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WUSTL Neuroscience Publications Archive - February 2013

February 27, 2013

 Albaugh, M.D.a , Ducharme, S.b , Collins, D.L.b , Botteron, K.N.c , Althoff, R.R.a , Evans, A.C.b , Karama, S.b d , Hudziak, J.J.a 
Evidence for a cerebral cortical thickness network anti-correlated with amygdalar volume in healthy youths: Implications for the neural substrates of emotion regulation
(2013) NeuroImage, 71, pp. 42-49. 


a Department of Psychiatry, University of Vermont College of Medicine, Burlington, VT, United States
b McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
c Mallinckrodt Institute of Radiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
d Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada


Abstract
Recent functional connectivity studies have demonstrated that, in resting humans, activity in a dorsally-situated neocortical network is inversely associated with activity in the amygdalae. Similarly, in human neuroimaging studies, aspects of emotion regulation have been associated with increased activity in dorsolateral, dorsomedial, orbital and ventromedial prefrontal regions, as well as concomitant decreases in amygdalar activity. These findings indicate the presence of two countervailing systems in the human brain that are reciprocally related: a dorsally-situated cognitive control network, and a ventrally-situated limbic network. We investigated the extent to which this functional reciprocity between limbic and dorsal neocortical regions is recapitulated from a purely structural standpoint. Specifically, we hypothesized that amygdalar volume would be related to cerebral cortical thickness in cortical regions implicated in aspects of emotion regulation. In 297 typically developing youths (162 females, 135 males; 572 MRIs), the relationship between cortical thickness and amygdalar volume was characterized. Amygdalar volume was found to be inversely associated with thickness in bilateral dorsolateral and dorsomedial prefrontal, inferior parietal, as well as bilateral orbital and ventromedial prefrontal cortices. Our findings are in line with previous work demonstrating that a predominantly dorsally-centered neocortical network is reciprocally related to core limbic structures such as the amygdalae. Future research may benefit from investigating the extent to which such cortical-limbic morphometric relations are qualified by the presence of mood and anxiety psychopathology. © 2012 Elsevier Inc.


Author Keywords
Amygdala;  Cortical thickness;  MRI;  Normal development


Document Type: Article
Source: Scopus

Selemon, L.D.a , Ceritoglu, C.b , Ratnanather, J.T.b , Wang, L.c , Harms, M.P.d , Aldridge, K.e , Begovic, A.a , Csernansky, J.G.c , Miller, M.I.b , Rakic, P.a f 
Distinct abnormalities of the primate prefrontal cortex caused by ionizing radiation in early or midgestation
(2013) Journal of Comparative Neurology, 521 (5), pp. 1040-1053. 


a Department of Neurobiology, Yale University, New Haven, CT, United States
b Center for Imaging Science, Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD, United States
c Department of Psychiatry and Behavioral Sciences, Northwestern University, Feinberg School of Medicine, Chicago, IL, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Pathology and Anatomical Sciences, University of Missouri, School of Medicine, Columbia, MO, United States
f Kavli Institute for Neuroscience, Yale University, New Haven, CT, United States


Abstract
Prenatal exposure of the brain to environmental insult causes different neurological symptoms and behavioral outcomes depending on the time of exposure. To examine the cellular bases for these differences, we exposed rhesus macaque fetuses to x-rays during early gestation (embryonic day [E]30-E42), i.e., before the onset of corticogenesis, or in midgestation (E70-E81), when superficial cortical layers are generated. Animals were delivered at term (~E165), and the size and cellular composition of prefrontal association cortex (area 46) examined in adults using magnetic resonance imaging (MRI) and stereologic analysis. Both early and midgestational radiation exposure diminished the surface area and volume of area 46. However, early exposure spared cortical thickness and did not alter laminar composition, and due to higher cell density, neuron number was within the normal range. In contrast, exposure to x-rays at midgestation reduced cortical thickness, mainly due to elimination of neurons destined for the superficial layers. A cell-sparse gap, observed within layer III, was not filled by the later-generated neurons destined for layer II, indicating that there is no subsequent replacement of the lost neurons. The distinct areal and laminar pathology consequent to temporally segregated irradiation is consistent with basic postulates of the radial unit hypothesis of cortical development. In addition, we show that an environmental disturbance inflicted in early gestation can induce subtle cytoarchitectonic alterations without loss of neurons, such as those observed in schizophrenia, whereas midgestational exposure causes selective elimination of neurons and cortical thinning as observed in some forms of mental retardation and fetal alcohol syndrome. © 2012 Wiley Periodicals, Inc.


Author Keywords
Magnetic resonance imaging;  Neurodevelopment;  Schizophrenia;  Stereology;  Thalamocortical


Document Type: Article
Source: Scopus

Izumi, Y.a c , Svrakic, N.a , O'Dell, K.a c , Zorumski, C.F.a b c 
Ammonia inhibits long-term potentiation via neurosteroid synthesis in hippocampal pyramidal neurons
(2013) Neuroscience, 233, pp. 166-173. 


a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States


Abstract
Neurosteroids are a class of endogenous steroids synthesized in the brain that are believed to be involved in the pathogenesis of neuropsychiatric disorders and memory impairment. Ammonia impairs long-term potentiation (LTP), a synaptic model of learning, in the hippocampus, a brain region involved in memory acquisition. Although mechanisms underlying ammonia-mediated LTP inhibition are not fully understood, we previously found that the activation of N-methyl- d-aspartate receptors (NMDARs) is important. Based on this, we hypothesize that metabolic stressors, including hyperammonemia, promote untimely NMDAR activation and result in neural adaptations that include the synthesis of allopregnanolone (alloP) and other GABA-potentiating neurosteroids that dampen neuronal activity and impair LTP and memory formation. Using an antibody against 5α-reduced neurosteroids, we found that 100 μM ammonia acutely enhanced neurosteroid immunostaining in pyramidal neurons in the CA1 region of rat hippocampal slices. The enhanced staining was blocked by finasteride, a selective inhibitor of 5α-reductase, a key enzyme required for alloP synthesis. Finasteride also overcame LTP inhibition by 100 μM ammonia, as did picrotoxin, an inhibitor of GABA-A receptors. These results indicate that GABA-enhancing neurosteroids, synthesized locally within pyramidal neurons, contribute significantly to ammonia-mediated synaptic dysfunction. These results suggest that the manipulation of neurosteroid synthesis could provide a strategy to improve cognitive function in individuals with hyperammonemia. © 2012 IBRO.


Author Keywords
Allopregnanolone;  Finasteride;  Hepatic encephalopathy;  LTP;  Neurosteroid;  Tetrahydrodeoxycorticosterone


Document Type: Article
Source: Scopus

Jones-Jordan, L.A.a , Walline, J.J.a , Sinnott, L.T.a , Kymes, S.M.b , Zadnik, K.a 
Asymmetry in keratoconus and vision-related quality of life
(2013) Cornea, 32 (3), pp. 267-272. 


a College of Optometry, Ohio State University, 338 West 10th Avenue, Columbus, OH 43210, United States
b Washington University School of Medicine, St Louis, MO, United States


Abstract
PURPOSE: To examine the relationship of increased ocular asymmetry over time to vision-related quality of life in keratoconus. METHODS: The subjects were from the Collaborative Longitudinal Evaluation of Keratoconus Study and had complete data on a least 1 scale of the National Eye Institute Visual Function Questionnaire and examination data at baseline and at least 1 follow-up visit. Three measures of disease asymmetry [visual acuity (VA), corneal curvature, and refractive error] and better eye status were assessed. Multilevel models were fit to the data. RESULTS: The analyses were completed using the data from 961 subjects. Six scales on the National Eye Institute Visual Function Questionnaire had adequate variability to the model (distance activity, driving, mental health, near activity, ocular pain, and role difficulties). Refractive error changes were not associated with statistically significant quality-of-life differences. Except for ocular pain, statistically significant, but not clinically meaningful, differences were found for VA changes and corneal curvature changes. For a 0.1-unit logarithm of the minimum angle of resolution of VA change, the quality-of-life scales decreased between 0.20 and 0.99 units. For a 1.00-diopter steepening of corneal curvature, these decreases were on the order of 0.20 to 0.59 units. Changes related to asymmetry were small as well; decreases were on the order of 0.20 to 0.38 units. CONCLUSIONS: Increasing ocular asymmetry and decreases in VA and corneal steepening in the better eye were associated with decreasing vision-related quality of life, although the magnitudes of the changes were not clinically meaningful. Of these 2 disease status indicators, the vision in the better eye had greater effect on the vision-related quality of life. Copyright © 2012 by Lippincott Williams & Wilkins.


