken together, our results support a biphasic mechanism for forebrain morphogenesis consisting of differential contractility (early) and stress-dependent growth (late). © 2016 Elsevier Ltd

Author Keywords
Actomyosin;  Brain;  Cerebrospinal fluid;  Development;  Mechanical feedback;  Morphogenesis

Document Type: Article
Source: Scopus


Crane, P.K.a , Walker, R.L.b , Sonnen, J.c , Gibbons, L.E.a , Melrose, R.d e , Hassenstab, J.f , Keene, C.D.g , Postupna, N.g , Montine, T.J.g , Larson, E.B.b
Glucose levels during life and neuropathologic findings at autopsy among people never treated for diabetes
(2016) Neurobiology of Aging, 48, pp. 72-82. 

DOI: 10.1016/j.neurobiolaging.2016.07.021

a Department of Medicine, University of Washington, Seattle, WA, United States
b Group Health Research Institute, Seattle, WA, United States
c Department of Pathology, University of Utah, Salt Lake City, UT, United States
d VA Greater Los Angeles Healthcare System, Los Angeles, CA, United States
e Department of Psychiatry and Biobehavioral Sciences at the David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
f Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
g Department of Pathology, University of Washington, Seattle, WA, United States

We evaluated associations between glucose and dementia-related neuropathologic findings among people without diabetes treatment history to elucidate mechanisms of glucose's potential effect on dementia. We used glucose and hemoglobin A1c values to characterize glucose exposures over 5 years before death (primary) and age bands from 55–59 through 80–84 (secondary). Autopsy evaluations included Braak stage for neurofibrillary tangles, Consortium to Establish a Registry for Alzheimer's Disease grade for neuritic plaques, macroscopic infarcts including lacunar infarcts, Lewy bodies, cerebral microinfarcts, and hippocampal sclerosis. Of 529 who came to autopsy, we included 430 with no history of diabetes treatment. We found no associations between glucose levels and Braak stage or Consortium to Establish a Registry for Alzheimer's Disease grade. There was a suggestion of a relationship between glucose and hippocampal sclerosis, although this was inconsistent across analyses. There was higher risk of Lewy bodies in substantia nigra and locus ceruleus with higher glucose levels in age band analyses. We did not find interactions between glucose levels, neuropathologic findings, and dementia. The mechanism by which glucose may impact dementia risk is still unknown. © 2016 Elsevier Inc.

Author Keywords
Glucose;  Hippocampal sclerosis;  Lewy bodies;  Neuritic plaques;  Neurofibrillary tangles;  Neuropathology

Document Type: Article
Source: Scopus


Baldassarre, A.a , Capotosto, P.a , Committeri, G.a , Corbetta, M.b c
Magnetic stimulation of visual cortex impairs perceptual learning
(2016) NeuroImage, 143, pp. 250-255. 

DOI: 10.1016/j.neuroimage.2016.08.063

a Department of Neuroscience, Imaging and Clinical Science - and ITAB, Institute of Advanced Biomedical Technologies University “G. D'Annunzio”, Via dei Vestini 33, Chieti, Chieti, Italy
b Department of Neurology, Radiology, Anatomy & Neurobiology, Washington University School of Medicine, St.Louis, United States
c Department of Neuroscience, University of Padua, Italy

The ability to learn and process visual stimuli more efficiently is important for survival. Previous neuroimaging studies have shown that perceptual learning on a shape identification task differently modulates activity in both frontal-parietal cortical regions and visual cortex (Sigman et al., 2005; Lewis et al., 2009). Specifically, fronto-parietal regions (i.e. intra parietal sulcus, pIPS) became less activated for trained as compared to untrained stimuli, while visual regions (i.e. V2d/V3 and LO) exhibited higher activation for familiar shape. Here, after the intensive training, we employed transcranial magnetic stimulation over both visual occipital and parietal regions, previously shown to be modulated, to investigate their causal role in learning the shape identification task. We report that interference with V2d/V3 and LO increased reaction times to learned stimuli as compared to pIPS and Sham control condition. Moreover, the impairment observed after stimulation over the two visual regions was positive correlated. These results strongly support the causal role of the visual network in the control of the perceptual learning. © 2016 Elsevier Inc.

Author Keywords
Perceptual learning;  TMS;  Visual cortex

Document Type: Article
Source: Scopus


Jahani-Asl, A.a b c , Cheng, C.a , Zhang, C.a , Bonni, A.a
Pathogenesis of Börjeson-Forssman-Lehmann syndrome: Insights from PHF6 function
(2016) Neurobiology of Disease, 96, pp. 227-235. 

DOI: 10.1016/j.nbd.2016.09.011

a Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
b Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC, Canada
c Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, Canada

Intellectual disability encompasses a large set of neurodevelopmental disorders of cognition that are more common in males than females. Although mutations in over 100 X-linked genes associated to intellectual disability have been identified, only a few X-linked intellectual disability proteins have been intensively studied. Hence, the molecular mechanisms underlying the majority of X-linked intellectual disability disorders remain poorly understood. A substantial fraction of X-linked intellectual disability genes encode nuclear proteins, suggesting that elucidating their functions in the regulation of transcription may provide novel insights into the pathogenesis of intellectual disability. Recent studies have uncovered mechanisms by which mutations of the gene encoding plant homeodomain (PHD)-like finger protein 6 (PHF6) contribute to the pathogenesis of the X-linked intellectual disability disorder Börjeson-Forssman-Lehmann syndrome (BFLS). PHF6 plays a critical role in the migration of neurons in the mouse cerebral cortex in vivo, and patient-specific mutations disrupt the ability of PHF6 to promote neuronal migration. Interestingly, PHF6 physically associates with the PAF1 transcriptional elongation complex and thereby drives neuronal migration in the cerebral cortex. PHF6 also interacts with the NuRD chromatin remodeling complex and with the nucleolar transcriptional regulator UBF, though the biological role of these interactions remains to be characterized. In other studies, PHF6 mRNA has been identified as the target of the microRNA miR-128 in the cerebral cortex, providing new insights into regulation of PHF6 function in neuronal migration. Importantly, deregulation of PHF6 function in neuronal migration triggers the formation of white matter heterotopias that harbor neuronal hyperexcitability, which may be relevant to the pathogenesis of intellectual disability and seizures in BFLS. Collectively, these studies are beginning to provide key insights into the molecular pathogenesis of BFLS. © 2016 Elsevier Inc.

Author Keywords
Börjeson-Forssman-Lehmann syndrome;  Heterotopia;  Neuronal positioning;  PAF1 complex;  PHF6;  Transcription;  X-linked intellectual disability

Document Type: Review
Source: Scopus


Pineda, R.G.
Feeding: an important, complex skill that impacts nutritional, social, motor and sensory experiences
(2016) Acta Paediatrica, International Journal of Paediatrics, 105 (10), p. e458. Cited 1 time.

DOI: 10.1111/apa.13535

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

Document Type: Note
Source: Scopus


White, J.K., Monosov, I.E.
Neurons in the primate dorsal striatum signal the uncertainty of object-reward associations
(2016) Nature Communications, 7, art. no. 12735, . 

DOI: 10.1038/ncomms12735

Department of Neuroscience, Washington University, School of Medicine, 660 S. Euclid Avenue, St Louis, MO, United States

To learn, obtain reward and survive, humans and other animals must monitor, approach and act on objects that are associated with variable or unknown rewards. However, the neuronal mechanisms that mediate behaviours aimed at uncertain objects are poorly understood. Here we demonstrate that a set of neurons in an internal-capsule bordering regions of the primate dorsal striatum, within the putamen and caudate nucleus, signal the uncertainty of object-reward associations. Their uncertainty responses depend on the presence of objects associated with reward uncertainty and evolve rapidly as monkeys learn novel object-reward associations. Therefore, beyond its established role in mediating actions aimed at known or certain rewards, the dorsal striatum also participates in behaviours aimed at reward-uncertain objects. © 2016 The Author(s}.

Document Type: Article
Source: Scopus


Kim, S.a , Maynard, J.C.c , Sasaki, Y.a , Strickland, A.a , Sherman, D.L.d , Brophy, P.J.d , Burlingame, A.L.c , Milbrandt, J.a b
Schwann cell O-GlcNAc glycosylation is required for myelin maintenance and axon integrity
(2016) Journal of Neuroscience, 36 (37), pp. 9633-9646. 

DOI: 10.1523/JNEUROSCI.1235-16.2016

a Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
b Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States
d Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom

Schwann cells (SCs), ensheathing glia of the peripheral nervous system, support axonal survival and function. Abnormalities in SC metabolism affect their ability to provide this support and maintain axon integrity. To further interrogate this metabolic influence on axon–glial interactions, we generated OGT-SCKO mice with SC-specific deletion of the metabolic/nutrient sensing protein O-GlcNAc transferase that mediates the O-linked addition of N-acetylglucosamine (GlcNAc) moieties to Ser and Thr residues. The OGT-SCKO mice develop tomaculous demyelinating neuropathy characterized by focal thickenings of the myelin sheath (tomacula), progressive demyelination, axonal loss, and motor and sensory nerve dysfunction. Proteomic analysis identified more than 100 O-GlcNAcylated proteins in rat sciatic nerve, including Periaxin (PRX), a myelin protein whose mutation causes inherited neuropathy in humans. PRX lacking O-GlcNAcylation is mislocalized within the myelin sheath of these mutant animals. Furthermore, phenotypes of OGT-SCKO and Prxdeficient mice are very similar, suggesting that metabolic control of PRX O-GlcNAcylation is crucial for myelin maintenance and axonal integrity. © 2016 the authors.

Author Keywords
CMT;  O-GlcNAc;  OGT;  Periaxin;  Schwann cell;  Tomacula

Document Type: Article
Source: Scopus


Thomas Roland, J.a , Buchman, C.b , Eisenberg, L.c , Henderson, L.d , He, S.e , Firszt, J.b , Francis, H.f , Dunn, C.g , Sladen, D.h , Arndt, S.i , May, B.f , Zeitler, D.a j , Niparko, J.K.c , Emmett, S.f , Tucci, D.a k , Chen, J.a l , McConkey Robbins, A.a m , Schwefler, E.a n , Geers, A.a o , Lederberg, A.a p , Hayes, H.a q , Hughes, M.e , Bierer, J.a r , Schafer, E.a s , Sorkin, D.b t , Kozma-Spytek, L.b u , Childress, T.b v
Proceedings of the Annual Symposium of the American Cochlear Implant Alliance†
(2016) Cochlear Implants International, pp. 1-27. Article in Press. 

DOI: 10.1080/14670100.2016.1225348

a NYU Medical Center
b Washington University School of Medicine
c Keck School of Medicine of USC
d University of North Carolina
e Boys Town National Research Hospital (previously University of North Carolina)
f Johns Hopkins University
g University of Iowa
h Mayo Clinic
i University of Freiberg, Germany
j Virginia Mason Clinic
k Duke Medicine
l University of Toronto
m Communication Consulting Services
n Contracting Officer USC Care
o University of Texas at Dallas
p Georgia State
q Washington University
r University of Washington
s University of North Texas
t ACI Alliance
u Gallaudet University
v Case Audiology and IL School for the Deaf

Document Type: Article in Press
Source: Scopus


Lock, J.a , Agras, W.S.a , Bryson, S.W.a , Brandt, H.b , Halmi, K.A.c , Kaye, W.d , Wilfley, D.e , Woodside, B.f , Pajarito, S.a , Jo, B.a
Does family-based treatment reduce the need for hospitalization in adolescent anorexia nervosa?
(2016) International Journal of Eating Disorders, 49 (9), pp. 891-894. 

DOI: 10.1002/eat.22536

a Department of Psychiatry and Behavioral Sciences, Stanford University, United States
b Sheppard Pratt Health System, 6501 N Charles St, Towson, MD, United States
c Department of Psychiatry, Weill Medical College, Cornell University, Westchester Division. 21 Bloomingdale Rd., White Plains, NY, United States
d Department of Psychiatry, University of San Diego, 9500 Gilman Dr, La Jolla, CA, United States
e Department of Psychiatry, Washington University, 4940 Childrens Pl, St Louis, MO, United States
f Department of Psychiatry, University of Toronto, 1001 Queen Street W., Toronto, ON, Canada

Objective: We examined the timing and number of days of hospitalization during the course of treatment, hospitalization effects on outcome, and predictors and moderators of the use of hospitalization in adolescents with anorexia nervosa (AN). Method: Data used in this study were collected from 158 adolescents (ages 12 to 18 years of age) who met DSM-IVTR criteria for AN (exclusive of the amenorrhea criteria) randomized to receive either Family Based Treatment (FBT) or Systemic Family Therapy (SyFT) in a 7 site study. Results: The trajectory of hospital day use is similar in the first 5 weeks irrespective of treatment allocation. However, days of hospitalization continued to increase throughout SyFT but leveled off in FBT after
5 weeks of treatment. Early hospitalization was a negative predictor for improvements in percent weight change for both treatment groups (t(1)=2.6, p = 0.011). Co-morbid psychopathology predicted early hospital use in both treatments. Higher levels of eating related obsessions and depression moderated hospitalization rates suggesting that FBT reduces early hospitalization rates compared to SyFT for these subgroups. Discussion: These data support and extend findings from previous studies by identifying patterns of hospital use, and predictors and moderators of treatment effect for early hospitalization use in adolescent AN. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016; 49:891–894). © 2016 Wiley Periodicals, Inc.

Author Keywords
adolescents;  anorexia nervosa;  family therapy;  hospitalization

Document Type: Article
Source: Scopus


Smyser, C.D.a b c
Role of connectome-based analysis techniques in functional neuroimaging investigations of neurodevelopmental disorders
(2016) Acta Paediatrica, International Journal of Paediatrics, 105 (9), pp. 1001-1003. Cited 1 time.

DOI: 10.1111/apa.13513

a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Pediatrics, Washington University School of Medicine, Saint Louis, MO, United States
c Mallinckrodt of Radiology, Washington University School of Medicine, Saint Louis, MO, United States

Document Type: Editorial
Source: Scopus



Waterman, L.a , Stahl, S.T.a , Buysse, D.J.a , Lenze, E.J.c , Blumberger, D.b , Mulsant, B.b , Butters, M.a , Gebara, M.A.a , Reynolds, C.F.a , Karp, J.F.a
Self-reported obstructive sleep apnea is associated with nonresponse to antidepressant pharmacotherapy in late-life depression
(2016) Depression and Anxiety, . Article in Press. 

DOI: 10.1002/da.22555

a Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine Pittsburgh, PA USA
b Centre for Addiction and Mental Health University of Toronto
c Department of Psychiatry Washington University in St. Louis St. Louis, MO USA

Background: Obstructive sleep apnea (OSA) is frequently comorbid with late-life depression. The purpose of this project was to determine, using a sample of older adults with major depressive disorder, whether patient-reported diagnosis of OSA was associated with rate of response to venlafaxine. Methods: Participants from this multisite study were adults ≥60 years old (n = 468) with major depressive disorder and a Montgomery Asberg Depression Rating Scale (MADRS) score of ≥15. Depression response was the outcome variable, defined as a MADRS score of ≤10 for two consecutive assessments at the end of 12 weeks of open-label treatment with venlafaxine 300 mg/day. To assess OSA, participants were asked if they had been diagnosed with OSA using polysomnography. Results: Eighty participants (17.1%) reported a diagnosis of OSA prior to baseline. Participants with OSA were more likely to be male, report greater impairment on measures of health, experience a longer duration of the index episode, and receive an adequate antidepressant trial prior to entering the study. During the 12 weeks of treatment, 40.8% responded to treatment with venlafaxine (43.6%, n = 169/388 of the no OSA group, and 27.5%, n = 22/80 of the OSA group). Participants without OSA were 1.79 times more likely to respond to treatment (HR: 1.79 [95%CI: 1.13-2.86], P < .05) compared to those with OSA. Conclusions: OSA may impair response to antidepressant pharmacotherapy in depressed older adults. Future studies of antidepressant response rates among depressed older adults with OSA should both prospectively diagnose OSA and monitor adherence to treatments such as continuous positive airway pressure. © 2016 Wiley Periodicals, Inc., a Wiley company.

Author Keywords
Antidepressant;  Depression;  Geriatrics;  Obstructive sleep apnea;  Response

Document Type: Article in Press
Source: Scopus


September 12, 2016



Mitra, A.a , Raichle, M.E.a b
How networks communicate: Propagation patterns in spontaneous brain activity
(2016) Philosophical Transactions of the Royal Society B: Biological Sciences, 371 (1705), art. no. 20150546, 9 p. Cited 1 time.

DOI: 10.1098/rstb.2015.0546

a Department of Radiology, Washington University, St Louis, MO, United States
b Department of Neurology, Washington University, St Louis, MO, United States

Initially regarded as 'noise', spontaneous (intrinsic) activity accounts for a large portion of the brain's metabolic cost.Moreover, it is now widely known that infra-slow (less than 0.1 Hz) spontaneous activity, measured using resting state functional magnetic resonance imaging of the blood oxygen level-dependent (BOLD) signal, is correlated within functionally defined resting state networks (RSNs).However, despite these advances, the temporal organization of spontaneous BOLD fluctuations has remained elusive.By studying temporal lags in the resting state BOLD signal, we have recently shown that spontaneous BOLD fluctuations consist of remarkably reproducible patterns of whole brain propagation.Embedded in these propagation patterns are unidirectional 'motifs' which, in turn, give rise to RSNs.Additionally, propagation patterns are markedly altered as a function of state, whether physiological or pathological.Understanding such propagation patterns will likely yield deeper insights into the role of spontaneous activity in brain function in health and disease. © 2016 The Author(s).

Author Keywords
Dynamics;  Functional magnetic resonance imaging;  Lags;  Network;  Propagation;  Resting state

Document Type: Review
Source: Scopus


Gruber, J.a , van Meter, A.b , Gilbert, K.E.c , Youngstrom, E.A.d , Youngstrom, J.K.d , Feeny, N.C.e , Findling, R.L.f
Positive Emotion Specificity and Mood Symptoms in an Adolescent Outpatient Sample
(2016) Cognitive Therapy and Research, pp. 1-13. Article in Press. 

DOI: 10.1007/s10608-016-9796-7

a Department of Psychology and Neuroscience, University of Colorado Boulder, 1905 Colorado Avenue, 345 UCB, Muenzinger D321C, Boulder, CO, United States
b Ferkauf Graduate School, Yeshiva University, New York, NY, United States
c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
d Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
e Case Western Reserve University, Cleveland, OH, United States
f Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, United States

Research on positive emotion disturbance has gained increasing attention, yet it is not clear which specific positive emotions are affected by mood symptoms, particularly during the critical period of adolescence. This is especially pertinent for identifying potential endophenotypic markers associated with mood disorder onset and course. The present study examined self-reported discrete positive and negative emotions in association with clinician-rated manic and depressive mood symptoms in a clinically and demographically diverse group of 401 outpatient adolescents between 11 and 18 years of age. Results indicated that higher self reported joy and contempt were associated with increased symptoms of mania, after controlling for symptoms of depression. Low levels of joy and high sadness uniquely predicted symptoms of depression, after controlling for symptoms of mania. Results were independent of age, ethnicity, gender and bipolar diagnosis. These findings extend work on specific emotions implicated in mood pathology in adulthood, and provide insights into associations between emotions associated with goal driven behavior with manic and depressive mood symptom severity in adolescence. In particular, joy was the only emotion associated with both depressive and manic symptoms across adolescent psychopathology, highlighting the importance of understanding positive emotion disturbance during adolescent development. © 2016 Springer Science+Business Media New York

Author Keywords
Adolescence;  Depression;  Mania;  Positive emotion

Document Type: Article in Press
Source: Scopus


Maciejewski, D.F.a , Renteria, M.E.b , Abdellaoui, A.c , Medland, S.E.b , Few, L.R.d , Gordon, S.D.b , Madden, P.A.F.d , Montgomery, G.b , Trull, T.J.e , Heath, A.C.d , Statham, D.J.f , Martin, N.G.b , Zietsch, B.P.b g , Verweij, K.J.H.c g
The Association of Genetic Predisposition to Depressive Symptoms with Non-suicidal and Suicidal Self-Injuries
(2016) Behavior Genetics, pp. 1-8. Article in Press. 

DOI: 10.1007/s10519-016-9809-z

a Department of Clinical Developmental Psychology and EMGO Institute for Health and Care Research, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
b Genetic Epidemiology, Molecular Epidemiology and Neurogenetics Laboratories, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
c Department of Biological Psychology, Vrije Universiteit Amsterdam, Van der Boechorststraat 1, Amsterdam, Netherlands
d Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
e Department of Psychological Sciences, University of Missouri, Columbia, MO, United States
f Faculty of Arts and Social Sciences, University of Sunshine Coast, Sippy Downs, QLD, Australia
g School of Psychology, University of Queensland, St. Lucia, Brisbane, QLD, Australia

Non-suicidal and suicidal self-injury are very destructive, yet surprisingly common behaviours. Depressed mood is a major risk factor for non-suicidal self-injury (NSSI), suicidal ideation and suicide attempts. We conducted a genetic risk prediction study to examine the polygenic overlap of depressive symptoms with lifetime NSSI, suicidal ideation, and suicide attempts in a sample of 6237 Australian adult twins and their family members (3740 females, mean age = 42.4 years). Polygenic risk scores for depressive symptoms significantly predicted suicidal ideation, and some predictive ability was found for suicide attempts; the polygenic risk scores explained a significant amount of variance in suicidal ideation (lowest p = 0.008, explained variance ranging from 0.10 to 0.16 %) and, less consistently, in suicide attempts (lowest p = 0.04, explained variance ranging from 0.12 to 0.23 %). Polygenic risk scores did not significantly predict NSSI. Results highlight that individuals genetically predisposed to depression are also more likely to experience suicidal ideation/behaviour, whereas we found no evidence that this is also the case for NSSI. © 2016 The Author(s)

Author Keywords
Depression;  Genetics;  Polygenic risk;  Self-injury;  Suicidal ideation;  Suicide attempts

Document Type: Article in Press
Source: Scopus


Fox, R.J.a , Coffey, C.S.b , Cudkowicz, M.E.c , Gleason, T.d , Goodman, A.e , Klawiter, E.C.f , Matsuda, K.g , McGovern, M.c , Conwit, R.h , Naismith, R.i , Ashokkumar, A.b , Bermel, R.a , Ecklund, D.b , Koepp, M.b , Long, J.b , Natarajan, S.a , Ramachandran, S.a , Skaramagas, T.a , Thornell, B.c , Yankey, J.b , Agius, M.j k , Bashir, K.l , Cohen, B.m , Coyle, P.n , Delgado, S.o , Dewitt, D.p , Flores, A.q , Giesser, B.r , Goldman, M.s , Jubelt, B.t , Lava, N.u , Lynch, S.v , Miravalle, A.w , Moses, H.x , Ontaneda, D.a , Perumal, J.y , Racke, M.z , Repovic, P.aa , Riley, C.ab , Severson, , Shinnar, , Suski, , Weinstock-Gutman, , Yadav, , Zabeti, A.ah
Design, rationale, and baseline characteristics of the randomized double-blind phase II clinical trial of ibudilast in progressive multiple sclerosis
(2016) Contemporary Clinical Trials, 50, pp. 166-177. 

DOI: 10.1016/j.cct.2016.08.009

a Cleveland Clinic, Neurological Institute, Cleveland, OH, United States
b Data Coordinating Center, NeuroNEXT, University of Iowa, Iowa City, IA, United States
c Clinical Coordinating Center, NeuroNEXT, Harvard Partners, Boston, MA, United States
d Patient Advocate, Seattle, WA, United States
e University of Rochester Medical Center, Rochester, NY, United States
f Massachusetts General Hospital, Boston, MA, United States
g Medicinova Inc., La Jolla, CA, United States
h National Institutes of Neurological Disease and Stroke, Bethesda, MD, United States
i Washington University School of Medicine, St. Louis, MO, United States
j University of California at Davis, Sacramento, CA, United States
k Barrows Neurological Institute, Phoenix, AZ, United States
l University of Alabama at Birmingham, Birmingham, AL, United States
m Northwestern University, Chicago, IL, United States
n State University of New York, Stony Brook, NY, United States
o University of Miami School of Medicine, Miami, FL, United States
p University of Utah, Salt Lake City, UT, United States
q University of Texas Southwestern Medical Center, Dallas, TX, United States
r University of California at Los Angeles, Los Angeles, CA, United States
s University of Virginia at Charlottesville, Charlottesville, VA, United States
t State University of New York Upstate Medical University, Syracuse, NY, United States
u Emory University, Atlanta, GA, United States
v University of Kansas Medical Center, Kansas City, KS, United States
w University of Colorado at Denver, Aurora, CO, United States
x Vanderbilt University, Nashville, TN, United States
y Weill Cornell Medical College, New York, NY, United States
z The Ohio State University, Columbus, OH, United States
aa Swedish Medical Center at Seattle, Seattle, WA, United States
ab Columbia University Medical Center, New York, NY, United States
ac Brigham and Women's Hospital, Brookline, MA, United States
ad Montefiore Medical Center, Bronx, NY, United States
ae University of Pittsburgh Medical Center, Pittsburgh, PA, United States
af State University of New York Buffalo, Buffalo, NY, United States
ag Oregon Health and Science University, Portland, OR, United States
ah University of Cincinnati, Cincinnati, OH, United States

Background Primary and secondary progressive multiple sclerosis (MS), collectively called progressive multiple sclerosis (PMS), is characterized by gradual progression of disability. The current anti-inflammatory treatments for MS have little or no efficacy in PMS in the absence of obvious active inflammation. Optimal biomarkers for phase II PMS trials is unknown. Ibudilast is an inhibitor of macrophage migration inhibitor factor and phosphodiesterases-4 and − 10 and exhibits possible neuroprotective properties. The goals of SPRINT-MS study are to evaluate the safety and efficacy of ibudilast in PMS and to directly compare several imaging metrics for utility in PMS trials. Methods SPRINT-MS is a randomized, placebo-controlled, phase II trial of ibudilast in patients with PMS. Eligible subjects were randomized 1:1 to receive either ibudilast (100 mg/day) or placebo for 96 weeks. Imaging is conducted every 24 weeks for whole brain atrophy, magnetization transfer ratio, diffusion tensor imaging, cortical brain atrophy, and retinal nerve fiber layer thickness. Clinical outcomes include neurologic disability and patient reported quality of life. Safety assessments include laboratory testing, electrocardiography, and suicidality screening. Results A total of 331 subjects were enrolled, of which 255 were randomized onto active study treatment. Randomized subjects were 53.7% female and mean age 55.7 (SD 7.3) years. The last subject is projected to complete the study in May 2017. Conclusion SPRINT-MS is designed to evaluate the safety and efficacy of ibudilast as a treatment for PMS while simultaneously validating five different imaging biomarkers as outcome metrics for use in future phase II proof-of-concept PMS trials. © 2016 Elsevier Inc.

Author Keywords
Clinical trial;  Ibudilast;  Magnetic resonance imaging;  Progressive multiple sclerosis

Document Type: Article
Source: Scopus


Glasser, M.F.a , Smith, S.M.b , Marcus, D.S.c , Andersson, J.L.R.b , Auerbach, E.J.d , Behrens, T.E.J.b , Coalson, T.S.a , Harms, M.P.e , Jenkinson, M.b , Moeller, S.d , Robinson, E.C.f , Sotiropoulos, S.N.b , Xu, J.g , Yacoub, E.d , Ugurbil, K.d , Van Essen, D.C.a
The Human Connectome Project's neuroimaging approach
(2016) Nature Neuroscience, 19 (9), pp. 1175-1187. 

DOI: 10.1038/nn.4361

a Department of Neuroscience, Washington University Medical School, St. Louis, MO, United States
b Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
c Department of Radiology, Washington University Medical School, St. Louis, MO, United States
d Center for Magnetic Resonance Research (CMRR), University of Minnesota, Minneapolis, MN, United States
e Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States
f Department of Computing, Imperial College London, London, United Kingdom
g Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Noninvasive human neuroimaging has yielded many discoveries about the brain. Numerous methodological advances have also occurred, though inertia has slowed their adoption. This paper presents an integrated approach to data acquisition, analysis and sharing that builds upon recent advances, particularly from the Human Connectome Project (HCP). The 'HCP-style' paradigm has seven core tenets: (i) collect multimodal imaging data from many subjects; (ii) acquire data at high spatial and temporal resolution; (iii) preprocess data to minimize distortions, blurring and temporal artifacts; (iv) represent data using the natural geometry of cortical and subcortical structures; (v) accurately align corresponding brain areas across subjects and studies; (vi) analyze data using neurobiologically accurate brain parcellations; and (vii) share published data via user-friendly databases. We illustrate the HCP-style paradigm using existing HCP data sets and provide guidance for future research. Widespread adoption of this paradigm should accelerate progress in understanding the brain in health and disease. © 2016 Nature America, Inc.

Document Type: Review
Source: Scopus


Koppaka, S.a b , Shklyar, I.c , Rutkove, S.B.c , Darras, B.T.e , Anthony, B.W.a b , Zaidman, C.M.f , Wu, J.S.d
Quantitative ultrasound assessment of duchenne muscular dystrophy using edge detection analysis
(2016) Journal of Ultrasound in Medicine, 35 (9), pp. 1889-1897. 

DOI: 10.7863/ultra.15.04065

a Laboratory for Manufacturing and Productivity, Massachusetts Institute of Technology, Cambridge, MA, United States
b Medical Electronic Device Realization Center, Massachusetts Institute of Technology, Cambridge, MA, United States
c Departments of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States
d Departments of Radiology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA, United States
e Department of Neurology, Boston Children's Hospital, Boston, MA, United States
f Departments of Neurology and Pediatrics, Washington University, St Louis, MO, United States

Objectives-The purpose of this study was to investigate the ability of quantitative ultrasound (US) using edge detection analysis to assess patients with Duchenne muscular dystrophy (DMD). Methods-After Institutional Review Board approval, US examinations with fixed technical parameters were performed unilaterally in 6 muscles (biceps, deltoid, wrist flexors, quadriceps, medial gastrocnemius, and tibialis anterior) in 19 boys with DMD and 21 age-matched control participants. The muscles of interest were outlined by a tracing tool, and the upper third of the muscle was used for analysis. Edge detection values for each muscle were quantified by the Canny edge detection algorithm and then normalized to the number of edge pixels in the muscle region. The edge detection values were extracted at multiple sensitivity thresholds (0.01-0.99) to determine the optimal threshold for distinguishing DMD from normal. Area under the receiver operating curve values were generated for each muscle and averaged across the 6 muscles. Results-The average age in the DMD group was 8.8 years (range, 3.0-14.3 years), and the average age in the control group was 8.7 years (range, 3.4-13.5 years). For edge detection, a Canny threshold of 0.05 provided the best discrimination between DMD and normal (area under the curve, 0.96; 95% confidence interval, 0.84-1.00). According to a Mann-Whitney test, edge detection values were significantly different between DMD and controls (P < .0001). Conclusions-Quantitative US imaging using edge detection can distinguish patients with DMD from healthy controls at low Canny thresholds, at which discrimination of small structures is best. Edge detection by itself or in combination with other tests can potentially serve as a useful biomarker of disease progression and effectiveness of therapy in muscle disorders. © 2016 by the American Institute of Ultrasound in Medicine.

Author Keywords
Duchenne muscular dystrophy;  Edge detection;  Muscle;  Musculoskeletal ultrasound;  Quantitative ultrasound

Document Type: Article
Source: Scopus


Davidson, S.a e , Golden, J.P.a , Copits, B.A.a , Ray, P.R.b , Vogt, S.K.a , Valtcheva, M.V.a , Schmidt, R.E.c , Ghetti, A.d , Price, T.J.b , Gereau, R.W.a
Group II mGluRs suppress hyperexcitability in mouse and human nociceptors
(2016) Pain, 157 (9), pp. 2081-2088. 

DOI: 10.1097/j.pain.0000000000000621

a Department of Anesthesiology, Pain Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b School of Sciences, University of Texas at Dallas, School of Behavioral and Brain Sciences, Richardson, TX, United States
c Department of Neuropathology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
d AnaBios Corporation, San Diego, CA, United States
e Pain Research Center, Department of Anesthesiology, University of Cincinnati, College of Medicine, Cincinnati, OH, United States

We introduce a strategy for preclinical research wherein promising targets for analgesia are tested in rodent and subsequently validated in human sensory neurons. We evaluate group II metabotropic glutamate receptors, the activation of which is efficacious in rodent models of pain. Immunohistochemical analysis showed positive immunoreactivity for mGlu2 in rodent dorsal root ganglia (DRG), peripheral fibers in skin, and central labeling in the spinal dorsal horn. We also found mGlu2-positive immunoreactivity in human neonatal and adult DRG. RNA-seq analysis of mouse and human DRG revealed a comparative expression profile between species for group II mGluRs and for opioid receptors. In rodent sensory neurons under basal conditions, activation of group II mGluRs with a selective group II agonist produced no changes to membrane excitability. However, membrane hyperexcitability in sensory neurons exposed to the inflammatory mediator prostaglandin E2 (PGE 2) was prevented by (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC). In human sensory neurons from donors without a history of chronic pain, we show that PGE 2 produced hyperexcitability that was similarly blocked by group II mGluR activation. These results reveal a mechanism for peripheral analgesia likely shared by mice and humans and demonstrate a translational research strategy to improve preclinical validation of novel analgesics using cultured human sensory neurons. © 2016 International Association for the Study of Pain.

Author Keywords
Dorsal root ganglia;  Glutamate;  Human;  Metabotropic;  Physiology;  Sensitization

Document Type: Article
Source: Scopus


Edwards, R.R.a , Dworkin, R.H.b , Turk, D.C.c , Angst, M.S.d , Dionne, R.e , Freeman, R.a , Hansson, P.f ak , Haroutounian, S.g , Arendt-Nielsen, L.h , Attal, N.i aj , Baron, R.j , Brell, J.k , Bujanover, S.l , Burke, L.B.m n , Carr, D.o , Chappell, A.S.p , Cowan, P.q , Etropolski, M.r , Fillingim, R.B.s , Gewandter, J.S.b , Katz, N.P.o t , Kopecky, E.A.u , Markman, J.D.b , Nomikos, G.v , Porter, L.w , Rappaport, B.A.x , Rice, A.S.C.y , Scavone, J.M.z , Scholz, J.aa , Simon, L.S.ab , Smith, S.M.b , Tobias, , Tockarshewsky, , Veasley, , Versavel, , Wasan, , Wen, W.ah , Yarnitsky,
Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations
(2016) Pain, 157 (9), pp. 1851-1871. 