Author Keywords
keratoconus;  longitudinal;  quality of life


Document Type: Article
Source: Scopus

Suzuki, H.a , Botteron, K.N.a b , Luby, J.L.a , Belden, A.C.a , Gaffrey, M.S.a , Babb, C.M.a , Nishino, T.a , Miller, M.I.cd e , Ratnanather, J.T.c d e , Barch, D.M.a b f g 
Structural-functional correlations between hippocampal volume and cortico-limbic emotional responses in depressed children
(2013) Cognitive, Affective and Behavioral Neuroscience, 13 (1), pp. 135-151. 


a Department of Psychiatry, Washington University School of Medicine, Campus Box 8134, 660 Euclid Ave., Saint Louis MO 63110, United States
b Department of Radiology, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis MO, United States
c Center for Imaging Science, Johns Hopkins University, Baltimore MD, United States
d Department of Biomedical Engineering, Whitaker Biomedical Engineering Institute, Johns Hopkins University, Baltimore MD, United States
e Institute for Computational Medicine, Johns Hopkins University, Baltimore MD, United States
f Department of Psychiatry, Silvio Conte Center for Neuroscience of Mental Disorders, Washington University School of Medicine, Saint Louis MO, United States
g Department of Psychology, Washington University in St. Louis, Saint Louis MO, United States


Abstract
Although hippocampal atrophy and altered functional brain responses to emotional stimuli have been found in major depressive disorder (MDD), the relationship between the two is not yet well understood. The present study focused on children with and without a history of preschool onset MDD (PO-MDD) and directly examined the relations between hippocampal volume and functional brain activation to affect-eliciting stimuli. Children completed annual diagnostic assessments starting at preschool. When children were school-aged, high-resolution structural MRI and task-related functional MRI data were acquired from N = 64 nonmedicated children. During fMRI, subjects were shown emotional faces. Results from the total sample indicated that smaller bilateral hippocampal volumes were associated with greater cortico-limbic (e.g., amygdala, hippocampus, dorsolateral prefrontal cortex) activation to sad or negative faces versus neutral faces. Left hippocampal volume was negatively associated with the cortico-limbic activation in both the PO-MDD and healthy children. Right hippocampal volume was negatively correlated with amygdala responses in the PO-MDD group, but not in the healthy comparison group. These findings suggest that there may be important interrelationships between reduced hippocampal volume and hyperactivation of brain responses in children, both those with and those without a history of PO-MDD. © 2012 Psychonomic Society, Inc.


Author Keywords
Child;  fMRI;  Hippocampus;  Preschool depression;  sMRI


Document Type: Article
Source: Scopus

McPherson, J.A.a , Harper, L.M.b , Odibo, A.O.a , Roehl, K.A.a , Cahill, A.G.a 
Maternal seizure disorder and risk of adverse pregnancy outcomes
(2013) American Journal of Obstetrics and Gynecology, . Article in Press. 


a Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, St. Louis, MO
b University of Alabama at Birmingham, Birmingham, AL


Abstract
Objective: We sought to estimate the association between maternal seizure disorder and adverse pregnancy outcomes. Study design: We performed a retrospective cohort study of singleton, nonanomalous pregnancies. Women with self-reported seizure disorder were compared to women without medical problems. The primary outcome was intrauterine growth restriction (IUGR) <10th percentile. Secondary outcomes included IUGR <5th percentile, stillbirth, preeclampsia, and preterm delivery. A sensitivity analysis was performed using women who reported using antiepileptics to estimate the impact of disease severity on pregnancy outcomes. Results: Of 47,118 women, 440 reported a seizure disorder. Women with seizure disorder were not at increased risk of IUGR <10th percentile (adjusted odds ratio, 1.11; 95% confidence interval, 0.82-1.50), IUGR <5th percentile, stillbirth, preeclampsia, or preterm delivery. The results were similar in the sensitivity analysis of women taking antiseizure medications. Conclusion: Our results suggest women with a seizure disorder are not at increased risk of IUGR, stillbirth, preeclampsia, or preterm delivery. © 2013 Mosby, Inc. All rights reserved.


Author Keywords
adverse pregnancy outcomes;  seizure disorder


Document Type: Article in Press
Source: Scopus

Novak, C.B.a g , Anastakis, D.J.a , Beaton, D.E.b , Mackinnon, S.E.c , Katz, J.d e f 
Validity of the Patient Specific Functional Scale in patients following upper extremity nerve injury
(2013) Hand, pp. 1-7. Article in Press. 


a Toronto Western Hospital Hand Centre, Division of Plastic and Reconstructive Surgery, University of Toronto, Toronto, Canada
b Mobility Program Clinical Research Unit, St. Michael's Hospital, University of Toronto, Toronto, Canada
c Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, United States
d Department of Psychology, York University, Toronto, Canada
e Department of Anesthesia and Pain Management, Toronto General Hospital, Toronto, Canada
f Department of Anesthesia, University of Toronto, Toronto, Canada
g University of Toronto, TWH Hand Centre, 399 Bathurst Street, EW 2-422, Toronto, M5T 2S8, Canada


Abstract
Purpose: This study evaluated the validity of the Patient Specific Functional Scale (PSFS) in patients with upper extremity nerve injury. Methods: Following Research Ethics Boards (REB) approval, we included English-speaking adults, with greater than 6 months after an upper extremity nerve injury. Patient reported questionnaires included: PSFS, 36-item short-form health survey (SF-36), Disabilities of the Arm, Shoulder and Hand (DASH), McGill Pain Questionnaire, Pain Catastrophizing Scale (PCS) and Pain Disability Index (PDI). Statistical analyses evaluated the relationships among the outcome measures and the independent variables (age, gender, nerve injured, time since injury, work status, worker's compensation/litigation). Linear regression was used to evaluate the variables that predicted the PSFS. Results: There were 157 patients (53 women, 104 men); median time since injury of 14 months. The mean ± SD scores were: PSFS 3.1 ± 2.3, DASH 44 ± 22, PCS 16 ± 15, pain intensity 4.2 ± 3.0, pain rating index 13 ± 11, PDI 28.3 ± 17.6 and SF-36 component scores physical (41.8 ± 8.7) mental (45.9 ± 12.6). There were moderate correlations between the PSFS and the DASH, and the SF-36 physical role domain. The PSFS was significantly lower in brachial plexus injuries. The final model explained 20.7 % of the variance and independent variables were DASH, nerve injured and age. Conclusion: This study provides evidence of construct validity of the PSFS for patients with upper extremity nerve injury. The PSFS is a valid method to assess functional limitations identified by the individual and can be completed in a shorter period of time than the DASH. © 2013 American Association for Hand Surgery.


Author Keywords
Nerve injury;  Outcome;  Self-report function;  Upper extremity;  Validity


Document Type: Article in Press
Source: Scopus

Koopmeiners, A.S.a , Mueller, S.b , Kramer, J.c , Hogan, Q.H.b d 
Effect of Electrical Field Stimulation on Dorsal Root Ganglion Neuronal Function
(2013) Neuromodulation, . Article in Press. 


a Department of Pathology Washington University of St. Louis St. Louis, MO USA
b Department of Anesthesiology Medical College of Wisconsin Milwaukee, WI USA
c Spinal Modulation, Inc. Palo Alto, CA USA
d Zablocki VA Medical Center Milwaukee, WI USA


Abstract
Objectives: Neural stimulation may provide analgesia for a variety of painful conditions. Activation of primary sensory neurons, which underlies pain relief by spinal cord stimulation, also may be achieved by stimulation at the level of the dorsal root ganglion (DRG). The DRG also is a site of pain pathogenesis, particularly in neuropathic pain. We therefore examined the hypothesis that field stimulation of the DRG directly suppresses excitability of sensory neurons. Materials and Methods: Intercellular Ca2+ level (Fura-2 microfluorimetry) and membrane potential were recorded in excised rat DRGs with ganglionic field stimulation (GFS) delivered by wire electrodes in the bath solution adjacent to the DRG. Neuronal excitability was evaluated by number of action potentials (APs) generated during neuronal depolarization, conduction velocity during axonal stimulation, and AP propagation failure. These were measured before and after 90sec of GFS at 60Hz. Data analysis employed chi-square, paired t-test, and analysis of variance. Results: GFS using 400-μsec pulses and 30V generated Ca2+ influx, indicative of DRG neuronal activation. Fewer neurons were able to fire one or more APs after GFS (N = 23) than in control neurons without GFS (N = 24, p &lt; 0.05), and fewer neurons were able to generate multiple APs after GFS compared with time controls (p &lt; 0.05). GFS significantly reduced conduction velocity compared with baseline before GFS (N = 16, p &lt; 0.05) while there was no change in the controls (N = 18). The peak rate at which APs could be propagated was reduced in 9 of 16 neurons by GFS, but propagation efficiency was reduced in only 4 of 18 control neurons (p &lt; 0.05), and the total number of APs generated in an ensemble of stimuli at different frequencies was reduced by GFS (N = 16, p &lt; 0.05) but not in time controls (N = 18). Conclusions: Our findings indicate that direct excitation of the DRG by electrical fields reduces neuronal excitability and may provide a new analgesic approach. © 2013 International Neuromodulation Society.


Author Keywords
Electrode placement;  Neuropathic pain;  Neurostimulation;  Peripheral nerve stimulation;  Rats;  Stimulation


Document Type: Article in Press
Source: Scopus

Waldron, M.a b , Bucholz, K.K.a , Lynskey, M.T.a , Madden, P.A.F.a , Heath, A.C.a 
Alcoholism and timing of separation in parents: Findings in a midwestern birth cohort
(2013) Journal of Studies on Alcohol and Drugs, 74 (2), pp. 337-348. 


a School of Education, Indiana University, Bloomington, IN, United States
b Midwest Alcoholism Research Center, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States


Abstract
Objective: We examined history of alcoholism and occurrence and timing of separation in parents of a female twin cohort. Method: Parental separation (never-together; never-married cohabitants who separated; married who separated) was predicted from maternal and paternal alcoholism in 326 African ancestry (AA) and 1,849 European/ other ancestry (EA) families. Broad (single-informant, reported in abstract) and narrow (self-report or two-informant) measures of alcoholism were compared. Results: Parental separation was more common in families with parental alcoholism: By the time twins were 18 years of age, parents had separated in only 24% of EA families in which neither parent was alcoholic, contrasted with 58% of families in which only the father was (father-only), 61% of families in which only the mother was (mother-only), and 75% in which both parents were alcoholic (two-parent); corresponding AA percentages were 59%, 71%, 82%, and 86%, respectively. Maternal alcoholism was more common in EA never-together couples (mother-only: odds ratio [OR] = 5.95; two parent: OR = 3.69). In ever-together couples, alcoholism in either parent predicted elevated risk of separation, with half of EA relationships ending in separation within 12 years of twins' birth for father-only families, 9 years for mother-only families, and 4 years for both parents alcoholic; corresponding median survival times for AA couples were 9, 4, and 2 years, respectively. EA maternal alcoholism was especially strongly associated with separation in the early postnatal years (mother-only: birth-5 years, hazard ratio [HR] = 4.43; 6 years on, HR = 2.52; two-parent: HRs = 5.76, 3.68, respectively). Conclusions: Parental separation is a childhood environmental exposure that is more common in children of alcoholics, with timing of separation highly dependent on alcoholic parent gender.


Document Type: Article
Source: Scopus

Dougherty, J.D.a b , Maloney, S.E.a b , Wozniak, D.F.b , Rieger, M.A.a b , Sonnenblick, L.c d e , Coppola, G.d , Mahieu, N.G.a , Zhang, J.f , Cai, J.h , Patti, G.J.a , Abrahams, B.S.h , Geschwind, D.H.c d e , Heintz, N.f g 
The disruption of Celf6, a gene identified by translational profiling of serotonergic neurons, results in autism-related behaviors
(2013) Journal of Neuroscience, 33 (7), pp. 2732-2753. 


a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c UCLA Center for Autism Research and Treatment, Semel Institute for Neuroscience and Behavior, United States
d Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
e Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, United States
f Laboratory of Molecular Biology, Howard Hughes Medical Institute, New York, NY 10065, United States
g The GENSAT Project, Rockefeller University, New York, NY 10065, United States
h Department of Genetics and Neuroscience, Albert Einstein College of Medicine, New York, NY 10461, United States


Abstract
The immense molecular diversity of neurons challenges our ability to understand the genetic and cellular etiology of neuropsychiatric disorders. Leveraging knowledge from neurobiology may help parse the genetic complexity: identifying genes important for a circuit that mediates a particular symptom of a disease may help identify polymorphisms that contribute to risk for the disease as a whole. The serotonergic system has long been suspected in disorders that have symptoms of repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit translational profiling of serotonergic neurons. From this, we identified several thousand serotonergic-cell expressed transcripts, of which 174 were highly enriched, including all known markers of these cells. Analysis of common variants near the corresponding genes in the AGRE collection implicated the RNA binding protein CELF6 in autism risk. Screening for rare variants in CELF6 identified an inherited premature stop codon in one of the probands. Subsequent disruption of Celf6 in mice resulted in animals exhibiting resistance to change and decreased ultrasonic vocalization as well as abnormal levels of serotonin in the brain. This work provides a reproducible and accurate method to profile serotonergic neurons under a variety of conditions and suggests a novel paradigm for gaining information on the etiology of psychiatric disorders. © 2013 the authors.


Document Type: Article
Source: Scopus

Li, M.a e , Yasumura, D.b , Ma, A.A.K.a , Matthes, M.T.b , Yang, H.b , Nielson, G.b , Huang, Y.c , Szoka, F.C.d , LaVail, M.M.b , Diamond, M.I.a 
Intravitreal Administration of HA-1077, a ROCK Inhibitor, Improves Retinal Function in a Mouse Model of Huntington Disease
(2013) PLoS ONE, 8 (2), art. no. e56026, . 


a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Beckman Vision Center, University of California San Francisco, San Francisco, CA, United States
c UCSF School of Pharmacy, Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, United States
d Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, CA, United States
e Vision Science Core, Gene Delivery Module, School of Optometry, University of California, Berkeley, CA, United States


Abstract
Huntington disease (HD) is an inherited neurodegenerative disease that affects multiple brain regions. It is caused by an expanded polyglutamine tract in huntingtin (Htt). The development of therapies for HD and other neurodegenerative diseases has been hampered by multiple factors, including the lack of clear therapeutic targets, and the cost and complexity of testing lead compounds in vivo. The R6/2 HD mouse model is widely used for pre-clinical trials because of its progressive and robust neural dysfunction, which includes retinal degeneration. Profilin-1 is a Htt binding protein that inhibits Htt aggregation. Its binding to Htt is regulated by the rho-associated kinase (ROCK), which phosphorylates profilin at Ser-137. ROCK is thus a therapeutic target in HD. The ROCK inhibitor Y-27632 reduces Htt toxicity in fly and mouse models. Here we characterized the progressive retinopathy of R6/2 mice between 6-19 weeks of age to determine an optimal treatment window. We then tested a clinically approved ROCK inhibitor, HA-1077, administered intravitreally via liposome-mediated drug delivery. HA-1077 increased photopic and flicker ERG response amplitudes in R6/2 mice, but not in wild-type littermate controls. By targeting ROCK with a new inhibitor, and testing its effects in a novel in vivo model, these results validate the in vivo efficacy of a therapeutic candidate, and establish the feasibility of using the retina as a readout for CNS function in models of neurodegenerative disease. © 2013 Li et al.


Document Type: Article
Source: Scopus

Pineda, R.G.a , Castellano, A.a , Rogers, C.b , Neil, J.J.c , Inder, T.c 
Factors associated with developmental concern and intent to access therapy following discharge from the NICU
(2013) Pediatric Physical Therapy, 25 (1), pp. 62-69. 


a Program in Occupational Therapy and Pediatrics, School of Medicine, Washington University, 660 S Euclid Ave, St. Louis, MO 63110, United States
b Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
c Departments of Pediatrics, Neurology, and Radiology, Washington University School of Medicine, St Louis, MO, United States


Abstract
Purpose: To determine factors associated with mothers' concern about infant development and intent to access therapy services following neonatal intensive care unit (NICU) discharge. Methods: Infant medical factors, magnetic resonance imaging results, neurobehavior at term, maternal factors, and maternal perceptions about developmental concern and intent to access therapy at NICU discharge were prospectively collected in 84 infants born premature (<30 weeks gestation). Regression was used to determine factors associated with developmental concern and intent to access therapy at NICU discharge. Results: Decreased developmental concern was reported by mothers with more children (P = .007). Infant stress signs (P = .038), higher maternal education (P = .047), reading books (P = .030), and maternal depression (P = .018) were associated with increased developmental concern. More maternal education was associated with more intent to access services (P = .040). Conclusion: Maternal factors, rather than infant factors, had important associations with caregiver concern. In contrast, abnormal term neurobehavior and/or the presence of cerebral injury were not associated with caregiver concern about development. © 2013 Wolters Kluwer Health | Lippincott Williams Wilkins.


Author Keywords
adult;  anxiety;  child;  disabled children/rehabilitation;  early intervention;  educational status;  female;  health services accessibility;  humans;  income;  infant;  male;  neonatal intensive care;  parents/psychology;  premature infant;  questionnaires;  severity of illness;  socioeconomic factors


Document Type: Article
Source: Scopus

Freedland, K.E.
Demanding attention: Reconsidering the role of attention control groups in behavioral intervention research
(2013) Psychosomatic Medicine, 75 (2), pp. 100-102. 


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


Abstract
Attention control groups play an important but controversial role in randomized controlled trials of behavioral interventions. The study by Pagoto et al. in this issue of Psychosomatic Medicine provides an informative example of some of the problems that attention control conditions can create in psychosomatic and behavioral medicine trials. This article discusses the reasons why these problems occur and provides some practical solutions. It also explains why controlling for attention is unnecessary and counterproductive in some behavioral trials. Copyright © 2013 by the American Psychosomatic Society.


Author Keywords
clinical trials;  confounding factors;  control groups;  placebo effect;  placebos;  psychotherapy;  randomized controlled trials


Document Type: Review
Source: Scopus

Willis, A.W.a , Schootman, M.b , Kung, N.a , Racette, B.A.a 
Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson's Disease in the United States
(2013) Parkinsonism and Related Disorders, 19 (2), pp. 202-206. 