DOI: 10.1097/j.pain.0000000000000602

a Harvard Medical School, Brigham and Women's Hospital, Boston, MA, United States
b University of Rochester, Rochester, NY, United States
c University of Washington, Seattle, WA, United States
d Stanford University, Palo Alto, CA, United States
e East Carolina University, Greenville, NC, United States
f Oslo University Hospital, Oslo, Norway
g Washington University, St. Louis, MO, United States
h Aalborg University, Aalborg, Denmark
i Hôpital Ambroise Paré, APHP and INSERM U 987, Boulogne-Billancourt, France
j University of Kiel, Kiel, Germany
k MetroHealth Medical Center, Cleveland, OH, United States
l Depomed, Newark, CA, United States
m LORA Group, LLC, Royal Oak, MD, United States
n University of Maryland, Baltimore, MD, United States
o Tufts University, Boston, MA, United States
p Eli Lilly, Indianapolis, IN, United States
q American Chronic Pain Association, Rocklin, CA, United States
r Johnson and Johnson, Titusville, NJ, United States
s University of Florida, Gainesville, FL, United States
t Analgesic Solutions, Natick, MA, United States
u Collegium Pharmaceutical, Inc., Canton, MA, United States
v Astellas Pharma, Northbrook, IL, United States
w National Institutes of Health, Bethesda, MD, United States
x Arlington, VA, United States
y Imperial College, London, United Kingdom
z Pfizer, Groton, CT, United States
aa Columbia University, New York, NY, United States
ab SDG LLC, Cambridge, MA, United States
ac Jazz Pharmaceuticals, Palo Alto, CA, United States
ad Ceres Consulting, Fort Montgomery, NY, United States
ae Chronic Pain Research Alliance, North Kingstown, RI, United States
af Zalicus, Cambridge, MA, United States
ag University of Pittsburgh, Pittsburgh, PA, United States
ah Purdue Pharma, Stamford, CT, United States
ai Rambam Health Care Campus, Technion Faculty of Medicine, Haifa, Israel
aj University Versailles Saint Quentin, Versailles, France
ak Karolinska Institute, Stockholm, Sweden

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for "precision medicine" or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain. © 2016 International Association for the Study of Pain.

Author Keywords
Central pain modulation;  Neuropathic;  Phenotype;  Psychosocial;  Quantitative sensory testing;  Sleep

Document Type: Review
Source: Scopus


Morales, D.M., Silver, S.A., Morgan, C.D., Mercer, D., Inder, T.E., Holtzman, D.M., Wallendorf, M.J., Rao, R., McAllister, J.P., Limbrick, D.D., Jr
Lumbar Cerebrospinal Fluid Biomarkers of Posthemorrhagic Hydrocephalus of Prematurity: Amyloid Precursor Protein, Soluble Amyloid Precursor Protein α, and L1 Cell Adhesion Molecule
(2016) Neurosurgery, . Article in Press. 

DOI: 10.1227/NEU.0000000000001415

*Department of Neurological Surgery, Washington University School of Medicine, St. Louis, Missouri; ‡Department of Neurological Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee; §Department of Pediatrics, Harvard University School of Medicine, Boston, Massachusetts; ¶Department of Neurology, Washington University School of Medicine, St. Louis, Missouri; ?Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri; #Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri; **Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri; ‡‡Department of Pediatrics, Washington University School of Medicine, S

BACKGROUND:: Intraventricular hemorrhage (IVH) is the most frequent, severe neurological complication of prematurity and is associated with posthemorrhagic hydrocephalus (PHH) in up to half of cases. PHH requires lifelong neurosurgical care and is associated with significant cognitive and psychomotor disability. Cerebrospinal fluid (CSF) biomarkers may provide both diagnostic information for PHH and novel insights into its pathophysiology. OBJECTIVE:: To explore the diagnostic ability of candidate CSF biomarkers for PHH. METHODS:: Concentrations of amyloid precursor protein (APP), soluble APPα (sAPPα), soluble APPβ, neural cell adhesion molecule-1 (NCAM-1), L1 cell adhesion molecule (L1CAM), tau, phosphorylated tau, and total protein (TP) were measured in lumbar CSF from neonates in 6 groups: (1) no known neurological disease (n = 33); (2) IVH grades I to II (n = 13); (3) IVH grades III to IV (n = 12); (4) PHH (n = 12); (5) ventricular enlargement without hydrocephalus (n = 10); and (6) hypoxic ischemic encephalopathy (n = 13). CSF protein levels were compared using analysis of variance, and logistic regression was performed to examine the predictive ability of each marker for PHH. RESULTS:: Lumbar CSF levels of APP, sAPPα, L1CAM, and TP were selectively increased in PHH compared with all other conditions (all P < .001). The sensitivity, specificity, and odds ratios of candidate CSF biomarkers for PHH were determined for APP, sAPPα, and L1CAM; cut points of 699, 514, and 113 ng/mL yielded odds ratios for PHH of 80.0, 200.0, and 68.75, respectively. CONCLUSION:: Lumbar CSF APP, sAPPα, L1CAM, and TP were selectively increased in PHH. These proteins, and sAPPα, in particular, hold promise as biomarkers of PHH and provide novel insight into PHH-associated neural injury and repair. ABBREVIATIONS:: APP, amyloid precursor proteinELISA, enzyme-linked immunosorbent assayHIE, hypoxic ischemic encephalopathyIVH, intraventricular hemorrhageL1CAM, L1 cell adhesion moleculeLP, lumbar punctureNCAM-1, neural cell adhesion molecule-1NICU, neonatal intensive care unitp-tau, phosphorylated tauPHH, posthemorrhagic hydrocephalusPMA, postmenstrual ageRCG, rostrocaudal gradientsAPPα, soluble amyloid precursor protein αsAPPβ, soluble amyloid precursor protein βTP, total proteinVAD, ventricular access deviceVEWOH, ventricular enlargement without hydrocephalus Copyright © by the Congress of Neurological Surgeons

Document Type: Article in Press
Source: Scopus


Kosik, K.S.a , Sejnowski, T.J.b c , Raichle, M.E.d , Ciechanover, A.e , Baltimore, D.f
A path toward understanding neurodegeneration
(2016) Science, 353 (6302), pp. 872-873. 

DOI: 10.1126/science.aai7622

a Department of Molecular, Cellular, and Developmental Biology, Neuroscience Research Institute, University of California, Santa Barbara, Santa Barbara, CA, United States
b Howard Hughes Medical Institute, Salk Institute for Biological Studies, San Diego, CA, United States
c Division of Biological Sciences, University of California, San Diego, San Diego, CA, United States
d Mallinckrodt Institute of Radiology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
e Cancer and Vascular Biology Research Center, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
f Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, United States

Document Type: Short Survey
Source: Scopus


Chen, W.a , Wilson, J.b , Tyree, S.c , Weinberger, K.Q.d , Chen, Y.a
Compressing convolutional neural networks in the frequency domain
(2016) Proceedings of the ACM SIGKDD International Conference on Knowledge Discovery and Data Mining, 13-17-August-2016, pp. 1475-1484. 

DOI: 10.1145/2939672.2939839

a Department of Computer Science and Engineering, Washington University in St. Louis, United States
b University of Edinburgh, United Kingdom
c NVIDIA, Santa Clara, CA, United States
d Department of Computer Science, Cornell University, United States

Convolutional neural networks (CNN) are increasingly used in many areas of computer vision. They are particularly attractive because of their ability to "absorb" great quantities of labeled data through millions of parameters. However, as model sizes increase, so do the storage and memory requirements of the classifiers, hindering many applications such as image and speech recognition on mobile phones and other devices. In this paper, we present a novel network architecture, Frequency-Sensitive Hashed Nets (FreshNets), which exploits inherent redundancy in both convolutional layers and fully-connected layers of a deep learning model, leading to dramatic savings in memory and storage consumption. Based on the key observation that the weights of learned convolutional filters are typically smooth and low-frequency, we first convert filter weights to the frequency domain with a discrete cosine transform (DCT) and use a low-cost hash function to randomly group frequency parameters into hash buckets. All parameters assigned the same hash bucket share a single value learned with standard backpropagation. To further reduce model size, we allocate fewer hash buckets to high-frequency components, which are generally less important. We evaluate FreshNets on eight data sets, and show that it leads to better compressed performance than several relevant baselines. © 2016 ACM.

Author Keywords
Convolutional neural networks;  Hashing;  Model compression

Document Type: Conference Paper
Source: Scopus


Roberts, C.R.a , Wofford, J.E.b , Hoy, H.M.b , Faddis, M.N.c
Implementation of a screening program for patients at risk for posttraumatic stress disorder
(2016) Clinical Medicine Insights: Cardiology, 10, pp. 129-137. 

DOI: 10.4137/CMC.S39957

a Washington University School of Medicine, Cardiac Electrophysiology, United States
b University of Alabama in Huntsville, United States
c Washington University School of Medicine, Medicine Division of Cardiovascular Diseases, Cardiac Electrophysiology, United States

Introduction: Implantable cardioverter defibrillator (ICD) recipients who suffer from posttraumatic stress disorder (PTSD) are known to be associated with significant cardiac-specific mortality. Clinical observations suggest that PTSD is frequently undetected in ICD recipients followed up at electrophysiology (EP) outpatient clinics. Early recognition of PTSD is important to reduce the risk of serious manifestations on patient outcomes.Methods: All ICD recipients aged 19 years or older at the Washington University School of Medicine (WASHU) EP clinic, a large urban EP clinic, were invited to participate in the project. An informed consent letter with an attached primary care: posttraumatic stress disorder (PC: PTSD) survey was offered to the participants who met the inclusion criteria. Those who completed the survey were included in the project. Individuals with positive survey result were offered a referral to mental health services. Comparisons between PTSD and non-PTSD patients were done using a two-sample t-test for continuous variables. Using Fisher’s exact test, PTSD prevalence was compared to the study by Ladwig et al in which prevalence was determined as the proportion of patients with positive findings of PTSD (n = 38/147). All analyses were conducted using SAS v9.4. The proportion of patients having PTSD was determined and an exact 95% confidence interval was evaluated based on the binomial distribution. Results: Using a convenience sample, 50 ICD recipients (33 males and 17 females) were enrolled. The project had a 30-day outcome period. Nine (18%) of the 50 participants had positive PC: PTSD findings and all these nine participants were referred to a mental health specialist. The current project demon-strated an 18% (9/50) PTSD prevalence rate when compared to a 26% (38/147) prevalence rate in the study by Ladwig et al (P = 0.34). Although this project did not demonstrate 20% PTSD prevalence rate, as hypothesized, the 18% PTSD prevalence rate is consistent with previous research. Conclusion: The prevalence of PTSD noted in the current project is consistent with previous research and validates underrecognition of PTSD in ICD patients. Offering a referral to all ICD recipients at EP clinic visits with a positive PC: PTSD screening to a mental health specialist is an important step in reducing the risk of serious manifestations on patient outcomes. © the authors, publisher and licensee Libertas Academica Limited.

Author Keywords
Anxiety;  Cognitive behavioral therapy;  Defibrillator;  Depression;  Emotion;  Evaluation;  ICD;  Implantable cardioverter-defibrillator;  Nursing;  Patient outcomes;  Post-traumatic stress disorder;  Psychological distress;  Psychosocial impact;  PTSD;  QL;  QoL;  Quality of life;  Randomized controlled trial;  SCA;  SCD;  Sudden cardiac arrest;  Sudden cardiac death;  Support group

Document Type: Article
Source: Scopus


Küffer, A.a , Lakkaraju, A.K.K.a , Mogha, A.b , Petersen, S.C.b , Airich, K.a , Doucerain, C.a , Marpakwar, R.a , Bakirci, P.a , Senatore, A.a , Monnard, A.a , Schiavi, C.a , Nuvolone, M.a , Grosshans, B.c , Hornemann, S.a , Bassilana, F.c , Monk, K.R.b , Aguzzi, A.a
The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6
(2016) Nature, 536 (7617), pp. 464-468. 

DOI: 10.1038/nature19312

a Institute of Neuropathology, University of Zurich, Zürich, Switzerland
b Washington University School of Medicine, Department of Developmental Biology, Hope Center for Neurological Disorders, 660 South Euclid Avenue, Campus Box 8103, St. Louis, MO, United States
c Novartis Institutes for Biomedical Research, Basel, Switzerland

Ablation of the cellular prion protein PrPC leads to a chronic demyelinating polyneuropathy affecting Schwann cells. Neuron-restricted expression of PrPC prevents the disease, suggesting that PrPC acts in trans through an unidentified Schwann cell receptor. Here we show that the cAMP concentration in sciatic nerves from PrPC -deficient mice is reduced, suggesting that PrPC acts via a G protein-coupled receptor (GPCR). The amino-terminal flexible tail (residues 23-120) of PrPC triggered a concentration-dependent increase in cAMP in primary Schwann cells, in the Schwann cell line SW10, and in HEK293T cells overexpressing the GPCR Adgrg6 (also known as Gpr126). By contrast, naive HEK293T cells and HEK293T cells expressing several other GPCRs did not react to the flexible tail, and ablation of Gpr126 from SW10 cells abolished the flexible tail-induced cAMP response. The flexible tail contains a polycationic cluster (KKRPKPG) similar to the GPRGKPG motif of the Gpr126 agonist type-IV collagen. A KKRPKPG-containing PrPC -derived peptide (FT 23-50) sufficed to induce a Gpr126-dependent cAMP response in cells and mice, and improved myelination in hypomorphic gpr126 mutant zebrafish (Danio rerio). Substitution of the cationic residues with alanines abolished the biological activity of both FT 23-50 and the equivalent type-IV collagen peptide. We conclude that PrPC promotes myelin homeostasis through flexible tail-mediated Gpr126 agonism. As well as clarifying the physiological role of PrPC, these observations are relevant to the pathogenesis of demyelinating polyneuropathies - common debilitating diseases for which there are limited therapeutic options.

Document Type: Article
Source: Scopus


Murphy, D.a e , Cieply, B.b , Carstens, R.b , Ramamurthy, V.c , Stoilov, P.d
The Musashi 1 Controls the Splicing of Photoreceptor-Specific Exons in the Vertebrate Retina
(2016) PLoS Genetics, 12 (8), art. no. e1006256, 27 p. 

DOI: 10.1371/journal.pgen.1006256

a Department of Biochemistry, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, United States
b Department of Medicine, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
c Departments of Biochemistry, Ophthalmology and Center for Neuroscience, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, United States
d Department of Biochemistry and Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, United States
e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Alternative pre-mRNA splicing expands the coding capacity of eukaryotic genomes, potentially enabling a limited number of genes to govern the development of complex anatomical structures. Alternative splicing is particularly prevalent in the vertebrate nervous system, where it is required for neuronal development and function. Here, we show that photoreceptor cells, a type of sensory neuron, express a characteristic splicing program that affects a broad set of transcripts and is initiated prior to the development of the light sensing outer segments. Surprisingly, photoreceptors lack prototypical neuronal splicing factors and their splicing profile is driven to a significant degree by the Musashi 1 (MSI1) protein. A striking feature of the photoreceptor splicing program are exons that display a "switch-like" pattern of high inclusion levels in photoreceptors and near complete exclusion outside of the retina. Several ubiquitously expressed genes that are involved in the biogenesis and function of primary cilia produce highly photoreceptor specific isoforms through use of such “switch-like” exons. Our results suggest a potential role for alternative splicing in the development of photoreceptors and the conversion of their primary cilia to the light sensing outer segments. © 2016 Murphy et al.

Document Type: Article
Source: Scopus


Myers, N.a , Lester, R.b , Hopper, K.c
Reflections on the anthropology of public psychiatry: The potential and limitations of transdisciplinary work
(2016) Transcultural Psychiatry, 53 (4), pp. 419-426. 

DOI: 10.1177/1363461516663883

a Southern Methodist University, Department of Anthropology, Office 440, Lab 455, Dallas, TX, United States
b Washington University St. Louis, United States
c Columbia University, United States

Document Type: Conference Paper
Source: Scopus


Sommers, M.
New directions for auditory training: Introduction
(2016) Journal of Speech, Language, and Hearing Research, 59 (4), pp. 860-861. 

DOI: 10.1044/2016_JSLHR-H-16-0299

Washington University, St. Louis, MO, United States

Document Type: Article
Source: Scopus


Barcroft, J.a , Spehar, B.b , Tye-Murray, N.b , Sommers, M.a
Task- and talker-specific gains in auditory training
(2016) Journal of Speech, Language, and Hearing Research, 59 (4), pp. 862-870. Cited 1 time.