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


Abstract
Background: To determine the demographic distribution of Young Onset Parkinson's Disease (YOPD) in the United States and to quantify the burden of neuropsychiatric disease manifestations. Methods: Cross sectional study of 3,459,986 disabled Americans, aged 30-54, who were receiving Medicare benefits in the year 2005. We calculated race and sex distributions of YOPD and used logistic regression to compare the likelihood of common and uncommon psychiatric disorders between beneficiaries with YOPD and the general disability beneficiary population, adjusting for race, age, and sex. Results: We identified 14,354 Medicare beneficiaries with YOPD (prevalence = 414.9 per 100,000 disabled Americans). White men comprised the majority of cases (48.9%), followed by White women (34.7%), Black men (6.8%), Black women (5.0%), Hispanic men (2.4%), and Hispanic women (1.2%). Asian men (0.6%) and Asian women (0.4%) were the least common race-sex pairs with a YOPD diagnosis in this population (chi square, p < 0.001). Compared to the general population of medically disabled Americans, those with YOPD were more likely to receive medical care for depression (OR: 1.89, 1.83-1.95), dementia (OR: 7.73, 7.38-8.09), substance abuse/dependence (OR: 3.00, 2.99-3.01), and were more likely to be hospitalized for psychosis (OR: 3.36, 3.19-3.53), personality/impulse control disorders (OR: 4.56, 3.28-6.34), and psychosocial dysfunction (OR: 3.85, 2.89-5.14). Conclusions: Young Onset Parkinson's Disease is most common among white males in our study population. Psychiatric illness, addiction, and cognitive impairment are more common in YOPD than in the general population of disabled Medicare beneficiaries. These may be key disabling factors in YOPD. © 2012 Elsevier Ltd.


Author Keywords
Addiction;  Dementia;  Medicare;  Psychiatry;  Young Onset Parkinson's Disease


Document Type: Article
Source: Scopus

Graboyes, E.M., Hullar, T.E.
The war of jenkins' ear
(2013) Otology and Neurotology, 34 (2), pp. 368-372. 


Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid Avenue, Louis, MO 63110, United States


Abstract
OBJECTIVE: In 1731, Spanish sailors boarded the British brig Rebecca off the coast of Cuba and sliced off the left ear of its captain, Robert Jenkins. This traumatic auriculectomy was used as a pretext by the British to declare war on Spain in 1739, a conflict that is now known as the War of Jenkins' Ear. Here, we examine the techniques available for auricular repair at the time of Jenkins' injury and relate them to the historical events surrounding the incident. METHODS: Review of relevant original published manuscripts and monographs. RESULTS: Surgeons in the mid-18th century did not have experience with repair of traumatic total auriculectomies. Some contemporary surgeons favored auricular prostheses over surgical treatment. Methods for the reconstruction of partial defects were available, and most authors advocated a local post-auricular flap instead of a free tissue transfer. Techniques for repair of defects of the auricle lagged behind those for repair of the nose. CONCLUSION: Limitations in care of traumatic auricular defects may have intensified the significance of Jenkins' injury and helped lead to the War of Jenkins' Ear, but conflict between Britain and Spain was probably unavoidable because of their conflicting commercial interests in the Caribbean. Copyright © 2013 Otology & Neurotology, Inc.


Author Keywords
Auricle repair;  Auriculectomy;  Austrian succession;  Jenkins' ear;  Otology;  Surgery;  Trauma surgery;  War


Document Type: Review
Source: Scopus

Zhang, N.a , Kolesnikov, A.V.b , Jastrzebska, B.a , Mustafi, D.a , Sawada, O.c , Maeda, T.a c , Genoud, C.d , Engel, A.a , Kefalov, V.J.b , Palczewski, K.a 
Autosomal recessive retinitis pigmentosa E150K opsin mice exhibit photoreceptor disorganization
(2013) Journal of Clinical Investigation, 123 (1), pp. 121-137. 


a Department of Pharmacology, School of Medicine, Case Western Reserve University (CWRU), 10900 Euclid Avenue, Cleveland, OH 44160, United States
b Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MI, United States
c Department of Ophthalmology, School of Medicine, CWRU, Cleveland, OH, United States
d Electron Microscopy Facility, Friedrich Miescher Institute, Basel, Switzerland


Abstract
The pathophysiology of the E150K mutation in the rod opsin gene associated with autosomal recessive retinitis pigmentosa (arRP) has yet to be determined. We generated knock-in mice carrying a single nucleotide change in exon 2 of the rod opsin gene resulting in the E150K mutation. This novel mouse model displayed severe retinal degeneration affecting rhodopsin's stabilization of rod outer segments (ROS). Homozygous E150K (KK) mice exhibited early-onset retinal degeneration, with disorganized ROS structures, autofluorescent deposits in the subretinal space, and aberrant photoreceptor phagocytosis. Heterozygous (EK) mice displayed a delayed-onset milder retinal degeneration. Further, mutant receptors were mislocalized to the inner segments and perinuclear region. Though KK mouse rods displayed markedly decreased phototransduction, biochemical studies of the mutant rhodopsin revealed only minimally affected chromophore binding and G protein activation. Ablation of the chromophore by crossing KK mice with mice lacking the critical visual cycle protein LRAT slowed retinal degeneration, whereas blocking phototransduction by crossing KK mice with GNAT1-deficient mice slightly accelerated this process. This study highlights the importance of proper higherorder organization of rhodopsin in the native tissue and provides information about the signaling properties of this mutant rhodopsin. Additionally, these results suggest that patients heterozygous for the E150K mutation should be periodically reevaluated for delayed-onset retinal degeneration.


Document Type: Article
Source: Scopus

Schermerhorn, A.C.a , DOnofrio, B.M.a , Slutske, W.S.b , Emery, R.E.c , Turkheimer, E.c , Harden, K.P.d , Heath, A.C.e , Martin, N.G.f 
Offspring ADHD as a risk factor for parental marital problems: Controls for genetic and environmental confounds
(2012) Twin Research and Human Genetics, 15 (6), pp. 700-713. 


a Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
b Psychological Sciences, University of Missouri, Columbia, MO, United States
c Department of Psychology, University of Virginia, Charlottesville, VA, United States
d Department of Psychology, University of Texas, Austin, TX, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
f Queensland Institute of Medical Research, Herston, QLD, Australia


Abstract
Background: Previous studies have found that child attention-deficit/ hyperactivity disorder (ADHD) is associated with more parental marital problems. However, the reasons for this association are unclear. The association might be due to genetic or environmental confounds that contribute to both marital problems and ADHD. Method: Data were drawn from the Australian Twin Registry, including 1,296 individual twins, their spouses, and offspring. We studied adult twins who were discordant for offspring ADHD. Using a discordant twin pairs design, we examined the extent to which genetic and environmental confounds, as well as measured parental and offspring characteristics, explain the ADHD-marital problems association. Results: Offspring ADHD predicted parental divorce and marital conflict. The associations were also robust when comparing differentially exposed identical twins to control for unmeasured genetic and environmental factors, when controlling for measured maternal and paternal psychopathology, when restricting the sample based on timing of parental divorce and ADHD onset, and when controlling for other forms of offspring psychopathology. Each of these controls rules out alternative explanations for the association. Conclusion: The results of the current study converge with those of prior research in suggesting that factors directly associated with offspring ADHD increase parental marital problems. © The Authors 2012.


Author Keywords
attention-deficit/hyperactivity disorder;  behavioral genetics;  divorce;  marital conflict


Document Type: Article
Source: Scopus

North, C.S.a , Cloninger, C.R.b 
Personality and major depression among directly exposed survivors of the oklahoma city bombing
(2012) Depression Research and Treatment, 2012, art. no. 204741, . 


a Departments of Psychiatry and Surgery, VA North Texas Health Care System, University of Texas Southwestern Medical Center at Dallas, 6363 Forest Park Road, Dallas, TX 75390-8828, United States
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO 63110, United States


Abstract
Background. Few disaster studies have specifically examined personality and resilience in association with disaster exposure, posttraumatic stress disorder (PTSD), and major depression. Methods. 151 directly-exposed survivors of the Oklahoma City bombing randomly selected from a bombing survivor registry completed PTSD, major depression, and personality assessments using the Diagnostic Interview Schedule for DSM-IV and the Temperament and Character Inventory, respectively. Results. The most prevalent postdisaster psychiatric disorder was bombing-related PTSD (32%); major depression was second in prevalence (21%). Bombing-related PTSD was associated with the combination of low self-directedness and low cooperativeness and also with high self-transcendence and high harm avoidance in most configurations. Postdisaster major depression was significantly more prevalent among those with (56%) than without (5%) bombing-related PTSD (P <.001) and those with (72%) than without (14%) predisaster major depression (P <.001). Incident major depression was not associated with the combination of low self-directedness and low cooperativeness. Conclusions. Personality features can distinguish resilience to a specific life-threatening stressor from general indicators of well-being. Unlike bombing-related PTSD, major depression was not a robust marker of low resilience. Development and validation of measures of resilience should utilize well-defined diagnoses whenever possible, rather than relying on nonspecific measures of psychological distress. © 2012 Carol S. North and C. Robert Cloninger.


Document Type: Article
Source: Scopus

Kitamura, T.a , Cloninger, C.R.b , Fossati, A.c , Richter, J.d 
Temperament and character domains of personality and depression 2012
(2012) Depression Research and Treatment, 2012, art. no. 946725, . 


a Kitamura Institute of Mental Health Tokyo, 101 Minato 8-5-13, Tokyo 107-0052, Japan
b Department of Psychiatry, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63130, United States
c Faculty of Psychology, Vita-Salute San Raffaele University, 20132 Milan, Italy
d Centre for Child and Adolescent Mental Health, Ulleval University Hospital, 0424 Oslo, Norway


Document Type: Editorial
Source: Scopus

Baughman, H.M.a , Giammarco, E.A.a , Veselka, L.a , Schermer, J.A.b , Martin, N.G.c , Lynskey, M.d , Vernon, P.A.a 
A behavioral genetic study of humor styles in an Australian sample
(2012) Twin Research and Human Genetics, 15 (5), pp. 663-667. 


a Department of Psychology, University of Western Ontario, London, ON, Canada
b Management and Organizational Studies, University of Western Ontario, London, ON, Canada
c Queensland Institute of Medical Research, Brisbane, QLD, Australia
d Department of Psychiatry, Washington University School of Medicine, St Louis, United States


Abstract
The present study investigated the extent to which individual differences in humor styles are attributable to genetic and/or environmental factors in an Australian sample. Participants were 934 same-sex pairs of adult twins from the Australian Twin Registry (546 monozygotic pairs, 388 dizygotic pairs) who completed the Humor Styles Questionnaire (HSQ). The HSQ measures four distinct styles of humor - affiliative, self-enhancing, aggressive, and self-defeating. Results revealed that additive genetic and non-shared environmental factors accounted for the variance in all four humor styles, thus replicating results previously obtained in a sample of twins from the United Kingdom. However, a study conducted with a U.S. sample produced different results and we interpret these findings in terms of cross-cultural differences in humor. © The Authors 2012.


Author Keywords
Genetic and Environmental contributions to individual differences;  Humor styles;  Twin study


Document Type: Article
Source: Scopus

Lynskey, M.T.a , Agrawal, A.a , Henders, A.b , Nelson, E.C.a , Madden, P.A.F.a , Martin, N.G.b 
An Australian twin study of cannabis and other illicit drug use and misuse, and other psychopathology
(2012) Twin Research and Human Genetics, 15 (5), pp. 631-641. 


a Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, United States
b Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, QLD, Australia


Abstract
Cannabis is the most widely used illicit drug throughout the developed world and there is consistent evidence of heritable influences on multiple stages of cannabis involvement including initiation of use and abuse/dependence. In this paper, we describe the methodology and preliminary results of a large-scale interview study of 3,824 young adult twins (born 1972-1979) and their siblings. Cannabis use was common with 75.2% of males and 64.7% of females reporting some lifetime use of cannabis while 24.5% of males and 11.8% of females reported meeting criteria for DSM-IV cannabis abuse or dependence. Rates of other drug use disorders and common psychiatric conditions were highly correlated with extent of cannabis involvement and there was consistent evidence of heritable influences across a range of cannabis phenotypes including early (≤15 years) opportunity to use (h 2 = 72%), early (≤16 years) onset use (h 2 = 80%), using cannabis 11+ times lifetime (h 2 = 76%), and DSM abuse/dependence (h 2 = 72%). Early age of onset of cannabis use was strongly associated with increased rates of subsequent use of other illicit drugs and with illicit drug abuse/dependence; further analyses indicating that some component of this association may have been mediated by increasing exposure to and opportunity to use other illicit drugs. © The Authors 2012.


Author Keywords
Cannabis;  Comorbidity;  Illicit drugs;  twin


Document Type: Article
Source: Scopus

Kotipatruni, R.P., Ferraro, D.J., Ren, X., Vanderwaal, R.P., Thotala, D.K., Hallahan, D.E., Jaboin, J.J.
NDRG4, the N-Myc downstream regulated gene, is important for cell survival, tumor invasion and angiogenesis in meningiomas.
(2012) Integrative biology : quantitative biosciences from nano to macro, 4 (10), pp. 1185-1197. 


Department of Radiation Oncology, Washington University in St Louis, St Louis, MO 63108, USA.


Abstract
Meningiomas are the second most common brain tumor, and 20-30% of these tumors are aggressive. The aggressive subtypes are characterized by a capacity for invasion of normal brain with frequent and destructive recurrence patterns. Effective local therapies include surgery and radiation, but there is a need for novel molecular targets to improve survival and reduce morbidity for this group or cancer patients. We have recently identified the N-Myc downstream regulated gene 4, NDRG4, protein as being overexpressed in aggressive meningioma, and in this report, demonstrate its role in cell survival, invasion/migration and angiogenesis. Downregulation of NDRG4 mRNA and protein expression in two high-grade meningioma cancer cell lines, IOMM-Lee and CH-157 MN resulted in reduction in cell survival, DNA fragmentation and G2-M cell cycle arrest. NDRG4 downregulation also decreased cellular invasion and migration, as determined by spheroid migration, linear and radial wound healing, Boyden chamber matrigel invasion, and 3D invasion assays. To determine the effect of NDRG4 depletion on angiogenesis, we studied the immortalized brain endothelial cell line, bEnd.3. We treated bEnd.3 cells with conditioned media from NDRG4-depleted IOMM-Lee and CH-157 MN cells and abrogated their ability to elicit bEnd.3 capillary-like tubes, to proliferate, and to invade. NDRG4 is not overexpressed in bEnd.3 cells and direct NDRG4 depletion had no effect on the cells. This study is significant as it is the first to demonstrate the functional role of NDRG4 in various aspects of meningioma tumor biology. NDRG4 is involved in modulating cell proliferation, invasion, migration and angiogenesis in meningioma, and may play a valuable role as a molecular target in its treatment.


Document Type: Article
Source: Scopus

Zayas, L.H., Hausmann-Stabile, C., Kuhlberg, J.
Can better mother-daughter relations reduce the chance of a suicide attempt among latinas?
(2011) Depression Research and Treatment, 2011, art. no. 403602, . 


Washington University in St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, MO 63130-4899, United States


Abstract
National surveys and other research on adolescent Latinas show that adolescent females have higher rates of suicidal ideation, planning, and attempts than other ethnic and racial minority youth. Internalizing behaviors and family conflicts are commonly associated with suicidality in research on adolescents. In the case of Latinas, we explore the connection between adolescent Hispanic cultural involvement, mother-adolescent mutuality, internalizing behaviors, and suicidality. This paper presents data from a study of 232 Latinas, some with a recent history of suicide attempts (n=122). The results show that higher adolescent Hispanic cultural involvement was associated with greater mother-daughter mutuality and thus led to reduction in the likelihood of suicide attempts. The relationship between mother-daughter mutuality and suicide attempts among Latinas is mediated by specific internalizing behaviors (withdrawn depressive). Our findings highlight the positive effect that Latino cultural values have in the relationship between Latina adolescent and their mothers and confirm the importance that internalizing behaviors and the mother-daughter relationship have for suicide attempters. © 2011 Luis H. Zayas et al.


Document Type: Article
Source: Scopus

Kitamura, T.a , Cloninger, C.R.b 
Temperament and character domains of personality and depression
(2011) Depression Research and Treatment, 2011, art. no. 765691, . 


a Kitamura Institute of Mental Health Tokyo, 8-12-4-305 Akasaka, Tokyo 107-0052, Japan
b Department of Psychiatry, Washington University in St. Louis, 660 South Euclid Avenue, St. Louis, MO 63130, United States


Document Type: Editorial

Source: Scopus 

February 22, 2013

 Bonner, M.F.a , Peelle, J.E.a c , Cook, P.A.b , Grossman, M.a 
Heteromodal conceptual processing in the angular gyrus
(2013) NeuroImage, 71, pp. 175-186. 

a Department of Neurology, University of Pennsylvania, Philadelphia, PA 19104, United States
b Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Otolaryngology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Concepts bind together the features commonly associated with objects and events to form networks in long-term semantic memory. These conceptual networks are the basis of human knowledge and underlie perception, imagination, and the ability to communicate about experiences and the contents of the environment. Although it is often assumed that this distributed semantic information is integrated in higher-level heteromodal association cortices, open questions remain about the role and anatomic basis of heteromodal representations in semantic memory. Here we used combined neuroimaging evidence from functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to characterize the cortical networks underlying concept representation. Using a lexical decision task, we examined the processing of concepts in four semantic categories that varied on their sensory-motor feature associations (sight, sound, manipulation, and abstract). We found that the angular gyrus was activated across all categories regardless of their modality-specific feature associations, consistent with a heteromodal account for the angular gyrus. Exploratory analyses suggested that categories with weighted sensory-motor features additionally recruited modality-specific association cortices. Furthermore, DTI tractography identified white matter tracts connecting these regions of modality-specific functional activation with the angular gyrus. These findings are consistent with a distributed semantic network that includes a heteromodal, integrative component in the angular gyrus in combination with sensory-motor feature representations in modality-specific association cortices. © 2013 Elsevier Inc.