DOI: 10.1044/2016_JSLHR-H-15-0170

a Washington University, St. Louis, United States
b Washington University, St. Louis School of Medicine, United States

Purpose: This investigation focused on generalization of outcomes for auditory training by examining the effects of task and/or talker overlap between training and at test. Method: Adults with hearing loss completed 12 hr of meaning-oriented auditory training and were placed in a group that trained on either multiple talkers or a single talker. A control group also completed 12 hr of training in American Sign Language. The experimental group’s training included a 4-choice discrimination task but not an open-set sentence test. The assessment phase included the same 4-choice discrimination task and an open-set sentence test, the Iowa Sentences Test (Tyler, Preece, & Tye-Murray, 1986). Results: Improvement on 4-choice discrimination was observed in the experimental group as compared with the control group. Gains were (a) highest when the task and talker were the same between training and assessment; (b) second highest when the task was the same but the talker only partially so; and (c) third highest when task and talker were different. Conclusions: The findings support applications of transfer-appropriate processing to auditory training and favor tailoring programs toward the specific needs of the individuals being trained for tasks, talkers, and perhaps, for stimuli, in addition to other factors. © 2016 American Speech-Language-Hearing Association.

Document Type: Article
Source: Scopus


Tye-Murray, N.a , Spehar, B.a , Sommers, M.b , Barcroft, J.b
Auditory training with frequent communication partners
(2016) Journal of Speech, Language, and Hearing Research, 59 (4), pp. 871-875. Cited 2 times.

DOI: 10.1044/2016_JSLHR-H-15-0171

a Washington University in St. LouisMO, United States
b Washington University in St. Louis School of MedicineMO, United States

Purpose: Individuals with hearing loss engage in auditory training to improve their speech recognition. They typically practice listening to utterances spoken by unfamiliar talkers but never to utterances spoken by their most frequent communication partner (FCP)—speech they most likely desire to recognize—under the assumption that familiarity with the FCP’s speech limits potential gains. This study determined whether auditory training with the speech of an individual’s FCP, in this case their spouse, would lead to enhanced recognition of their spouse’s speech. Method: Ten couples completed a 6-week computerized auditory training program in which the spouse recorded the stimuli and the participant (partner with hearing loss) completed auditory training that presented recordings of their spouse. Results: Training led participants to better discriminate their FCP’s speech. Responses on the Client Oriented Scale of Improvement (Dillon, James, & Ginis, 1997) indicated subjectively that training reduced participants’ communication difficulties. Peformance on a word identification task did not change. Conclusions: Results suggest that auditory training might improve the ability of older participants with hearing loss to recognize the speech of their spouse and might improve communication interactions between couples. The results support a task-appropriate processing framework of learning, which assumes that human learning depends on the degree of similarity between training tasks and desired outcomes. © 2016 American Speech-Language-Hearing Association.

Document Type: Article
Source: Scopus


Stein, P.S.G.a , Daniels-McQueen, S.a , Lai, J.a , Liu, Z.a b , Corman, T.S.a c
Modular organization of the multipartite central pattern generator for turtle rostral scratch: Knee-related interneurons during deletions
(2016) Journal of Neurophysiology, 115 (6), pp. 3130-3139. 

DOI: 10.1152/jn.00871.2015

a Department of Biology, Washington University, St. Louis, MO, United States
b Dept. of Diagnostic Radiology, Boston University Medical Center, 820 Harrison Ave., FGH Building (3rd floor), Boston, MA, United States
c Dept. of Genetics, Perelman School of Medicine, University of Pennsylvania, 415 Curie Blvd., Philadelphia, PA, United States

Central pattern generators (CPGs) are neuronal networks in the spinal cord that generate rhythmic patterns of motor activity in the absence of movement-related sensory feedback. For many vertebrate rhythmic behaviors, CPGs generate normal patterns of motor neuron activities as well as variations of the normal patterns, termed deletions, in which bursts in one or more motor nerves are absent from one or more cycles of the rhythm. Prior work with hip-extensor deletions during turtle rostral scratch supports hypotheses of hip-extensor interneurons in a hip-extensor module and of hip-flexor interneurons in a hip-flexor module. We present here single-unit interneuronal recording data that support hypotheses of knee-extensor interneurons in a knee-extensor module and of kneeflexor interneurons in a knee-flexor module. Members of knee-related modules are not members of hip-related modules and vice versa. These results in turtle provide experimental support at the single-unit interneuronal level for the organizational concept that the rostralscratch CPG for the turtle hindlimb is multipartite, that is, composed of more than two modules. This work, when combined with experimental and computational work in other vertebrates, does not support the classical view that the vertebrate limb CPG is bipartite with only two modules, one controlling all the flexors of the limb and the other controlling all the extensors of the limb. Instead, these results support the general principle that spinal CPGs are multipartite. © 2016 the American Physiological Society.

Author Keywords
Central pattern generator;  Fictive motor rhythms;  Module;  Scratch;  Spinal cord

Document Type: Article
Source: Scopus


Sun, M.-Y.a , Izumi, Y.a c , Benz, A.a , Zorumski, C.F.a b c , Mennerick, S.a b c
Endogenous 24S-hydroxycholesterol modulates NMDAR-mediated function in hippocampal slices
(2016) Journal of Neurophysiology, 115 (3), pp. 1263-1272. 

DOI: 10.1152/jn.00890.2015

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

N-methyl-Daspartate receptors (NMDARs), a major subtype of glutamate receptors mediating excitatory transmission throughout the central nervous system (CNS), play critical roles in governing brain function and cognition. Because NMDAR dysfunction contributes to the etiology of neurological and psychiatric disorders including stroke and schizophrenia, NMDAR modulators are potential drug candidates. Our group recently demonstrated that the major brain cholesterol metabolite, 24S-hydroxycholesterol (24S-HC), positively modulates NMDARs when exogenously administered. Here, we studied whether endogenous 24S-HC regulates NMDAR activity in hippocampal slices. In CYP46A1-1- (knockout; KO) slices where endogenous 24S-HC is greatly reduced, NMDAR tone, measured as NMDAR-to-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid receptor (AMPAR) excitatory postsynaptic current (EPSC) ratio, was reduced. This difference translated into more NMDAR-driven spiking in wild-type (WT) slices compared with KO slices. Application of SGE-301, a 24S-HC analog, had comparable potentiating effects on NMDAR EPSCs in both WT and KO slices, suggesting that endogenous 24S-HC does not saturate its NMDAR modulatory site in ex vivo slices. KO slices did not differ from WT slices in either spontaneous neurotransmission or in neuronal intrinsic excitability, and exhibited LTP indistinguishable from WT slices. However, KO slices exhibited higher resistance to persistent NMDAR-dependent depression of synaptic transmission induced by oxygen-glucose deprivation (OGD), an effect restored by SGE- 301. Together, our results suggest that loss of positive NMDAR tone does not elicit compensatory changes in excitability or transmission, but it protects transmission against NMDAR-mediated dysfunction. We expect that manipulating this endogenous NMDAR modulator may offer new treatment strategies for neuropsychiatric dysfunction. © 2016 the American Physiological Society.

Author Keywords
24S-hydroxycholesterol;  CYP46A1 knockout mice;  Hippocampal slice;  NMDAR

Document Type: Article
Source: Scopus


Tauchi, R.a , Lee, S.-H.b , Kim, J.-Y.c , Kim, Y.-C.d , Peters, C.c , Imagama, S.a , Ishiguro, N.a , Buchowski, J.c , Riew, K.D.e
Postoperative severe headache following cervical posterior surgical fixation from C2 distally
(2016) Asian Spine Journal, 10 (4), pp. 728-733. 

DOI: 10.4184/asj.2016.10.4.728

a Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
b Department of Orthopaedic Surgery, Kyung-Hee University School of Medicine, Seoul, South Korea
c Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, United States
d Department of Orthopaedic Surgery, Hallym University Sacred Heart Hospital, Seoul, South Korea
e Department of Orthopaedic Surgery, Columbia University, New York, NY, United States

Study Design: Retrospective study.Purpose: To identify the prevalence of severe headache occurring after cervical posterior surgical fixation (PSF) and to evaluate theclinical and radiological findings associated with severe headache after surgery.Overview of Literature: Several studies have reported on the axial pain after cervical surgery. However, to our knowledge, the incidenceof severe headache after cervical PSF has not been elucidated.Methods: The medical records and radiological assessment of patients who underwent surgical treatment from August 2002 to May2012 were reviewed to identify the prevalence and risk factors for severe headaches occurring following PSF from C2 distally. Neckdisability index scores (NDI) (the item for neck pain), the type of C2 screw, number of cervical fused levels (1-6), and smoking habitwere calculated preoperatively and postoperatively. In addition, radiological parameters (T1 slope angle, C1/2 angle, C2-7 Cobbangle, C2-7 sagittal vertical axis and C1-implant distance) were assessed for all patients. Severe headache was defined as a highNDI headache score (>4 out of 5).Results: Eighty-two patients met the inclusion criteria. The mean age was 59.2 years (range, 21-78 years), and the mean number offused levels was 5.1. The mean follow-up period was 2.9 years (range, 1-10.9 years). While only one severe headache occurred denovo postoperatively in a patient in the C3 or C4 distally group (total 30 patients, average age of 50.2 years), 11 patients in the C2 distallygroup (p =0.04) had severe headache occur postoperatively. The radiological parameters were not significantly different betweenthe postoperative milder headache and severe headache (SH) groups. The SH group had a significantly higher preoperative NDI score(neck pain) (p <0.01).Conclusions: Newly occurring severe headaches can occur in 18% of patients after PSF from C2 distally. The patients with newlyoccurring severe headaches had significantly higher preoperative NDI score (neck pain). © 2016 by Korean Society of Spine Surgery.

Author Keywords
Cervical;  Headache;  Posterior surgical fixation;  Surgery

Document Type: Article
Source: Scopus


Zhang, B., Zou, J., Han, L., Rensing, N., Wong, M.
Microglial activation during epileptogenesis in a mouse model of tuberous sclerosis complex
(2016) Epilepsia, 57 (8), pp. 1317-1325. 

DOI: 10.1111/epi.13429

Department of Neurology and the Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Objective: Tuberous sclerosis complex (TSC) is a genetic disorder, characterized by tumor formation in multiple organs and severe neurologic manifestations, including epilepsy, intellectual disability, and autism. Abnormalities of both neurons and astrocytes have been implicated in contributing to the neurologic phenotype of TSC, but the role of microglia in TSC has not been investigated. The objectives of this study were to characterize microglial activation in a mouse model of TSC, involving conditional inactivation of the Tsc1 gene predominantly in glial cells (Tsc1GFAPCKO mice), and to test the hypothesis that microglial activation contributes to epileptogenesis in this mouse model. Methods: Microglial and astrocyte activation was examined in Tsc1GFAPCKO mice by ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein immunohistochemistry. Cytokine and chemokine expression was evaluated with quantitative polymerase chain reaction. Seizures were monitored by video–electroencephalography (EEG). The effect of minocycline in inhibiting microglial and astrocyte activation, cytokine expression, and seizures was tested. Results: Microglial cell number and size were increased in cortex and hippocampus of 3- to 4-week-old Tsc1GFAPCKO mice, which correlated with the onset of seizures. Minocycline treatment prevented the increase in number and cell size of microglia in 4-week-old Tsc1GFAPCKO mice. However, minocycline treatment had no effect on astrocyte proliferation and cytokine/chemokine expression and the progression of seizures in Tsc1GFAPCKO mice. Significance: Microglia cell number and size are abnormal in Tsc1GFAPCKO mice, and minocycline treatment inhibits this microglia activation, but does not suppress seizures. Microglia may play a role in the neurologic manifestations of TSC, but additional studies are needed in other models and human studies to determine whether microglia are critical for epileptogenesis in TSC. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy

Author Keywords
Astrocyte;  Epilepsy;  Inflammation;  Microglia;  Seizure

Document Type: Article
Source: Scopus


Wilson, T.J.a , McCoy, K.E.b , Al-Holou, W.N.a , Molina, S.L.b , Smyth, M.D.b , Sullivan, S.E.a
Comparison of the accuracy and proximal shunt failure rate of freehand placement versus intraoperative guidance in parietooccipital ventricular catheter placement
(2016) Neurosurgical Focus, 41 (3), art. no. E10, . 

DOI: 10.3171/2016.5.FOCUS16159

a Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
b Department of Neurosurgery, Washington University in St. LouisMO, United States

Objective The aim of this paper is to compare the accuracy of the freehand technique versus the use of intraoperative guidance (either ultrasound guidance or frameless stereotaxy) for placement of parietooccipital ventricular catheters and to determine factors associated with reduced proximal shunt failure. Met hods This retrospective cohort study included all patients from 2 institutions who underwent a ventricular cerebrospinal fluid (CSF) shunting procedure in which a new parietooccipital ventricular catheter was placed between January 2005 and December 2013. Data abstracted for each patient included age, sex, method of ventricular catheter placement, side of ventricular catheter placement, Evans ratio, and bifrontal ventricular span. Postoperative radiographic studies were reviewed for accuracy of ventricular catheter placement. Medical records were also reviewed for evidence of shunt failure requiring revision. Standard statistical methods were used for analysis. Resu lts A total of 257 patients were included in the study: 134 from the University of Michigan and 123 from Washington University in St. Louis. Accurate ventricular catheter placement was achieved in 81.2% of cases in which intraoperative guidance was used versus 67.3% when the freehand technique was used. Increasing age reduced the likelihood of accurate catheter placement (OR 0.983, 95% CI 0.971-0.995; p = 0.005), while the use of intraoperative guidance significantly increased the likelihood (OR 2.809, 95% CI 1.406-5.618; p = 0.016). During the study period, 108 patients (42.0%) experienced shunt failure, 79 patients (30.7%) had failure involving the proximal catheter, and 53 patients (20.6%) had distal failure (valve or distal catheter). Increasing age reduced the likelihood of being free from proximal shunt failure (OR 0.983, 95% CI 0.970-0.995; p = 0.008), while both the use of intraoperative guidance (OR 2.385, 95% CI 1.227-5.032; p = 0.011), and accurate ventricular catheter placement (OR 3.424, 95% CI 1.796-6.524; p = 0.009) increased the likelihood. Conc lusions The use of intraoperative guidance during parietooccipital ventricular catheter placement as part of a CSF shunt system significantly increases the likelihood of accurate catheter placement and subsequently reduces the rate of proximal shunt failure. © AANS, 2016.

Author Keywords
Cerebrospinal fluid;  Ventricular catheter;  Ventriculoperitoneal shunt

Document Type: Article
Source: Scopus



McDaniel, M.A.a , Bugg, J.M.b , Liu, Y.c , Brick, J.d
When does the test-study-test sequence optimize learning and retention?
(2015) Journal of experimental psychology. Applied, 21 (4), pp. 370-382. 

DOI: 10.1037/xap0000063

a Department of Psychology, Washington University in St. Louis
b Department of Psychology, Washington University in St. Louis
c Department of Psychology, Washington University in St. Louis
d Department of Psychology, Washington University in St. Louis

In educational learning contexts, unlike typical contemporary laboratory paradigms, students have repeated opportunities to study and learn target material, thereby potentially allowing different sequences of testing and studying. We investigated learning and retention after several plausible sequences that were patterned on a classic memory paradigm. After initially reading a research methods text, 2 days later in 1 condition participants repeatedly restudied the material 3 times (SSS), in another condition they engaged in a test-restudy-test sequence (TST), and in a third condition participants repeatedly tested on the studied material (3 times: TTT). Participants received a final test 5 days later. In Experiment 1, both TST and TTT produced better final performance than did SSS; however, TST was not better than TTT. In Experiment 2 the TST condition was altered so that after the first test, correct/incorrect feedback was provided and the test and feedback were available during the study phase. With this protocol, TST produced better learning and retention than did TTT or SSS. These findings suggest possible critical aspects regarding test feedback and the availability of previous tests for helping students to optimize their restudy efforts after low- or no-stakes quizzes. (c) 2015 APA, all rights reserved).

Document Type: Article
Source: Scopus


September 1, 2016


Kafashan, M.a , Nandi, A.a , Ching, S.a b
Relating observability and compressed sensing of time-varying signals in recurrent linear networks
(2016) Neural Networks, 83, pp. 11-20. 

DOI: 10.1016/j.neunet.2016.07.007

a Department of Electrical and Systems Engineering, Washington University in St. Louis, One Brookings Drive, Campus Box 1042, United States
b Division of Biology and Biomedical Sciences, Washington University in St. Louis, One Brookings Drive, Campus Box 1042, United States

In this paper, we study how the dynamics of recurrent networks, formulated as general dynamical systems, mediate the recovery of sparse, time-varying signals. Our formulation resembles the well-described problem of compressed sensing, but in a dynamic setting. We specifically consider the problem of recovering a high-dimensional network input, over time, from observation of only a subset of the network states (i.e., the network output). Our goal is to ascertain how the network dynamics may enable recovery, even if classical methods fail at each time instant. We are particularly interested in understanding performance in scenarios where both the input and output are corrupted by disturbance and noise, respectively. Our main results consist of the development of analytical conditions, including a generalized observability criterion, that ensure exact and stable input recovery in a dynamic, recurrent network setting. © 2016 Elsevier Ltd

Author Keywords
l1 minimization;  Linear dynamical systems;  Over-actuated systems;  Recurrent networks;  Sparse input

Document Type: Article
Source: Scopus


Custer, P.L.a b , Fitzgerald, M.E.c , Herman, D.C.a d , Lee, P.P.a e f , Cowan, C.L.a g , Cantor, L.B.h i , Bartley, G.B.j k
Building a Culture of Safety in Ophthalmology
(2016) Ophthalmology, 123 (9), pp. S40-S45. Cited 1 time.