Author Keywords
DTI;  FMRI;  Heteromodal;  Language;  Semantic memory;  Sensory-motor

Document Type: Article
Source: Scopus

Harms, M.B.a b , Neumann, D.c , Benitez, B.A.c , Cooper, B.c , Carrell, D.c , Racette, B.A.a b , Perlmutter, J.S.a b d , Goate, A.b c , Cruchaga, C.b c 
Parkinson disease is not associated with C9ORF72 repeat expansions
(2013) Neurobiology of Aging, 34 (5), pp. 1519.e1-1519.e2. 

a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
b Hope Center for Neurological Disorders, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
d Mallinckrodt Institute of Radiology, Neurobiology, Physical Therapy and Occupational Therapy, Saint Louis, MO, United States

Abstract
Hexanucleotide expansions in the C9ORF72 gene are frequently found in patients with amyotrophic lateral sclerosis, frontotemporal dementia or both, some of whom exhibit concurrent extrapyramidal symptoms. To determine if repeat expansions are a cause of Parkinson's disease (PD), we used repeat-primed polymerase chain reaction to investigate the frequency of C9ORF72 repeat expansions in a cohort of 478 patients with PD and 662 control subjects. Three control subjects were found to be expansion carriers, and no expansions were found among patients, suggesting that C9ORF72 expansions are not a common cause of PD. © 2013 Elsevier Inc.

Author Keywords
C9ORF72;  Genetics;  Hexanucleotide repeat;  Parkinson disease

Document Type: Article
Source: Scopus

Xu, J.a , Vangveravong, S.a , Li, S.a , Fan, J.a , Jones, L.A.a , Cui, J.a , Wang, R.a , Tu, Z.a , Chu, W.a , Perlmutter, J.S.a , Mach, R.H.a b c 
Positron emission tomography imaging of dopamine D2 receptors using a highly selective radiolabeled D2 receptor partial agonist
(2013) NeuroImage, 71, pp. 168-174. 

a Department of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States
c Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 510 S. Kingshighway Blvd., St. Louis, MO 63110, United States

Abstract
A series of microPET imaging studies were conducted in anesthetized rhesus monkeys using the dopamine D2-selective partial agonist, [11C]SV-III-130. There was a high uptake in regions of brain known to express a high density of D2 receptors under baseline conditions. Rapid displacement in the caudate and putamen, but not in the cerebellum, was observed after injection of the dopamine D2/3 receptor nonselective ligand S(-)-eticlopride at a low dosage (0.025mg/kg/i.v.); no obvious displacement in the caudate, putamen and cerebellum was observed after the treatment with a dopamine D3 receptor selective ligand WC-34 (0.1mg/kg/i.v.). Pretreatment with lorazepam (1mg/kg, i.v. 30min) to reduce endogenous dopamine prior to tracer injection resulted in unchanged binding potential (BP) values, a measure of D2 receptor binding in vivo, in the caudate and putamen. d-Amphetamine challenge studies indicate that there is a significant displacement of [11C]SV-III-130 by d-Amphetamine-induced increases in synaptic dopamine levels. © 2013 Elsevier Inc.

Author Keywords
Dopamine;  Dopamine D2 receptors;  Positron emission tomography

Document Type: Article
Source: Scopus

Barch, D.M.
Introduction to Special Issue on the Neurobiology of Depression
(2013) Neurobiology of Disease, 52, pp. 1-3. 

Washington University in St. Louis, United States

Document Type: Editorial
Source: Scopus

Bogdan, R.a b , Nikolova, Y.S.b , Pizzagalli, D.A.c 
Neurogenetics of depression: A focus on reward processing and stress sensitivity
(2013) Neurobiology of Disease, 52, pp. 12-23. Cited 2 times.

a BRAIN Laboratory, Department of Psychology, Washington University in St. Louis, Box 1125, One Brookings Drive, St. Louis, MO 63130, United States
b Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Box 90086, 417 Chapel Drive, Durham, NC, 27708, United States
c Center for Depression, Anxiety and Stress Research and McLean Imaging Center, McLean Hospital, Harvard Medical School, 115 Mill St., Belmont, MA 02478, United States

Abstract
Major depressive disorder (MDD) is etiologically complex and has a heterogeneous presentation. This heterogeneity hinders the ability of molecular genetic research to reliably detect the small effects conferred by common genetic variation. As a result, significant research efforts have been directed at investigating more homogenous intermediate phenotypes believed to be more proximal to gene function and lie between genes and/or environmental effects and disease processes. In the current review we survey and integrate research on two promising intermediate phenotypes linked to depression: reward processing and stress sensitivity. A synthesis of this burgeoning literature indicates that a molecular genetic approach focused on intermediate phenotypes holds significant promise to fundamentally improve our understanding of the pathophysiology and etiology of depression, which will be required for improved diagnostic definitions and the development of novel and more efficacious treatment and prevention strategies. We conclude by highlighting challenges facing intermediate phenotype research and future development that will be required to propel this pivotal research into new directions. © 2012 Elsevier Inc.

Author Keywords
CRH;  Depression;  Dopamine;  Fmri;  Gene;  HPA axis;  Intermediate phenotype;  Reward;  Stress

Document Type: Review
Source: Scopus

Gaffrey, M.S.a , Luby, J.L.a , Barch, D.M.a b c 
Towards the study of functional brain development in depression: An Interactive Specialization approach
(2013) Neurobiology of Disease, 52, pp. 38-48. Cited 1 time.

a Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
b Department of Psychology, Washington University in St. Louis, Saint Louis, MO, United States
c The Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Depression is a significant and impairing mood disorder with onset possible as early as age 3 and into adulthood. Given this varying pattern of age of onset, identifying the relationship between brain development and depression across the lifespan has proven elusive. This review identifies some of the factors that may have limited the advancement of our knowledge in this area and discusses how synthesizing established models of depression and normative brain development may help to overcome them. More specifically, it is suggested that current neurobiological models of depression fail to account for the developmental variance associated with early neural network development and the potential influence of experience on this process. The utility of applying an established framework of normative brain development to this topic is described and its potential utility for conceptualizing the influence of depression on brain function across the life span is addressed. Future directions including longitudinal neuroimaging studies of early onset depression and groups at risk for this disorder are proposed. © 2012 Elsevier Inc.

Author Keywords
Brain;  Brain development;  Depression;  Interactive Specialization;  Pediatric depression;  Preschool depression

Document Type: Review
Source: Scopus

Croteau, D.a , Rossi, S.S.b , Best, B.M.b c , Capparelli, E.b , Ellis, R.J.a , Clifford, D.B.d , Collier, A.C.e , Gelman, B.B.f , Marra, C.M.e , Mcarthur, J.g , Mccutchan, J.A.h , Morgello, S.i , Simpson, D.M.j , Grant, I.k , Letendre, S.h 
Darunavir is predominantly unbound to protein in cerebrospinal fluid and concentrations exceed the wild-type HIV-1 median 90% inhibitory concentration
(2013) Journal of Antimicrobial Chemotherapy, 68 (3), pp. 684-689. 

a Department of Neurosciences, University of California San Diego, San Diego, 220 Dickinson Street, Suite B, San Diego, CA 92103, United States
b Department of Pediatrics (Rady Children's Hospital), University of California San Diego, 3020 Children's Way, San Diego, CA 92123, United States
c Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States
d Department of Neurology, Washington University, 660 South Euclid Ave, Campus Box 8111, St Louis, MO 63110, United States
e Division of Allergy and Infectious Diseases, University of Washington, 1959 NE Pacific Street, UW 356423, Seattle, WA 98195, United States
f Department of Pathology, University of Texas Medical Branch, Keiller Building, 301 University Boulevard, Galveston, TX 77555-0609, United States
g Department of Neurology, Johns Hopkins University, Meyer 6-113, 600 N. Wolfe Street, Baltimore, MD 21287, United States
h Department of Medicine, University of California San Diego, 220 Dickinson Street, Suite A, San Diego, CA 92103, United States
i Department of Pathology, Mount Sinai School of Medicine, 1468 Madison Avenue, New York, NY 10029, United States
j Department of Neurology, Mount Sinai School of Medicine, 1468 Madison Avenue, Annenberg 2nd Floor, Box 1052, New York, NY 10029, United States
k Department of Psychiatry, University of California San Diego, 220 Dickinson Street, Suite A, San Diego, CA 92103, United States

Abstract
Objectives: Higher CSF antiretroviral concentrations may be associated with better control of HIV replication and neurocognitive performance, but only the unbound fraction of antiretrovirals is available to inhibit HIV. Therefore, the objective of this study was to determine total and unbound darunavir concentrations in CSF and compare findings with plasma concentrations as well as the wild-type HIV-1 90% inhibitory concentration (IC. 90). Methods: Subjects with HIV infection were selected based on the use of darunavir-containing regimens with a twice-daily dosing schedule and availability of stored CSF and matched plasma. Total darunavir was measured by HPLC for plasma or liquid chromatography-tandem mass spectroscopy (LC/MS/MS) for CSF. Plasma unbound darunavir was measured by ultrafiltration and LC/MS/MS. CSF protein binding was determined by competitive binding exchange with radiolabelled darunavir. Results: Twenty-nine matched CSF-plasma pairs were analysed and darunavir was detected in all CSF specimens (median total concentration 55.8 ng/mL), with a CSF unbound fraction of 93.5%. Median fractional penetrance was 1.4% of median total and 9.4% of median unbound plasma concentrations. Unbound darunavir concentrations in CSF exceeded the median IC. 90 for wild-type HIV in all subjects by a median of 20.6-fold, despite the relatively low fractional penetrance. Total darunavir concentrations in CSF correlated with both total and unbound darunavir concentrations in plasma. Conclusions: Darunavir should contribute to the control of HIV replication in the CNS as a component of effective combination antiretroviral regimens. © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.