DOI: 10.1016/j.ophtha.2016.06.019

a Director, American Board of Ophthalmology, Bala Cynwyd, Pennsylvania, United States
b Professor of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States
c Public Director, American Board of Ophthalmology, Bala Cynwyd, Pennsylvania, United States
d CEO, Essentia Health, Duluth, Minnesota, United States
e Vice Chair, American Board of Ophthalmology, Bala Cynwyd, Pennsylvania, United States
f F. Bruce Fralick Professor and Chair of the Department of Ophthalmology, and Director of the W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, United States
g Clinical Professor of Ophthalmology at Georgetown University Medical Center, Washington, DC, United States
h Chairman and Professor of Ophthalmology, Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education, and Director of the Glaucoma Service, Department of Ophthalmology, Eugene and Marilyn Glick Eye Institute, Indiana University, Indianapolis, Indiana, United States
i Senior Secretary for Clinical Education, American Academy of Ophthalmology, San Francisco, California, United States
j Emeritus Director, American Board of Ophthalmology, Bala Cynwyd, Pennsylvania, United States
k Louis J. and Evelyn Krueger Professor of Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States

Patient safety focused on a reduction in both procedural and diagnostic error is the number one concern of the United States healthcare system in the 21st century. The American Board of Ophthalmology has a longstanding interest in patient safety, and in 2015, teamed with the American Academy of Ophthalmology to convene all ophthalmology subspecialties and other prominent national organizations to address patient safety in ophthalmology. This article reviews the topic and highlights concerns for ophthalmologists. © 2016 American Academy of Ophthalmology

Document Type: Conference Paper
Source: Scopus


Gerassi, L., Jonson-Reid, M., Drake, B.
Sexually Transmitted Infections in a Sample of At-Risk Youth: Roles of Mental Health and Trauma Histories
(2016) Journal of Child and Adolescent Trauma, 9 (3), pp. 209-216. 

DOI: 10.1007/s40653-015-0074-8

Brown School of Social Work, Washington University in St. Louis, Saint Louis, MO, United States

Little is known about whether there are specific subpopulations of youth with known problem behaviors that are more likely to engage in sexual risk behaviors. This study’s sample (n = 4117) was drawn from a larger longitudinal administrative data, consisting of young adults with child abuse and/or poverty histories and records of some form of high-risk behavior or mental health diagnosis during adolescence. A cluster-controlled, logistic regression resulted in 11 statistically significant relationships. Youth treated for a mental health disorder and experienced multiple forms of abuse were more likely to be treated for Sexually Transmitted Infections (STIs). Youth who were delinquent, treated for substance abuse and had substance use related offenses were less likely to be treated for STIs. Youth treated for STIs were more likely to be identified through mental health systems or child protective services system than through known delinquent behaviors. Health care providers treating youth for STIs should explore the possible role of mental health and trauma histories. © 2015, Springer International Publishing.

Author Keywords
Adolescents;  Child abuse;  Child protective services;  Mental health;  Mental health systems;  Sexually transmitted infections;  Trauma;  Youth

Document Type: Article
Source: Scopus


Sy, J.R.a , Green, L.b , Gratz, O.c , Ervin, T.c
An Evaluation of the Effects of a Mild Delayed Verbal Punisher on Choice of an Immediate Reinforcer by Children With Autism
(2016) Behavior Modification, 40 (5), pp. 713-730. 

DOI: 10.1177/0145445515622382

a University of Maryland, Baltimore County, MD, United States
b Washington University in St. LouisMO, United States
c Saint Louis UniversityMO, United States

Different combinations of immediate and delayed consequences differentially affect choice. Basic research has found that nonhuman animals are more likely to choose an alternative that produces an immediate reinforcer that is followed by a delayed punisher as the delay to punishment increases. The purpose of the current effort was to examine the choices of three individuals with autism when they were given the choice between receiving a larger amount of preferred food followed by a mild, delayed verbal punisher and a smaller amount of the preferred food. A secondary purpose was to determine whether signal presence and duration would affect the efficacy of the punisher (i.e., whether children would be more likely to select the smaller reward that was not followed by a delayed punisher). Results were idiosyncratic across children and highlight the need to evaluate choice under multiple arrangements. © 2016, © The Author(s) 2016.

Author Keywords
choice;  delayed punishment;  rule-following

Document Type: Article
Source: Scopus


Cheah, C.Y.a b c , Bröckelmann, P.J.d e , Chihara, D.a , Moskowitz, A.J.e , Engert, A.d , Jerkeman, M.f , El-Galaly, T.C.g , Augustson, B.b c , Vose, J.h , Bartlett, N.L.i , Villa, D.j , Connors, J.M.j , Feldman, T.k , Pinnix, C.C.l , Milgrom, S.A.l , Dabaja, B.l , Oki, Y.a , Fanale, M.A.a
Clinical characteristics and outcomes of patients with Hodgkin lymphoma with central nervous system involvement: An international multicenter collaboration
(2016) American Journal of Hematology, 91 (9), pp. 894-899. 

DOI: 10.1002/ajh.24429

a Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX, United States
b Department of Haematology, Sir Charles Gairdner Hospital and Pathwest Laboratory Medicine WA, Perth, WA, Australia
c University of Western Australia, Crawley, WA, Australia
d Department of Internal Medicine and German Hodgkin Study Group, University Hospital of Cologne, Cologne, Germany
e Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States
f Department of Oncology, Lund University, Lund, Sweden
g Department of Hematology, Aalborg University Hospital, Aalborg, Denmark
h Department of Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE, United States
i Division of Oncology, Washington University, St Louis, MO, United States
j British Columbia Cancer Agency Centre for Lymphoid Cancer, Vancouver, BC, Canada
k Department of Hematology, Hackensack University Cancer Center, Hackensack, NJ, United States
l Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States

Central nervous system (CNS) involvement is rare in patients with Hodgkin lymphoma (HL). Thus, the clinical features and outcomes are not well described. Cases of histologically confirmed CNS HL diagnosed between 1995 and 2015 were retrospectively identified in institutional (n = 7), national (n = 2), and cooperative group (n = 1) databases. We screened 30,781 patients with HL in our combined databases and identified 21 patients meeting eligibility criteria, an estimated frequency of 0.07%. CNS involvement was present at initial diagnosis in 10 patients (48%) and a feature of relapsed/refractory disease in 11 (52%). Among these 11 patients, the median time from initial diagnosis of HL to development of CNS involvement was 1.9 years (range 0.4–6.6) and the median number of prior lines of therapy was 2 (range 1–7). Altogether, treatments included radiation, multiagent systemic chemotherapy, combined modality therapy, and subtotal resection. The overall response rate was 65%. After a median follow-up of 3.6 years (range 0.8–13.2) from diagnosis of CNS HL, the median PFS and OS were 7.6 and 29 months, respectively. CNS involvement as a feature of relapsed/refractory disease was adversely prognostic for both PFS and OS; however, four patients remain alive and free of relapse at 7–78 months follow-up. CNS involvement in HL is exceedingly rare and has a distinct clinical presentation with predilection for parenchymal lesions with dural extension. Around one-quarter of patients, mostly with CNS involvement at initial HL diagnosis, experience prolonged disease-free survival. Am. J. Hematol. 91:894–899, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Document Type: Article
Source: Scopus


Kumar, G., Ching, S.
The geometry of plasticity-induced sensitization in isoinhibitory rate motifs
(2016) Neural Computation, 28 (9), pp. 1889-1926. 

DOI: 10.1162/NECO_a_00865

Electrical and Systems Engineering Washington University in St. Louis, St. Louis, MO, United States

A well-known phenomenon in sensory perception is desensitization, wherein behavioral responses to persistent stimuli become attenuated over time. In this letter, our focus is on studying mechanisms through which desensitization may be mediated at the network level and, specifically, how sensitivity changes arise as a function of long-term plasticity. Our principal object of study is a generic isoinhibitory motif: a small excitatory-inhibitory network with recurrent inhibition. Such a motif is of interest due to its overrepresentation in laminar sensory network architectures. Here, we introduce a sensitivity analysis derived from control theory in which we characterize the fixed-energy reachable set of themotif. This set describes the regions of the phase-space that are more easily (in terms of stimulus energy) accessed, thus providing a holistic assessment of sensitivity.We specifically focus on how the geometry of this set changes due to repetitive application of a persistent stimulus. We find that for certain motif dynamics, this geometry contracts along the stimulus orientationwhile expanding in orthogonal directions. In other words, the motif not only desensitizes to the persistent input, but heightens its responsiveness (sensitizes) to those that are orthogonal.We develop a perturbation analysis that links this sensitization to both plasticity-induced changes in synaptic weights and the intrinsic dynamics of the network, highlighting that the effect is not purely due to weight-dependent disinhibition. Instead, this effect depends on the relative neuronal time constants and the consequent stimulus-induced drift that arises in the motif phase-space. For tightly distributed (but random) parameter ranges, sensitization is quite generic and manifests in larger recurrent E-I networks within which the motif is embedded. © 2016 Massachusetts Institute of Technology.

Document Type: Article
Source: Scopus


Ambike, S.a , Mattos, D.b , Zatsiorsky, V.M.c , Latash, M.L.c
Unsteady steady-states: central causes of unintentional force drift
(2016) Experimental Brain Research, pp. 1-15. Article in Press. 

DOI: 10.1007/s00221-016-4757-7

a Department of Health and Kinesiology, Purdue University, 800 West Stadium Ave, West Lafayette, IN, United States
b Program in Occupational Therapy, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Kinesiology, The Pennsylvania State University, University Park, PA, United States

We applied the theory of synergies to analyze the processes that lead to unintentional decline in isometric fingertip force when visual feedback of the produced force is removed. We tracked the changes in hypothetical control variables involved in single fingertip force production based on the equilibrium-point hypothesis, namely the fingertip referent coordinate (RFT) and its apparent stiffness (CFT). The system’s state is defined by a point in the {RFT; CFT} space. We tested the hypothesis that, after visual feedback removal, this point (1) moves along directions leading to drop in the output fingertip force, and (2) has even greater motion along directions that leaves the force unchanged. Subjects produced a prescribed fingertip force using visual feedback and attempted to maintain this force for 15 s after the feedback was removed. We used the “inverse piano” apparatus to apply small and smooth positional perturbations to fingers at various times after visual feedback removal. The time courses of RFT and CFT showed that force drop was mostly due to a drift in RFT toward the actual fingertip position. Three analysis techniques, namely hyperbolic regression, surrogate data analysis, and computation of motor-equivalent and non-motor-equivalent motions, suggested strong covariation in RFT and CFT stabilizing the force magnitude. Finally, the changes in the two hypothetical control variables {RFT; CFT} relative to their average trends also displayed covariation. On the whole, the findings suggest that unintentional force drop is associated with (a) a slow drift of the referent coordinate that pulls the system toward a low-energy state and (b) a faster synergic motion of RFT and CFT that tends to stabilize the output fingertip force about the slowly drifting equilibrium point. © 2016 Springer-Verlag Berlin Heidelberg

Author Keywords
Apparent stiffness;  Finger force;  Isometric;  Uncontrolled manifold

Document Type: Article in Press
Source: Scopus


Gilbert, K.a , Luking, K.b , Pagliaccio, D.c , Luby, J.a , Barch, D.a d e
Dampening, Positive Rumination, and Positive Life Events: Associations with Depressive Symptoms in Children at Risk for Depression
(2016) Cognitive Therapy and Research, pp. 1-12. Article in Press. 

DOI: 10.1007/s10608-016-9798-5

a Department of Psychiatry, Washington University in St. Louis, 4444 Forest Park Avenue, St. Louis, MO, United States
b Department of Psychology, Stony Brook University, Stony Brook, NY, United States
c Emotion and Development Branch, National Institute of Mental Health, Bethesda, MD, United States
d Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
e Department of Radiology, Washington University in St. Louis, St Louis, MO, United States

Blunted positive affect is characteristic of depression. Altered positive affect regulation may contribute to this blunting, and two regulation strategies, dampening positive affect and positive rumination, have been implicated in depression. However, the conditions under which these strategies impart risk/protective effects prior to onset of depression are unknown. The current study examined 81 healthy children (age 7–10) at low and high risk for depression on the basis of maternal history of depression and tested how dampening and positive rumination interacted with the experience of recent positive life events to predict depressive symptoms. Children at high and low risk did not differ in their use of dampening or positive rumination. However, elevated use of dampening in the context of many positive life events predicted current depressive symptoms, and specifically anhedonic symptoms, in children at low-risk for depression. These findings held when controlling for negative rumination and negative life events. Positive rumination did not interact with positive life events but was associated with higher depressive symptoms in high-risk children. Results indicate that prior to the onset of depression, positive life events may impart risk when dampening positive affect is utilized in this context, while positive rumination may increase risk for depressive symptoms. © 2016 Springer Science+Business Media New York

Author Keywords
Children;  Dampening;  Positive affect regulation;  Positive rumination;  Risk for depression

Document Type: Article in Press
Source: Scopus


Bierut, T.a , Krauss, M.J.b , Sowles, S.J.b , Cavazos-Rehg, P.A.b
Exploring Marijuana Advertising on Weedmaps, a Popular Online Directory
(2016) Prevention Science, pp. 1-10. Article in Press. 

DOI: 10.1007/s11121-016-0702-z

a Hamilton College, Clinton, NY, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Box 8134, St. Louis, MO, United States

With an increase in the legalization of recreational marijuana across the USA, advertising for marijuana products is more widespread, especially on the Internet where such practices pose a regulatory challenge. In this study, we examined the content of marijuana advertising on Weedmaps, a popular website that markets marijuana retailers online. A total of 146 recreational marijuana retailers in Colorado and Washington were examined on Weedmaps. We studied the age verification practices made in retailers’ own websites, the presence of health claims they made about marijuana on Weedmaps, and the characteristics of followers of Weedmaps on social media sites. Many retailers had no security measure to determine age (41 % in Colorado, 35 % in Washington). Approximately 61 % of retailers in Colorado and 44 % in Washington made health claims about the benefits of marijuana, including anxiety reduction, treatment of depression, insomnia, and pain/inflammation. Inferred demographic characteristics of followers of Weedmaps on Twitter and Instagram revealed that over 60 % were male and nearly 70 % or more were age 20–29 years old, yet some (15–18 %) were under the age of 20. Our findings indicate that marijuana retailers have a visible presence on the Internet. Potential customers might be enticed by retailers who tout health claims about marijuana use. It may also be appealing for a younger demographic to overlook age restrictions and engage with marijuana retailers via social media. As a whole, our findings can help to guide future policy making on the issue of marijuana-related advertising. © 2016 Society for Prevention Research

Author Keywords
Advertising;  Cannabis;  Marijuana;  Social media

Document Type: Article in Press
Source: Scopus


Agarwal, P.K.a , Finley, J.R.b , Rose, N.S.c , Roediger, H.L., IIIa
Benefits from retrieval practice are greater for students with lower working memory capacity
(2016) Memory, pp. 1-8. Article in Press. 

DOI: 10.1080/09658211.2016.1220579

a Department of Psychology, Washington University in St. Louis, St. Louis, MO, USA
b Department of Psychology, Fontbonne University, Clayton, MO, USA
c Department of Psychology, University of Notre Dame, Notre Dame, IN, USA

We examined the effects of retrieval practice for students who varied in working memory capacity as a function of the lag between study of material and its initial test, whether or not feedback was given after the test, and the retention interval of the final test. We sought to determine whether a blend of these conditions exists that maximises benefits from retrieval practice for lower and higher working memory capacity students. College students learned general knowledge facts and then restudied the facts or were tested on them (with or without feedback) at lags of 0–9 intervening items. Final cued recall performance was better for tested items than for restudied items after both 10 minutes and 2 days, particularly for longer study–test lags. Furthermore, on the 2-day delayed test the benefits from retrieval practice with feedback were significantly greater for students with lower working memory capacity than for students with higher working memory capacity (r = −.42). Retrieval practice may be an especially effective learning strategy for lower ability students. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Author Keywords
feedback;  lag;  retrieval practice;  Testing effect;  working memory

Document Type: Article in Press
Source: Scopus


Freedland, K.E.a , Lemos, M.b , Doyle, F.c , Steinmeyer, B.C.a , Csik, I.a , Carney, R.M.a
The Techniques for Overcoming Depression Questionnaire: Mokken Scale Analysis, Reliability, and Concurrent Validity in Depressed Cardiac Patients
(2016) Cognitive Therapy and Research, pp. 1-13. Article in Press. 