Author Keywords
Antiretroviral therapy;  Central nervous system;  HIV;  Protein binding

Document Type: Article
Source: Scopus

Sharma, S.a , Gangopadhyay, M.b , Austin, E.c , Mandal, M.K.d 
Development and Validation of a Situational Judgment Test of Emotional Intelligence
(2013) International Journal of Selection and Assessment, 21 (1), pp. 57-73. 

a Olin Business School, Washington University in St. Louis, 1 Brooking drive, St. Louis, MO, 63130, United States
b Department of Psychology, University of Delhi, Delhi, India
c Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom
d Department of Humanities and Social Sciences, IIT-Kharagpur, Kharagpur, West Bengal, India

Abstract
The present study describes the development and validation of a situational judgment test (SJT) of emotional intelligence (EI). Initially, 80 situations and three response alternatives for each situation were created based on the available theoretical models. Principal component factor analysis with direct oblimin rotation of data (N=213) yielded a three-factor structure with 46 items. These factors were (1) utilizing own emotion, (2) sensing other's emotion, and (3) understanding emotional context. Additional studies showed that the measure had good internal consistency and test-retest reliability. None of the three factors strongly correlated with the Big Five factors of personality (NEO Five-Factor Inventory, thus establishing its identity as a construct distinct from personality. Findings of confirmatory factor analysis on secondary data reconfirm the three-factor model for a 46-item SJT of EI. The second study also found no correlation among these three factors, intelligence scores measured using Raven's Matrices, and trait EI score measured using the Trait Emotional Intelligence Questionnaire. The third study was conducted in order to determine the relationship of SJT of EI with academic achievement and life satisfaction. All three factors of SJT-based EI measure were significantly associated with academic achievement and life satisfaction. © 2013 Blackwell Publishing Ltd.

Document Type: Article
Source: Scopus

Svrakic, D.M.a b , Zorumski, C.F.a , Svrakic, N.M.a , Zwir, I.a , Cloninger, C.R.a 
Risk architecture of schizophrenia: The role of epigenetics
(2013) Current Opinion in Psychiatry, 26 (2), pp. 188-195. 

a Department of Psychiatry, Washington University School of Medicine in St Louis, Campus Box 8134, 660 S Euclid Avenue, St Louis, MO 63110, United States
b VA Medical Center, St Louis, MO, United States

Abstract
PURPOSE OF REVIEW: To systematize existing data and review new findings on the cause of schizophrenia and outline an improved mixed model of schizophrenia risk. RECENT FINDINGS: Multiple and variable genetic and environmental factors interact to influence the risk of schizophrenia. Both rare variants with large effect and common variants with small effect contribute to genetic risk of schizophrenia, with no indication for differential impact on its clinical features. Accumulating evidence supports a genetic architecture of schizophrenia with multiple scenarios, including additive polygenic, heterogeneity, and mixed polygenic-heterogeneity. The epigenetic mechanisms that mediate gene-environment (GxE) interactions provide a framework to incorporate environmental factors into models of schizophrenia risk. Environmental pathogens with small effect on risk have robust effects in the context of family history of schizophrenia. Hence, genetic risk for schizophrenia may be expressed in part as sensitivity to environmental factors. SUMMARY: We propose an improved mixed model of schizophrenia risk in which abnormal epigenetic states with large effects are superimposed on a polygenic liability to schizophrenia. This scenario can account for GxE interactions and shared family environment, which in many cases are not explained by a single structural variant of large effect superimposed on polygenes (the traditional mixed model). © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Author Keywords
epigenetics;  genetics;  risk factors;  schziophrenia

Document Type: Review
Source: Scopus

Karasinska, J.M.a , de Haan, W.a , Franciosi, S.a , Ruddle, P.a , Fan, J.b , Kruit, J.K.a , Stukas, S.b , Lütjohann, D.c , Gutmann, D.H.d , Wellington, C.L.b , Hayden, M.R.a 
ABCA1 influences neuroinflammation and neuronal death
(2013) Neurobiology of Disease, . Article in Press. 

a Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada
b Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
c Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
d Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

Abstract
ATP-binding cassette transporter A1 (ABCA1) mediates cellular cholesterol efflux in the brain and influences whole brain cholesterol homeostasis. Activation of liver X receptors (LXRs), transcription factors that increase the expression of cholesterol transport genes including ABCA1, reduces neuroinflammation and pathology in neurodegenerative animal models suggesting that in addition to its involvement in cholesterol transport, ABCA1 may play a role in modulating the inflammatory response in the brain. We investigated the cell-type specific role of ABCA1 in neuroinflammation in vivo using mice specifically lacking brain ABCA1 (ABCA1- B/- B) as well as mice lacking neuronal (ABCA1- N/- N) and astrocytic (ABCA1- Ast/- Ast) ABCA1. ABCA1- B/- B mice exhibit cortical astrogliosis, increased inflammatory gene expression as well as activation of mitogen-activated protein kinases (MAPKs) following acute lipopolysaccharide (LPS) administration. Microglia cultured from ABCA1- B/- B mice exhibit augmented LPS-induced secretion of tumor necrosis factor α (TNFα) and decreased phagocytic activity, indicating an increase in a pro-inflammatory response. ABCA1- N/- N mice develop astrogliosis but show no change in inflammatory gene expression. Intriguingly, ABCA1- Ast/- Ast mice show neither astrogliosis nor elevated expression of inflammatory markers. Cortical apolipoprotein E (apoE) levels are reduced in ABCA1- Ast/- Ast but not in ABCA1- N/- N mice, providing in vivo evidence for the specific role of astrocyte ABCA1 in regulating brain apoE levels. Interestingly, cortical neuronal death is increased in 17 month-old ABCA1- B/- B mice but not in ABCA1- N/- N or ABCA1- Ast/- Ast mice. Our findings suggest that coordinated ABCA1 activity across neurons and glial cells influences neuroinflammation and neurodegeneration. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
ABCA1;  Apolipoproteins;  Brain cholesterol metabolism;  Neurodegeneration;  Neuroinflammation

Document Type: Article in Press
Source: Scopus

Antenor-Dorsey, J.A.V.a , Laforest, R.b , Moerlein, S.M.b , Videen, T.O.b c , Perlmutter, J.S.a b c d e 
Erratum to: Radiation dosimetry of N-([11C]methyl)benperidol as determined by whole-body PET imaging of primates
(2013) European Journal of Nuclear Medicine and Molecular Imaging, pp. 1-2. Article in Press. 

a Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, United States
d Program in Physical Therapy, Washington University School of Medicine, St. Louis, United States
e Campus Box 8225, 4525 Scott Avenue, St. Louis, 63110, United States

Abstract
Purpose: N-([11C]Methyl)benperidol ([11C]NMB) can be used for PET measurements of D2-like dopamine receptor binding in vivo. We report the absorbed radiation dosimetry of i.v.-administered [11C]NMB, a critical step prior to applying this radioligand to imaging studies in humans. Materials and methods: Whole-body PET imaging with a CTI/Siemens ECAT 953B scanner was done in a male and a female baboon. Following i.v. injection of 370-555 kBq of [11C]NMB, sequential images taken from the head to the pelvis were collected for three hours. Volumes of interest (VOIs) were identified that entirely encompassed small organs (whole brain, striatum, eyes, and myocardium). Large organs (liver, lungs, kidneys, lower large intestine, and urinary bladder) were sampled by drawing representative regions within the organ volume. Time-activity curves for each VOI were extracted from the PET and organ residence times were calculated by analytical integration of a multi-exponential fit of the time-activity curves. Human radiation doses were estimated using OLINDA/EXM 1.0 and the standard human model. Results: Highest retention was observed in the blood and liver, each with total residence times of 1.5 min. The highest absorbed radiation doses were to the heart (10.5 μGy/MBq) and kidney (9.10 μGy/MBq), making these the critical organs for [11C]NMB. A heart absorption of 0.5 μGy would result from an injected dose of 4847 kBq [11C]NMB. Conclusions: Thus, up to 3700 kBq of [11C]NMB can be safely administered to human subjects for PET studies. Total body dose and effective dose for [11C]NMB are 2.8 μGy/MBq and 3.7 μSv/MBq, respectively. © 2013 Springer-Verlag Berlin Heidelberg.