DOI: 10.1007/s10608-016-9797-6

a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Universidad EAFIT, Medellín, Colombia
c Division of Population Health Sciences (Psychology), Royal College of Surgeons in Ireland, Dublin, Ireland

The Techniques for Overcoming Depression (TOD) questionnaire assesses the frequency with which patients being treated for depression use cognitive-behavioral techniques in daily life. This study examined its latent structure, reliability and concurrent validity in depressed cardiac patients. The TOD was administered at the initial and final treatment sessions in three trials of cognitive behavior therapy (CBT) (n = 260) for depression in cardiac patients. Mokken scaling was used to determine its dimensionality. The TOD is unidimensional in depressed cardiac patients, both at the initial evaluation (H = .46) and the end of treatment (H = .47). It is sensitive to change and the total score correlates with therapist ratings of the patient’s socialization to CBT (r = .40, p < .05), homework adherence (r = .36, p < .05), and use of cognitive-behavioral techniques (r = .51, p < .01). TOD scores were associated with post-treatment depression scores in two of the trials (p < .01 in both analyses). The TOD is a unidimensional, reliable, valid, and clinically informative measure of self-reported use of cognitive-behavioral techniques for overcoming depression in cardiac patients. Studies of the TOD in other depressed patient populations are needed. © 2016 Springer Science+Business Media New York

Author Keywords
Cognitive therapy;  Depressive disorder;  Heart diseases;  Patient compliance;  Psychometrics;  Questionnaires

Document Type: Article in Press
Source: Scopus


Sinopoli, A.a , Giuffrida, A.b , Tomasello, M.F.b , Giuffrida, M.L.b , Leone, M.c , Attanasio, F.b , Caraci, F.d , De Bona, P.e , Naletova, I.f , Saviano, M.g , Copani, A.d , Pappalardo, G.b , Rizzarelli, E.b h
Ac-LPFFD-Th: A Trehalose-Conjugated Peptidomimetic as a Strong Suppressor of Amyloid-β Oligomer Formation and Cytotoxicity
(2016) ChemBioChem, pp. 1541-1549. 

DOI: 10.1002/cbic.201600243

a PhD Program in Translational Biomedicine, University of Catania, Viale A. Doria 6, Catania, Italy
b Institute of Biostructures and Bioimaging, CNR, Via P. Gaifami 18, Catania, Italy
c Institute of Biostructures and Bioimaging, CNR, Via Mezzocannone 16, Naples, Italy
d Department of Drug Sciences, University of Catania, Viale A. Doria 6, Catania, Italy
e Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8231, St. Louis, MO, United States
f Department of Biomedical Sciences, University of Catania, Viale A. Doria 6, Catania, Italy
g Institute of Crystallography, CNR, Via G. Amendola 122/O, Bari, Italy
h Department of Chemical Sciences, University of Catania, Viale A. Doria 6, Catania, Italy

The inhibition of amyloid formation is a promising therapeutic approach for the treatment of neurodegenerative diseases. Peptide-based inhibitors, which have been widely investigated, are generally derived from original amyloid sequences. Most interestingly, trehalose, a nonreducing disaccharide of α-glucose, is effective in preventing the aggregation of numerous proteins. We have determined that the development of hybrid compounds could provide new molecules with improved properties that might synergically increase the potency of their single moieties. In this work, the ability of Ac-LPFFD-Th, a C-terminally trehalose-conjugated derivative, to slow down the Aβ aggregation process was investigated by means of different biophysical techniques, including thioflavin T fluorescence, dynamic light scattering, ESI-MS, and NMR spectroscopy. Moreover, we demonstrate that Ac-LPFFD-Th modifies the aggregation features of Aβ and protects neurons from Aβ oligomers' toxic insult. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Author Keywords
Alzheimer's disease;  amyloid beta-peptides;  inhibitors;  oligomers;  peptidomimetics;  trehalose

Document Type: Article
Source: Scopus


Li, P.a , Miao, Y.a , Dani, A.a b , Vig, M.a
α-SNAP regulates dynamic, on-site assembly and calcium selectivity of Orai1 channels
(2016) Molecular Biology of the Cell, 27 (16), pp. 2542-2553. 

DOI: 10.1091/mbc.E16-03-0163

a Department of Pathology and Immunology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Hope Center for Neurological Disorders, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Orai1 forms a highly calcium-selective pore of the calcium release activated channel, and α-SNAP is necessary for its function. Here we show that α-SNAP regulates on-site assembly of Orai1 dimers into calcium-selective multimers. We find that Orai1 is a dimer in resting primary mouse embryonic fibroblasts but displays variable stoichiometry in the plasma membrane of store-depleted cells. Remarkably, α-SNAP depletion induces formation of higher-order Orai1 oligomers, which permeate significant levels of sodium via Orai1 channels. Sodium permeation in α-SNAP-deficient cells cannot be corrected by tethering multiple Stim1 domains to Orai1 C-terminal tail, demonstrating that α-SNAP regulates functional assembly and calcium selectivity of Orai1 multimers independently of Stim1 levels. Fluorescence nanoscopy reveals sustained coassociation of α-SNAP with Stim1 and Orai1, and α- SNAP-depleted cells show faster and less constrained mobility of Orai1 within ER-PM junctions, suggesting Orai1 and Stim1 coentrapment without stable contacts. Furthermore, α-SNAP depletion significantly reduces fluorescence resonance energy transfer between Stim1 and Orai1 N-terminus but not C-terminus. Taken together, these data reveal a unique role of α-SNAP in the on-site functional assembly of Orai1 subunits and suggest that this process may, in part, involve enabling crucial low-affinity interactions between Orai1 N-terminus and Stim1. © 2016 Li, Miao, et al.

Document Type: Article
Source: Scopus


Mattingly, G.a , Anderson, R.H.b , Mattingly, S.G.b , Anderson, E.Q.b
The impact of cognitive challenges in major depression: the role of the primary care physician
(2016) Postgraduate Medicine, pp. 1-7. Article in Press. 

DOI: 10.1080/00325481.2016.1221318

a Department of Psychiatry, Washington University School of Medicine, Saint Charles, MO, USA
b Midwest Research Group, Saint Charles, MO, USA

Nearly 1 in 5 Americans will struggle with major depression in their lives; some will have recurring bouts. Recent psychiatric research has given new attention to the prevalence of cognitive deficits in major depression and the impact such deficits have on remission and overall life functioning. When depression is partially treated i.e., leaving residual symptoms, patients have higher rates of relapse and lower functional outcomes. Impaired cognitive functioning is a frequent residual symptom, persisting in about 45% of patients even when emotional symptoms have improved, and results in a disproportionate share of the functional impairment, particularly in the workplace. Patients with depression have disrupted circuitry in brain regions responsible for cognition and it is therefore important to screen depressed patients for cognitive as well as emotional symptoms. Cognitive dysfunction should be evaluated in every mood disordered patient with validated self-report scales such as the Patient Health Questionnaire-9 or the Beck Depression Inventory and objective measures of cognitive function are also very very useful. Two easily administered tests are the Trails B Test and the Digit Symbol Substitution Test. Each take less than two minutes and measure working memory, executive function, and processing speed and can track cognitive improvement in depressed patients. Treatment of cognitive dysfunction in major depression is complicated by the ‘serotonin conundrum’: SSRI’s frequently do not treat to full remission, and can cause cognitive blunting—actually adding to cognitive problems. Based on recent data including results from a recently completed meta-analysis by McIntyre and colleagues, an evidence-based algorithm for treating cognitive symptoms in depression is presented. A hierarchy of antidepressants and augmentation strategies based on the best available evidence is discussed. In conclusion, cognitive symptoms in major depressive disorder have been recognized as a target of therapeutic improvement by the FDA and have become a focus of clinical importance. © 2016 Informa UK Limited, trading as Taylor & Francis Group

Author Keywords
antidepressant;  cognition;  Depression;  disability;  duloxetine;  residual symptoms;  vortioxetine

Document Type: Article in Press
Source: Scopus


Carlozzi, N.E.a , Schilling, S.G.a b , Lai, J.-S.c , Paulsen, J.S.d e f , Hahn, E.A.c , Perlmutter, J.S.g h , Ross, C.A.i , Downing, N.R.j , Kratz, A.L.a , McCormack, M.K.k , Nance, M.A.l m , Quaid, K.A.n , Stout, J.C.o , Gershon, R.C.c p , Ready, R.E.q , Miner, J.A.a , Barton, S.K.g , Perlman, S.L.r , Rao, S.M.s , Frank, S.t , Shoulson, I.u , Marin, H.v , Geschwind, M.D.w , Dayalu, P.x , Goodnight, S.M.a , Cella, D.c
HDQLIFE: development and assessment of health-related quality of life in Huntington disease (HD)
(2016) Quality of Life Research, pp. 1-15. Article in Press. 

DOI: 10.1007/s11136-016-1386-3

a Department of Physical Medicine and Rehabilitation, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Building NCRC B14, Room G216, Ann Arbor, MI, United States
b Institute for Social Research, University of Michigan, Ann Arbor, MI, United States
c Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
d Department of Psychiatry, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States
e Department of Neurology, Carver College of Medicine, The University of Iowa, Iowa City, IA, United States
f Department of Psychology, The University of Iowa, Iowa City, IA, United States
g Departments of Neurology, Radiology, and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
h Program in Occupational Therapy and Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
i Departments of Psychiatry, Neurology, Pharmacology and Neuroscience, Johns Hopkins University, Baltimore, MD, United States
j College of Nursing, The University of Iowa, Iowa City, IA, United States
k Department of Pathology, Rowan University, Piscataway, NJ, United States
l Struthers Parkinson’s Center, Golden Valley, MN, United States
m Hennepin County Medical Center, Minneapolis, MN, United States
n Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
o School of Psychological Sciences, Monash University, Clayton, VIC, Australia
p Department of Preventative Medicine, Northwestern University, Evanston, IL, United States
q Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, United States
r Department of Neurology, David Geffen School of Medicine, UCLA, Los Angeles, CA, United States
s Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, United States
t Beth Israel Deaconess Medical Center, Boston, MA, United States
u Department of Neurology, Georgetown University, Washington, DC, United States
v Department of Psychiatry, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States
w Memory and Aging Center, UCSF, San Francisco, CA, United States
x Department of Neurology, University of Michigan, Ann Arbor, MI, United States

Purpose: Huntington disease (HD) is a chronic, debilitating genetic disease that affects physical, emotional, cognitive, and social health. Existing patient-reported outcomes (PROs) of health-related quality of life (HRQOL) used in HD are neither comprehensive, nor do they adequately account for clinically meaningful changes in function. While new PROs examining HRQOL (i.e., Neuro-QoL—Quality of Life in Neurological Disorders and PROMIS—Patient-Reported Outcomes Measurement Information System) offer solutions to many of these shortcomings, they do not include HD-specific content, nor have they been validated in HD. HDQLIFE addresses this by validating 12 PROMIS/Neuro-QoL domains in individuals with HD and by using established PROMIS methodology to develop new, HD-specific content. Methods: New item pools were developed using cognitive debriefing with individuals with HD, and expert, literacy, and translatability reviews. Existing item banks and new item pools were field tested in 536 individuals with prodromal, early-, or late-stage HD. Results: Moderate to strong relationships between Neuro-QoL/PROMIS measures and generic self-report measures of HRQOL, and moderate relationships between Neuro-QoL/PROMIS and clinician-rated measures of similar constructs supported the validity of Neuro-QoL/PROMIS in individuals with HD. Exploratory and confirmatory factor analysis, item response theory, and differential item functioning analyses were utilized to develop new item banks for Chorea, Speech Difficulties, Swallowing Difficulties, and Concern with Death and Dying, with corresponding six-item short forms. A four-item short form was developed for Meaning and Purpose. Conclusions: HDQLIFE encompasses both validated Neuro-QoL/PROMIS measures, as well as five new scales in order to provide a comprehensive assessment of HRQOL in HD. © 2016 Springer International Publishing Switzerland

Author Keywords
HDQLIFE;  Health-related quality of life;  Huntington disease;  Neuro-QoL;  Patient-reported outcome (PRO);  PROMIS

Document Type: Article in Press
Source: Scopus


Pan, Y.a , Daito, T.a , Sasaki, Y.b , Chung, Y.H.a , Xing, X.b , Pondugula, S.c , Swamidass, S.J.d , Wang, T.b , Kim, A.H.a e f g , Yano, H.a b e g
Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity
(2016) Scientific Reports, 6, art. no. 31022, . 

DOI: 10.1038/srep31022

a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Immunology and Pathology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
g Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States

Although epigenetic abnormalities have been described in Huntington's disease (HD), the causal epigenetic mechanisms driving neurodegeneration in HD cortex and striatum remain undefined. Using an epigenetic pathway-targeted drug screen, we report that inhibitors of DNA methyltransferases (DNMTs), decitabine and FdCyd, block mutant huntingtin (Htt)-induced toxicity in primary cortical and striatal neurons. In addition, knockdown of DNMT3A or DNMT1 protected neurons against mutant Htt-induced toxicity, together demonstrating a requirement for DNMTs in mutant Htt-triggered neuronal death and suggesting a neurodegenerative mechanism based on DNA methylation-mediated transcriptional repression. Inhibition of DNMTs in HD model primary cortical or striatal neurons restored the expression of several key genes, including Bdnf, an important neurotrophic factor implicated in HD. Accordingly, the Bdnf promoter exhibited aberrant cytosine methylation in mutant Htt-expressing cortical neurons. In vivo, pharmacological inhibition of DNMTs in HD mouse brains restored the mRNA levels of key striatal genes known to be downregulated in HD. Thus, disturbances in DNA methylation play a critical role in mutant Htt-induced neuronal dysfunction and death, raising the possibility that epigenetic strategies targeting abnormal DNA methylation may have therapeutic utility in HD. © 2016 The Author(s).

Document Type: Article
Source: Scopus


Caldwell, B.a , Ustione, A.b , Piston, D.W.a b
Dopamine Receptor Signaling in MIN6 β-Cells Revealed by Fluorescence Fluctuation Spectroscopy
(2016) Biophysical Journal, 111 (3), pp. 609-618. 

DOI: 10.1016/j.bpj.2016.06.026

a Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, United States
b Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri, United States

Insulin secretion defects are central to the development of type II diabetes mellitus. Glucose stimulation of insulin secretion has been extensively studied, but its regulation by other stimuli such as incretins and neurotransmitters is not as well understood. We investigated the mechanisms underlying the inhibition of insulin secretion by dopamine, which is synthesized in pancreatic β-cells from circulating L-dopa. Previous research has shown that this inhibition is mediated primarily by activation of the dopamine receptor D3 subtype (DRD3), even though both DRD2 and DRD3 are expressed in β-cells. To understand this dichotomy, we investigated the dynamic interactions between the dopamine receptor subtypes and their G-proteins using two-color fluorescence fluctuation spectroscopy (FFS) of mouse MIN6 β-cells. We show that proper membrane localization of exogenous G-proteins depends on both the Gβ and Gγ subunits being overexpressed in the cell. Triple transfections of the dopamine receptor subtype and Gβ and Gγ subunits, each labeled with a different-colored fluorescent protein (FP), yielded plasma membrane expression of all three FPs and permitted an FFS evaluation of interactions between the dopamine receptors and the Gβγ complex. Upon dopamine stimulation, we measured a significant decrease in interactions between DRD3 and the Gβγ complex, which is consistent with receptor activation. In contrast, dopamine stimulation did not cause significant changes in the interactions between DRD2 and the Gβγ complex. These results demonstrate that two-color FFS is a powerful tool for measuring dynamic protein interactions in living cells, and show that preferential DRD3 signaling in β-cells occurs at the level of G-protein release. © 2016 Biophysical Society

Document Type: Article
Source: Scopus


Ohna, T.-L.a b c d , Rutherford, M.A.a e , Jing, Z.b d f , Jung, S.a g h , Duque-Afonso, C.J.a b , Hoch, G.a , Picher, M.M.a b , Scharinger, A.i j , Strenzke, N.b d f , Moser, T.a b c d g h k
Hair cells use active zones with different voltage dependence of Ca2+ influx to decompose sounds into complementary neural codes
(2016) Proceedings of the National Academy of Sciences of the United States of America, 113 (32), pp. E4716-E4725. 

DOI: 10.1073/pnas.1605737113

a Institute for Auditory Neuroscience and InnerEarLab, University Medical Center Göttingen, Goettingen, Germany
b Göttingen Graduate School for Neurosciences and Molecular Biosciences, University of Göttingen, Goettingen, Germany
c Bernstein Focus for Neurotechnology, University of Göttingen, Goettingen, Germany
d Collaborative Research Center 889, University of Göttingen, Goettingen, Germany
e Department of Otolaryngology, Washington University, School of Medicine, St. Louis, MO, United States
f Auditory Systems Physiology Group, InnerEarLab, Department of Otolaryngology, University Medical Center Göttingen, Goettingen, Germany
g Synaptic Nanophysiology Group, Max Planck Institute for Biophysical Chemistry, Goettingen, Germany
h Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University of Göttingen, Goettingen, Germany
i Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria
j Center for Chemistry and Biomedicine, University of Innsbruck, Innsbruck, Austria
k Bernstein Center for Computational Neuroscience, University of Göttingen, Goettingen, Germany

For sounds of a given frequency, spiral ganglion neurons (SGNs) with different thresholds and dynamic ranges collectively encode the wide range of audible sound pressures. Heterogeneity of synapses between inner hair cells (IHCs) and SGNs is an attractive candidate mechanism for generating complementary neural codes covering the entire dynamic range. Here, we quantified active zone (AZ) properties as a function of AZ position within mouse IHCs by combining patch clamp and imaging of presynaptic Ca2+ influx and by immunohistochemistry. We report substantial AZ heterogeneity whereby the voltage of half-maximal activation of Ca2+ influx ranged over 20 mV. Ca2+ influx at AZs facing away from the ganglion activated at weaker depolarizations. Estimates of AZ size and Ca2+ channel number were correlated and larger when AZs faced the ganglion. Disruption of the deafness gene GIPC3 in mice shifted the activation of presynaptic Ca2+ influx to more hyperpolarized potentials and increased the spontaneous SGN discharge. Moreover, Gipc3 disruption enhanced Ca2+ influx and exocytosis in IHCs, reversed the spatial gradient of maximal Ca2+ influx in IHCs, and increased the maximal firing rate of SGNs at sound onset. We propose that IHCs diversify Ca2+ channel properties among AZs and thereby contribute to decomposing auditory information into complementary representations in SGNs.

Author Keywords
Auditory system|spiral ganglion neuron;  Dynamic range;  Presynaptic heterogeneity;  Synaptic strength

Document Type: Conference Paper
Source: Scopus


Lucey, B.P.
Biomarker changes in early Alzheimer's disease
(2016) Science Translational Medicine, 8 (350), p. 350ec123. 

DOI: 10.1126/scitranslmed.aah4510

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

Document Type: Short Survey
Source: Scopus


Glasser, M.F.a , Coalson, T.S.a , Robinson, E.C.b c , Hacker, C.D.d , Harwell, J.e , Yacoub, E.e , Ugurbil, K.b , Andersson, J.f g , Beckmann, C.F.b , Jenkinson, M.b , Smith, S.M.b , Van Essen, D.C.a
A multi-modal parcellation of human cerebral cortex
(2016) Nature, 536 (7615), pp. 171-178. Cited 1 time.

DOI: 10.1038/nature18933

a Department of Neuroscience, Washington University Medical School, Saint Louis, MO, United States
b FMRIB Centre, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
c Department of Computing, Imperial College, London, United Kingdom
d Department of Biomedical Engineering, Washington University, Saint Louis, MO, United States
e Center for Magnetic Resonance Research (CMRR), University of Minnesota, Minneapolis, MN, United States
f Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, EN, Netherlands
g Department of Cognitive Neuroscience, Radboud University Medical Centre Nijmegen, Postbus 9101, Nijmegen, HB, Netherlands

Understanding the amazingly complex human cerebral cortex requires a map (or parcellation) of its major subdivisions, known as cortical areas. Making an accurate areal map has been a century-old objective in neuroscience. Using multi-modal magnetic resonance images from the Human Connectome Project (HCP) and an objective semi-automated neuroanatomical approach, we delineated 180 areas per hemisphere bounded by sharp changes in cortical architecture, function, connectivity, and/or topography in a precisely aligned group average of 210 healthy young adults. We characterized 97 new areas and 83 areas previously reported using post-mortem microscopy or other specialized study-specific approaches. To enable automated delineation and identification of these areas in new HCP subjects and in future studies, we trained a machine-learning classifier to recognize the multi-modal 'fingerprint' of each cortical area. This classifier detected the presence of 96.6% of the cortical areas in new subjects, replicated the group parcellation, and could correctly locate areas in individuals with atypical parcellations. The freely available parcellation and classifier will enable substantially improved neuroanatomical precision for studies of the structural and functional organization of human cerebral cortex and its variation across individuals and in development, aging, and disease. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Document Type: Article
Source: Scopus


Buchholz, K.R.a , Bruce, S.E.a b , Koucky, E.M.a , Artime, T.M.a , Wojtalik, J.A.a , Brown, W.J.a , Sheline, Y.I.b
Neural Correlates of Trait Rumination During an Emotion Interference Task in Women With PTSD
(2016) Journal of Traumatic Stress, 29 (4), pp. 317-324. 

DOI: 10.1002/jts.22112

a Department of Psychology, University of Missouri-St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Rumination, defined as repetitive, negative, self-focused thinking, is hypothesized to be a transdiagnostic factor that is associated with depression, anxiety, and posttraumatic stress disorder (PTSD). Theory has suggested that in individuals with PTSD, rumination serves as a cognitive avoidance factor that contributes to the maintenance of symptoms by inhibiting the cognitive and emotional processing of the traumatic event, subsequently interfering with treatment engagement and outcome. Little is known about the neural correlates of rumination in women with PTSD. The current study utilized functional magnetic resonance imaging (fMRI) to examine neural correlates during an emotion interference task of self-reported rumination in women with PTSD. Women with PTSD (39 participants) were recruited at a university-based trauma clinic and completed a clinical evaluation that included measures of PTSD symptoms, rumination, and depressive symptoms, as well as a neuroimaging session in which the participants were administered an emotion interference task. There was a significant relationship between self-reported rumination and activity in the right orbital frontal cortex, BA 11; t(37) = 5.62, p =.004, k = 46 during the task. This finding suggested that women with PTSD, who had higher levels of rumination, may experience greater difficulty inhibiting negative emotional stimuli compared to women with lower levels of rumination. Copyright © 2016 International Society for Traumatic Stress Studies

Document Type: Article
Source: Scopus


Salehi, A.a , Ott, K.a , Skolnick, G.B.b , Nguyen, D.C.b , Naidoo, S.D.b , Kane, A.A.c , Woo, A.S.b , Patel, K.B.b , Smyth, M.D.a
Neosuture formation after endoscope-assisted craniosynostosis repair
(2016) Journal of Neurosurgery: Pediatrics, 18 (2), pp. 196-200. 

DOI: 10.3171/2016.2.PEDS15231

a Department of Neurological Surgery, Washington University School of Medicine, Campus Box 8057, 660 S Euclid Ave., St. Louis, MO, United States
b Department of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Plastic Surgery, University of Texas Southwestern Medical Center, Dallas, TX, United States

OBJECTIVE: The goal of this study was to identify the rate of neosuture formation in patients with craniosynostosis treated with endoscope-assisted strip craniectomy and investigate whether neosuture formation in sagittal craniosynostosis has an effect on postoperative calvarial shape. METHODS: The authors retrospectively reviewed 166 cases of nonsyndromic craniosynostosis that underwent endoscope-assisted repair between 2006 and 2014. Preoperative and 1-year postoperative head CT scans were evaluated, and the rate of neosuture formation was calculated. Three-dimensional reconstructions of the CT data were used to measure cephalic index (CI) (ratio of head width and length) of patients with sagittal synostosis. Regression analysis was used to calculate significant differences between patients with and without neosuture accounting for age at surgery and preoperative CI. RESULTS: Review of 96 patients revealed that some degree of neosuture development occurred in 23 patients (23.9%): 16 sagittal, 2 bilateral coronal, 4 unilateral coronal, and 1 lambdoid synostosis. Complete neosuture formation was seen in 14 of those 23 patients (9 of 16 sagittal, 1 of 2 bilateral coronal, 3 of 4 unilateral coronal, and 1 of 1 lambdoid). Mean pre- and postoperative CI in the complete sagittal neosuture group was 67.4% and 75.5%, respectively, and in the non-neosuture group was 69.8% and 74.4%, respectively. There was no statistically significant difference in the CI between the neosuture and fused suture groups preoperatively or 17 months postoperatively in patients with sagittal synostosis. CONCLUSIONS: Neosuture development can occur after endoscope-assisted strip craniectomy and molding helmet therapy for patients with craniosynostosis. Although the authors did not detect a significant difference in calvarial shape postoperatively in the group with sagittal synostosis, the relevance of neosuture formation remains to be determined. Further studies are required to discover long-term outcomes comparing patients with and without neosuture formation. ©AANS, 2016.

Author Keywords
Craniofacial;  Endoscopy;  Neosuture;  Sagittal craniosynostosis;  Scaphocephaly;  Strip craniectomy;  Suture re-formation

Document Type: Article
Source: Scopus


Saffran, K.a , Fitzsimmons-Craft, E.E.b , Kass, A.E.c , Wilfley, D.E.b , Taylor, C.B.a d , Trockel, M.a
Facebook usage among those who have received treatment for an eating disorder in a group setting
(2016) International Journal of Eating Disorders, 49 (8), pp. 764-777. 

DOI: 10.1002/eat.22567

a Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, Canada
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Department of Medicine, The University of ChicagoChicago, Israel
d Center for mHealth, Palo Alto University, Palo Alto, CA, United States

Objective: This study explored Facebook use among individuals with a history of receiving treatment for an eating disorder (ED) in a group setting (e.g., inpatient, residential, outpatient group), focusing primarily on comparisons individuals make about their bodies, eating, or exercise to those of their peers from treatment on Facebook and the relation between these comparisons and ED pathology. Method: Individuals (N = 415; mean age 28.15 years ± 8.41; 98.1% female) who self-reported receipt of ED treatment in a group setting were recruited via e-mail and social media to complete an online survey. Results: Participants reported having an average of 10–19 Facebook friends from treatment and spending up to 30 min per day interacting on Facebook with individuals from treatment or ED-related organizations. More comparison to treatment peers on Facebook was associated with greater ED psychopathology and ED-related impairment. Conversely, positive interaction with treatment peers on Facebook was associated with lower ED psychopathology and ED-related impairment. Individuals who had been in treatment longer, more times, and more recently had more Facebook friends from treatment and ED-related organizations as well as spent more time in ED groups' pages on Facebook. Few participants (19.5%) reported that a therapist asked about the impact of Facebook on pathology. Discussion: Interactions on Facebook could affect patients' recovery and potential for relapse. It may be helpful for treatment providers to discuss Facebook use and its potential benefits and drawbacks with patients preparing for discharge from group treatment. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:764–777). © 2016 Wiley Periodicals, Inc.

Author Keywords
eating disorders;  Facebook;  group treatment;  social media

Document Type: Article
Source: Scopus


Madaelil, T.P.a , Wallace, A.N.a , Chatterjee, A.N.a , Zipfel, G.J.b c , Dacey, R.G., Jr.c , Iii, D.T.C.a b , Moran, C.J.a b , Derdeyn, C.P.a b c
Endovascular parent vessel sacrifice in ruptured dissecting vertebral and posterior inferior cerebellar artery aneurysms: Clinical outcomes and review of the literature
(2016) Journal of NeuroInterventional Surgery, 8 (8), pp. 796-801. 

DOI: 10.1136/neurintsurg-2015-011732

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 South Kingshighway, Boulevard, St Louis, MO, United States
b Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Background Ruptured intracranial dissecting aneurysms must be secured quickly to prevent rehemorrhage. Endovascular sacrifice of the diseased segment is a well-established treatment method, however postoperative outcomes of symptomatic stroke and re-hemorrhage rates are not well reported, particularly for the perforator-rich distal vertebral artery or proximal posterior inferior cerebellar artery (PICA). Methods We retrospectively reviewed cases of ruptured distal vertebral artery or PICA dissecting aneurysms that underwent endovascular treatment. Diagnosis was based on the presence of subarachnoid hemorrhage on initial CT imaging and of a dissecting aneurysm on catheter angiography. Patients with vertebral artery aneurysms were selected for coil embolization of the diseased arterial segment based on the adequacy of flow to the basilar artery from the contralateral vertebral artery. Patients with PICA aneurysms were generally treated only if they were poor surgical candidates. Outcomes included symptomatic and asymptomatic procedurerelated cerebral infarction, recurrent aneurysm rupture, angiographic aneurysm recurrence, and estimated modified Rankin Scale (MRS). Results During the study period, 12 patients with dissecting aneurysms involving the distal vertebral artery (n=10) or PICA (n=2) were treated with endovascular sacrifice. Two patients suffered an ischemic infarction, one of whom was symptomatic (8.3%). One patient (8.3%) died prior to hospital discharge. No aneurysm recurrence was identified on follow-up imaging. Ten patients (83%) made a good recovery (MRS ≤2). Median clinical and imaging follow-up periods were 41.7 months (range 0-126.4 months) and 14.3 months (range 0.03-88.6 months), respectively. Conclusions In patients with good collateral circulation, endovascular sacrifice may be the preferred treatment for acutely ruptured dissecting aneurysms involving the distal vertebral artery.

Document Type: Article
Source: Scopus


Gordon, B.A.a b , Friedrichsen, K.a , Brier, M.c , Blazey, T.d , Su, Y.a , Christensen, J.a , Aldea, P.a , McConathy, J.a , Holtzman, D.M.b c d e , Cairns, N.J.b c e , Morris, J.C.b c , Fagan, A.M.b c e , Ances, B.M.b c e , Benzinger, T.L.S.a b f
The relationship between cerebrospinal fluid markers of Alzheimer pathology and positron emission tomography tau imaging
(2016) Brain, 139 (8), pp. 2249-2260. 

DOI: 10.1093/brain/aww139

a Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, United States
b Knight Alzheimer's Disease Research Center, Washington University in St. Louis, 4488 Forest Park Avenue, St. Louis, MO, United States
c Department of Neurology, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, United States
d Division of Biology and Biomedical Sciences, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO, United States

The two primary molecular pathologies in Alzheimer's disease are amyloid-β plaques and tau-immunoreactive neurofibrillary tangles. Investigations into these pathologies have been restricted to cerebrospinal fluid assays, and positron emission tomography tracers that can image amyloid-β plaques. Tau tracers have recently been introduced into the field, although the utility of the tracer and its relationship to other Alzheimer biomarkers are still unknown. Here we examined tau deposition in 41 cognitively normal and 11 cognitively impaired older adults using the radioactive tau ligand 18F-AV-1451 (previously known as T807) who also underwent a lumbar puncture to assess cerebrospinal fluid levels of total tau (t-tau), phosphorylated tau181 (p-tau181) and amyloid-β42. Voxel-wise statistical analyses examined spatial patterns of tau deposition associated with cognitive impairment. We then related the amount of tau tracer uptake to levels of cerebrospinal fluid biomarkers. All analyses controlled for age and gender and, when appropriate, the time between imaging and lumbar puncture assessments. Symptomatic individuals (Clinical Dementia Rating &gt; 0) demonstrated markedly increased levels of tau tracer uptake. This elevation was most prominent in the temporal lobe and temporoparietal junction, but extended more broadly into parietal and frontal cortices. In the entire cohort, there were significant relationships among all cerebrospinal fluid biomarkers and tracer uptake, notably for tau-related cerebrospinal fluid markers. After controlling for levels of amyloid-β42, the correlations with tau uptake were r = 0.490 (P &lt; 0.001) for t-tau and r = 0.492 (P &lt; 0.001) for p-tau181. Within the cognitively normal cohort, levels of amyloid-β42, but not t-tau or p-tau181, were associated with elevated tracer binding that was confined primarily to the medial temporal lobe and adjacent neocortical regions. AV-1451 tau binding in the medial temporal, parietal, and frontal cortices is correlated with tau-related cerebrospinal fluid measures. In preclinical Alzheimer's disease, there is focal tauopathy in the medial temporal lobes and adjacent cortices. © 2016 The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Author Keywords
Alzheimer's disease;  cerebrospinal fluid;  positron emission tomography;  preclinical;  tau imaging

Document Type: Article
Source: Scopus


Horvát, S.a , Gamanu?, R.a , Ercsey-Ravasz, M.b c , Magrou, L.a , Gamanu?, B.a , Van Essen, D.C.d , Burkhalter, A.d , Knoblauch, K.a , Toroczkai, Z.e f , Kennedy, H.a
Spatial Embedding and Wiring Cost Constrain the Functional Layout of the Cortical Network of Rodents and Primates
(2016) PLoS Biology, 14 (7), art. no. e1002512, . 

DOI: 10.1371/journal.pbio.1002512

a Univ Lyon, Université Claude Bernard Lyon 1, Inserm, Stem-cell and Brain Research Institute U1208, Bron, France
b Faculty of Physics, Babes-Bolyai University, Cluj-Napoca, Romania
c Romanian Institute of Science and Technology, Cluj-Napoca, Romania
d Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Physics, University of Notre Dame, Notre Dame, IN, United States
f Interdisciplinary Center for Network Science and Applications, University of Notre Dame, Notre Dame, IN, United States

Mammals show a wide range of brain sizes, reflecting adaptation to diverse habitats. Comparing interareal cortical networks across brains of different sizes and mammalian orders provides robust information on evolutionarily preserved features and species-specific processing modalities. However, these networks are spatially embedded, directed, and weighted, making comparisons challenging. Using tract tracing data from macaque and mouse, we show the existence of a general organizational principle based on an exponential distance rule (EDR) and cortical geometry, enabling network comparisons within the same model framework. These comparisons reveal the existence of network invariants between mouse and macaque, exemplified in graph motif profiles and connection similarity indices, but also significant differences, such as fractionally smaller and much weaker long-distance connections in the macaque than in mouse. The latter lends credence to the prediction that long-distance cortico-cortical connections could be very weak in the much-expanded human cortex, implying an increased susceptibility to disconnection syndromes such as Alzheimer disease and schizophrenia. Finally, our data from tracer experiments involving only gray matter connections in the primary visual areas of both species show that an EDR holds at local scales as well (within 1.5 mm), supporting the hypothesis that it is a universally valid property across all scales and, possibly, across the mammalian class. © 2016 Public Library of Science. All rights reserved.

Document Type: Article
Source: Scopus


St John, T.a b , Estes, A.M.a b , Dager, S.R.b c , Kostopoulos, P.d , Wolff, J.J.e , Pandey, J.e , Elison, J.T.g , Paterson, S.J.f , Schultz, R.T.f , Botteron, K.h , Hazlett, H.i j , Piven, J.i j
Emerging executive functioning and motor development in infants at high and low risk for autism spectrum disorder
(2016) Frontiers in Psychology, 7 (JUL), art. no. 1016, . 

DOI: 10.3389/fpsyg.2016.01016

a Speech and Hearing Sciences, University of Washington, Seattle, WA, United States
b UW Autism Center, Center on Human Development and Disability, University of Washington, Seattle, WA, United States
c Department of Radiology, University of Washington, Seattle, WA, United States
d McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, CA, United States
e Department of Educational Psychology, University of Minnesota, Minneapolis, MN, United States
f Department of Pediatrics, Center for Autism Research, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
g Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
h Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
i Carolina Institute for Developmental Disabilities, Chapel Hill, NC, United States
j Department of Psychiatry, University of North Carolina, Chapel Hill, NC, United States

Existing evidence suggests executive functioning (EF) deficits may be present in children with autism spectrum disorder (ASD) by 3 years of age. It is less clear when, prior to 3 years, EF deficits may emerge and how EF unfold over time. The contribution of motor skill difficulties to poorer EF in children with ASD has not been systematically studied. We investigated the developmental trajectory of EF in infants at high and low familial risk for ASD (HR and LR) and the potential associations between motor skills, diagnostic group, and EF performance. Participants included 186 HR and 76 LR infants. EF (A-not-B), motor skills (Fine and Gross Motor), and cognitive ability were directly assessed at 12 months and 24 months of age. Participants were directly evaluated for ASD at 24 months using DSM-IV-TR criteria and categorized as HR-ASD, HR-Negative, and LR-Negative. HR-ASD and HR-Negative siblings demonstrated less improvement in EF over time compared to the LR-Negative group. Motor skills were associated with group and EF performance at 12 months. No group differences were found at 12 months, but at 24 months, the HR-ASD and HR-Negative groups performed worse than the LR-Negative group overall after controlling for visual reception and maternal education. On reversal trials, the HR-ASD group performed worse than the LR-Negative group. Motor skills were associated with group and EF performance on reversal trials at 24 months. Findings suggest that HR siblings demonstrate altered EF development and that motor skills may play an important role in this process. © 2016 St. John, Estes, Dager, Kostopoulos, Wolff, Pandey, Elison, Paterson, Schultz, Botteron, Hazlett and Piven.

Author Keywords
Autism;  Executive functioning;  high-risk;  Inhibition;  Motor skills;  Working memory

Document Type: Article
Source: Scopus


Perkins, K.S.a , Tharp, B.E.b , Ramsey, A.T.c , Patterson Silver Wolf (Adelv Unegv Waya), D.d
Mapping the Evidence to Improve Retention Rates in Addiction Services
(2016) Journal of Social Work Practice in the Addictions, 16 (3), pp. 233-251. 

DOI: 10.1080/1533256X.2016.1200055

a Research Scholar, George Warren Brown School of Social Work, Washington University inSt. Louis, St. Louis, MO, United States
b Doctoral Student, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, ND, United States
c NIMH Postdoctoral Research Scholar, Center for Mental Health Services Research, George Warren Brown School of Social Work, Washington University in St. Louis, St. Louis, MO, United States
d Associate Professor, George Warren Brown School of Social Work, Washington Universityin St. Louis, St. Louis, MO, United States

Untreated alcohol and drug addiction continues to be a major health issue in the United States. To meet the challenges of this chronic illness, treatment should be based in the best, most up-to-date science. Treatment retention and completion have been continually shown to significantly improve health and wellness outcomes. Unfortunately, most individuals who enter programs do not successfully complete them. The goal of this study is to use evidence mapping to define the best evidence-based practices and strategies to improve retention rates within addiction services and to present recommendations. Copyright © Taylor & Francis Group, LLC.

Author Keywords
addiction;  client outcomes;  evidence mapping;  evidence-based practices;  retention;  treatment

Document Type: Article
Source: Scopus


Stanley, M., Macauley, S.L., Holtzman, D.M.
Changes in insulin and insulin signaling in Alzheimer's disease: Cause or consequence?
(2016) Journal of Experimental Medicine, 213 (8), pp. 1375-1385. 

DOI: 10.1084/jem.20160493

Department of Neurology, Hope Center for Neurological Disorders, Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Individuals with type 2 diabetes have an increased risk for developing Alzheimer's disease (AD), although the causal relationship remains poorly understood. Alterations in insulin signaling (IS) are reported in the AD brain. Moreover, oligomers/fibrils of amyloid-ß (Aß) can lead to neuronal insulin resistance and intranasal insulin is being explored as a potential therapy for AD. Conversely, elevated insulin levels (ins) are found in AD patients and high insulin has been reported to increase Aß levelsand tau phosphorylation, which could exacerbate AD pathology. Herein, we explore whether changes in ins and IS are a cause or consequence of AD. © 2016 Stanley et al.

Document Type: Article
Source: Scopus


Werner, K.B.a , Grant, J.D.b , McCutcheon, V.V.b , Madden, P.A.F.b , Heath, A.C.b , Bucholz, K.K.b , Sartor, C.E.c d
Differences in Childhood Physical Abuse Reporting and the Association between CPA and Alcohol Use Disorder in European American and African American Women
(2016) Psychology of Addictive Behaviors, 30 (4), pp. 423-433. 

DOI: 10.1037/adb0000174

a George Warren Brown School of Social Work, Washington University in St. Louis, 4560 Clayton Avenue, St. Louis, MO, United States
b Alcohol Research Center, Department of Psychiatry, Washington University, United States
c Alcohol Research Center, Washington University, School of Medicine, United States
d Department of Psychiatry, Yale University, School of Medicine, United States

The goal of the current study was to examine whether the magnitude of the association between childhood physical abuse (CPA) and alcohol use disorder (AUD) varies by type of CPA assessment and race of the respondents. Data are from the Missouri adolescent female twins study and the Missouri family study (N = 4508) where 21.2% identified as African American (AA) and 78.8% as European American (EA); mean age = 23.8. Data were collected using a structured comprehensive interview which assessed CPA experiences using behavioral questions about specific abusive behaviors and trauma checklist items. Cox proportional hazards regression analyses were conducted, adjusting for additional risk factors associated with AUD, including co-occurring psychiatric disorders (defined as time-varying) and parental alcohol misuse. Overall, CPA reporting patterns were highly correlated (tetrachoric ρ = 0.73); although, only 25.8% of women who endorsed behaviorally defined CPA also endorsed checklist items whereas 72.2% of women who endorsed checklist items also endorsed behavioral questions. Racial disparities were evident, with behaviorally defined CPA increasing the hazard for AUD in EA but not AA women. Additional racial disparities in the risk for AUD were observed: increased hazard for AUD were associated with major depressive disorder in AA, and cannabis dependence and paternal alcohol problems in EA, women. Results demonstrate the relevance of the type of CPA measure in assessing CPA in studies of alcohol-related problems-behavioral items may be more inclusive of CPA exposure and more predictive of AUD-and highlight racial distinctions of AUD etiology in women. © 2016 American Psychological Association.

Author Keywords
alcohol use disorder;  Childhood physical abuse;  racial disparities;  women

Document Type: Article
Source: Scopus


Balota, D.A.
Speed Reading: You Can't Always Get What You Want, but Can You Sometimes Get What You Need?
(2016) Psychological science in the public interest : a journal of the American Psychological Society, 17 (1), pp. 1-3. 

DOI: 10.1177/1529100615623268

Department of Psychological and Brain Sciences, Washington University in St. Louis

Document Type: Note
Source: Scopus


Roland, L.T.a , Kallogjeri, D.a , Sinks, B.C.a , Rauch, S.D.b , Shepard, N.T.c , White, J.A.d , Goebel, J.A.a
Utility of an abbreviated dizziness questionnaire to differentiate between causes of vertigo and guide appropriate referral: A multicenter prospective blinded study
(2015) Otology and Neurotology, 36 (10), pp. 1687-1694. 

DOI: 10.1097/MAO.0000000000000884

a Department of Otolaryngology - Head and Neck Surgery, Washington University in St Louis, School of Medicine, St Louis, MO, United States
b Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Boston, MA, United States
c Division of Audiology, Mayo Clinic, Rochester, MN, United States
d Section of Vestibular and Balance Disorders, Head and Neck Institute, Cleveland Clinic, Cleveland, OH, United States

Objective: Test performance of a focused dizziness questionnaire's ability to discriminate between peripheral and nonperipheral causes of vertigo. Study Design: Prospective multicenter. Setting: Four academic centers with experienced balance specialists. Patients: New dizzy patients. Interventions: A 32-question survey was given to participants. Balance specialists were blinded and a diagnosis was established for all participating patients within 6 months. Main Outcomes: Multinomial logistic regression was used to evaluate questionnaire performance in predicting final diagnosis and differentiating between peripheral and nonperipheral vertigo. Univariate and multivariable stepwise logistic regression were used to identify questions as significant predictors of the ultimate diagnosis. C-index was used to evaluate performance and discriminative power of the multivariable models. Results: In total, 437 patients participated in the study. Eight participants without confirmed diagnoses were excluded and 429 were included in the analysis. Multinomial regression revealed that the model had good overall predictive accuracy of 78.5% for the final diagnosis and 75.5% for differentiating between peripheral and nonperipheral vertigo. Univariate logistic regression identified significant predictors of three main categories of vertigo: peripheral, central, and other. Predictors were entered into forward stepwise multivariable logistic regression. The discriminative power of the final models for peripheral, central, and other causes was considered good as measured by c-indices of 0.75, 0.7, and 0.78, respectively. Conclusion: This multicenter study demonstrates a focused dizziness questionnaire can accurately predict diagnosis for patients with chronic/relapsing dizziness referred to outpatient clinics. Additionally, this survey has significant capability to differentiate peripheral from nonperipheral causes of vertigo and may, in the future, serve as a screening tool for specialty referral. Clinical utility of this questionnaire to guide specialty referral is discussed. © 2015 Otology & Neurotology, Inc.

Author Keywords
History;  Questionnaire;  Vertigo

Document Type: Article
Source: Scopus


Leuthardt, E.C., Allen, M., Kamran, M., Hawasli, A.H., Snyder, A.Z., Hacker, C.D., Mitchell, T.J., Shimony, J.S.
Resting-State Blood Oxygen Level-Dependent Functional MRI: A Paradigm Shift in Preoperative Brain Mapping
(2015) Stereotactic and Functional Neurosurgery, 93 (6), pp. 427-439. 

DOI: 10.1159/000442424

Washington University, School of Medicine, Department of Neurological Surgery, 660 South Euclid Avenue, Saint Louis, MO, United States

Currently, functional magnetic resonance imaging (fMRI) facilitates a preoperative awareness of an association of an eloquent region with a tumor. This information gives the neurosurgeon helpful information that can aid in creating a surgical strategy. Typically, task-based fMRI has been employed to preoperatively localize speech and motor function. Task-based fMRI depends on the patient's ability to comply with the task paradigm, which often is impaired in the setting of a brain tumor. This problem is overcome by using resting-state fMRI (rs-fMRI) to localize function. rs-fMRI measures spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal, representing the brain's functional organization. In a neurosurgical context, it allows noninvasive simultaneous assessment of multiple large-scale distributed networks. Compared with task-related fMRI, rs-fMRI provides more comprehensive information on the functional architecture of the brain and is applicable in settings where task-related fMRI may provide inadequate information or could not be performed. Taken together, rs-fMRI substantially expands the preoperative mapping capability in efficiency, effectiveness, and scope. In this article, a brief introduction into rs-fMRI processing methods is followed by a detailed discussion on the role rs-fMRI plays in presurgical planning. © 2016 S. Karger AG, Basel. All rights reserved.

Author Keywords
Functional MRI;  Multilayer perceptron;  Resting state networks;  Resting-state functional MRI

Document Type: Article
Source: Scopus


McNeely, M.E.a b , Mai, M.M.c , Duncan, R.P.a b , Earhart, G.M.a b d
Differential effects of tango versus dance for PD in Parkinson disease
(2015) Frontiers in Aging Neuroscience, 7 (DEC), art. no. 239, . 

DOI: 10.3389/fnagi.2015.00239

a Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Anthropology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Department of Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Over half of the general population does not achieve recommended daily levels of physical activity, and activity levels in people with Parkinson disease (PD) are lower than in healthy older adults. Dance can serve as an adjunct to traditional treatments to improve gait, balance, and quality of life in people with PD. This study directly compares a tango dance intervention and a dance intervention based on the Dance for PD model, which integrates multiple dance styles. Eleven people with PD participated in a community-based mixed styles dance intervention called Dance for Parkinson's (D4PD). Participants in the D4PD group were matched to participants in an ongoing community-based exercise study who participated in tango dance. The groups received 12 weeks of intervention, attending 1-h group classes twice a week. Participants were evaluated off anti-PD medication before and after intervention. Measures of balance, repeated sit-to-stand performance and endurance (mini-balance evaluation systems test, four square step test, five times sit to stand, 6-min walk time) improved from pre to post similarly in both groups. Motor sign severity (movement disorders society unified Parkinson disease rating scale motor subsection) and functional mobility (timed up and go) improved in the tango group and worsened in the D4PD group. Gait velocity was not affected by either intervention. Direct comparisons of different interventions are critical for developing optimal exercise interventions designed to specifically target motor impairments in PD. Tango dance interventions may preferentially improve mobility and motor signs in people with PD, compared to D4PD. © 2015 McNeely, Mai, Duncan and Earhart.

Author Keywords
Balance;  Dance;  Gait;  Mobility;  Parkinson disease;  Tango

Document Type: Article
Source: Scopus


Kafashan, M.a , Ching, S.a b
Optimal stimulus scheduling for active estimation of evoked brain networks
(2015) Journal of Neural Engineering, 12 (6), art. no. 066011, . Cited 1 time.

DOI: 10.1088/1741-2560/12/6/066011

a Department of Electrical and Systems Engineering, Washington University in St., Louis, MO, United States
b Division of Biology and Biomedical Sciences, Washington University in St., Louis, MO, United States

Objective. We consider the problem of optimal probing to learn connections in an evoked dynamic network. Such a network, in which each edge measures an input-output relationship between sites in sensor/actuator-space, is relevant to emerging applications in neural mapping and neural connectivity estimation. Approach. We show that the problem of scheduling nodes to a probe (i.e., stimulate) amounts to a problem of optimal sensor scheduling. Main results. By formulating the evoked network in state-space, we show that the solution to the greedy probing strategy has a convenient form and, under certain conditions, is optimal over a finite horizon. We adopt an expectation maximization technique to update the state-space parameters in an online fashion and demonstrate the efficacy of the overall approach in a series of detailed numerical examples. Significance. The proposed method provides a principled means to actively probe time-varying connections in neuronal networks. The overall method can be implemented in real time and is particularly well-suited to applications in stimulation-based cortical mapping in which the underlying network dynamics are changing over time. © 2015 IOP Publishing Ltd.

Author Keywords
Active stimulation;  Brain dynamics;  Evoked connectivity;  Network inference;  Network structure

Document Type: Article
Source: Scopus



Gardner, J.R.a , Song, X.a , Weinberger, K.Q.a , Barbour, D.a , Cunningham, J.P.b
Psychophysical detection testing with Bayesian active learning
(2015) Uncertainty in Artificial Intelligence - Proceedings of the 31st Conference, UAI 2015, pp. 286-295. 

a Washington University in St. Louis, St. Louis, MO, United States
b Columbia University, New York, NY, United States

Psychophysical detection tests are ubiquitous in the study of human sensation and the diagnosis and treatment of virtually all sensory impairments. In many of these settings, the goal is to recover, from a series of binary observations from a human subject, the latent function that describes the discriminability of a sensory stimulus over some relevant domain. The auditory detection test, for example, seeks to understand a subject's likelihood of hearing sounds as a function of frequency and amplitude. Conventional methods for performing these tests involve testing stimuli on a pre-determined grid. This approach not only samples at very uninformative locations, but also fails to learn critical features of a subject's latent discriminability function. Here we advance active learning with Gaussian processes to the setting of psychophysical testing. We develop a model that incorporates strong prior knowledge about the class of stimuli, we derive a sensible method for choosing sample points, and we demonstrate how to evaluate this model efficiently. Finally, we develop a novel likelihood that enables testing of multiple stimuli simultaneously. We evaluate our method in both simulated and real auditory detection tests, demonstrating the merit of our approach.

Document Type: Conference Paper
Source: Scopus