Document Type: Article in Press
Source: Scopus

Reynolds, L.C.a , Duncan, M.M.a , Smith, G.C.b , Mathur, A.b , Neil, J.c d e , Inder, T.c d e , Pineda, R.G.b f 
Parental presence and holding in the neonatal intensive care unit and associations with early neurobehavior
(2013) Journal of Perinatology, . Article in Press. 

a Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, USA
b Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
c 1] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA
d Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
e Department of Radiology, Washington University School of Medicine, St Louis, MO, USA
f 1] Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, USA

Abstract
Objective:To investigate the effects of parental presence and infant holding in the neonatal intensive care unit (NICU) on neurobehavior at term equivalent.Study Design:Prospective cohort enrolled 81 infants born ≤30 weeks gestation. Nurses tracked parent visitation, holding and skin-to-skin care throughout the NICU hospitalization. At term, the NICU Network Neurobehavioral Scale was administered. Associations between visitation, holding and early neurobehavior were determined using linear and logistic regression. Result:The mean hours per week of parent visitation was 21.33±20.88 (median=13.90; interquartile range 10.10 to 23.60). Infants were held an average of 2.29±1.47 days per week (median=2.00; interquartile range 1.20 to 3.10). Over the hospital stay, visitation hours decreased (P=0.01), while holding frequencies increased (P<0.001). More visitation was associated with better quality of movement (P=0.02), less arousal (P=0.01), less excitability (P=0.03), more lethargy (P=0.01) and more hypotonia (P<0.01). More holding was associated with improved quality of movement (P<0.01), less stress (P<0.01), less arousal (P=0.04) and less excitability (P<0.01). Conclusion:Infants of caregivers who were visited and held more often in the NICU had differences in early neurobehavior by term equivalent, which supports the need for and importance of early parenting in the NICU.Journal of Perinatology advance online publication, 14 February 2013; doi:10.1038/jp.2013.4.

Document Type: Article in Press
Source: Scopus

Doshi, R.R.a , Harocopos, G.J.b , Schwab, I.R.c , Cunningham Jr., E.T.a d 
The spectrum of postoperative scleral necrosis
(2013) Survey of Ophthalmology, . Article in Press. 

a The Department of Ophthalmology, California Pacific Medical Center, San Francisco, California, USA
b The Departments of Ophthalmology and Visual Sciences and of Pathology and Immunology, Washington University, St. Louis, Missouri, USA
c The Department of Ophthalmology and Vision Science, University of California-Davis, Sacramento, California, USA
d The Department of Ophthalmology, Stanford University School of Medicine, Stanford, California, USA

Abstract
An otherwise healthy 62-year-old woman developed necrotizing scleritis 23 years following pterygium excision with adjunctive beta-radiation. Surgically induced necrotizing scleritis (SINS) was diagnosed, but the scleritis progressed despite anti-inflammatory therapy, and 10 weeks after presentation the patient developed a hypopyon and decreased vision. After cultures revealed no growth at 72 hours, immunosuppressive therapy was escalated, with a subsequent deterioration in the patient's clinical course. Scedosporium superinfection was eventually cultured and found on histological examination of the enucleated globe. In reported cases, infectious scleral necrosis occurs most commonly following pterygium (71.4%) and scleral buckling (97.2%) surgery. Hypopyon is uncommon (10.0%) in patients with postoperative scleral necrosis, but when present is a strong predictor of infection (odds ratio, 21.2; 95% confidence interval, 2.9-157.5). Rates of underlying autoimmune disease are generally low (0.0-12.5%) except following cataract and lens procedures, where the occurence of SINS heralds systemic illness in 42.9% of cases. © 2013 Elsevier Inc. All rights reserved.

Author Keywords
beta-radiation;  fungal scleritis;  pterygium;  scleral necrosis;  surgically induced necrotizing scleritis

Document Type: Article in Press
Source: Scopus

Mac Donald, C.a , Johnson, A.a , Cooper, D.a , Malone, T.a , Sorrell, J.a , Shimony, J.b , Parsons, M.b , Snyder, A.b , Raichle, M.b , Fang, R.c e , Flaherty, S.c f , Russell, M.d , Brody, D.L.a 
Cerebellar White Matter Abnormalities following Primary Blast Injury in US Military Personnel
(2013) PLoS ONE, 8 (2), art. no. e55823, . 

a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
c Department of Trauma Surgery, Landstuhl Regional Medical Center, Landstuhl, Germany
d Rehabilitation and Reintegration Division, US Army, San Antonio, TX, United States
e Department of Surgery, University of Maryland, Baltimore, MD, United States
f Department of Trauma, Cape Fear Valley Medical Center, Fayetteville, NC, United States

Abstract
Little is known about the effects of blast exposure on the human brain in the absence of head impact. Clinical reports, experimental animal studies, and computational modeling of blast exposure have suggested effects on the cerebellum and brainstem. In US military personnel with isolated, primary blast-related 'mild' traumatic brain injury and no other known insult, we found diffusion tensor MRI abnormalities consistent with cerebellar white matter injury in 3 of 4 subjects. No abnormalities in other brain regions were detected. These findings add to the evidence supporting the hypothesis that primary blast exposure contributes to brain injury in the absence of head impact and that the cerebellum may be particularly vulnerable. However, the clinical effects of these abnormalities cannot be determined with certainty; none of the subjects had ataxia or other detected evidence of cerebellar dysfunction. The details of the blast events themselves cannot be disclosed at this time, thus additional animal and computational modeling will be required to dissect the mechanisms underlying primary blast-related traumatic brain injury. Furthermore, the effects of possible subconcussive impacts and other military-related exposures cannot be determined from the data presented. Thus many aspects of topic will require further investigation. © 2013 Mac Donald et al.

Document Type: Article
Source: Scopus

Wang, W.a b c d , Collinger, J.L.a b e , Degenhart, A.D.b d , Tyler-Kabara, E.C.a b f , Schwartz, A.B.a b d g , Moran, D.W.h , Weber, D.J.a b d e , Wodlinger, B.a d , Vinjamuri, R.K.a , Ashmore, R.C.a , Kelly, J.W.i , Boninger, M.L.a b c e 
An Electrocorticographic Brain Interface in an Individual with Tetraplegia
(2013) PLoS ONE, 8 (2), art. no. e55344, . 

a Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, PA, United States
b Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
c Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA, United States
d Center for the Neural Basis of Cognition, Carnegie Mellon University and the University of Pittsburgh, Pittsburgh, PA, United States
e Human Engineering Research Laboratories, Department of Veterans Affairs, Pittsburgh, PA, United States
f Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, United States
g Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, United States
h Departments of Biomedical Engineering and Neurobiology, Washington University in St. Louis, St. Louis, MO, United States
i Department of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, United States

Abstract
Brain-computer interface (BCI) technology aims to help individuals with disability to control assistive devices and reanimate paralyzed limbs. Our study investigated the feasibility of an electrocorticography (ECoG)-based BCI system in an individual with tetraplegia caused by C4 level spinal cord injury. ECoG signals were recorded with a high-density 32-electrode grid over the hand and arm area of the left sensorimotor cortex. The participant was able to voluntarily activate his sensorimotor cortex using attempted movements, with distinct cortical activity patterns for different segments of the upper limb. Using only brain activity, the participant achieved robust control of 3D cursor movement. The ECoG grid was explanted 28 days post-implantation with no adverse effect. This study demonstrates that ECoG signals recorded from the sensorimotor cortex can be used for real-time device control in paralyzed individuals.

Document Type: Article
Source: Scopus

Bagchi, D.P.a b c , Yu, L.c d , Perlmutter, J.S.a c d e f g , Xu, J.c d , Mach, R.H.c d , Tu, Z.c d , Kotzbauer, P.T.a b c 
Binding of the Radioligand SIL23 to α-Synuclein Fibrils in Parkinson Disease Brain Tissue Establishes Feasibility and Screening Approaches for Developing a Parkinson Disease Imaging Agent
(2013) PLoS ONE, 8 (2), art. no. e55031, . 

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, United States
f Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
g Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Accumulation of α-synuclein (α-syn) fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson disease (PD). Ligands that bind α-syn fibrils could be utilized as imaging agents to improve the diagnosis of PD and to monitor disease progression. However, ligands for α-syn fibrils in PD brain tissue have not been previously identified and the feasibility of quantifying α-syn fibrils in brain tissue is unknown. We report the identification of the 125I-labeled α-syn radioligand SIL23. [125I]SIL23 binds α-syn fibrils in postmortem brain tissue from PD patients as well as an α-syn transgenic mouse model for PD. The density of SIL23 binding sites correlates with the level of fibrillar α-syn in PD brain tissue, and [125I]SIL23 binding site densities in brain tissue are sufficiently high to enable in vivo imaging with high affinity ligands. These results identify a SIL23 binding site on α-syn fibrils that is a feasible target for development of an α-syn imaging agent. The affinity of SIL23 for α-syn and its selectivity for α-syn versus Aβ and tau fibrils is not optimal for imaging fibrillar α-syn in vivo, but we show that SIL23 competitive binding assays can be used to screen additional ligands for suitable affinity and selectivity, which will accelerate the development of an α-syn imaging agent for PD. © 2013 Bagchi et al.

Document Type: Article
Source: Scopus

Meng, W.a , Lyle, N.b , Luan, B.a , Raleigh, D.P.a c , Pappu, R.V.b 
Experiments and simulations show how long-range contacts can form in expanded unfolded proteins with negligible secondary structure
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (6), pp. 2123-2128. 

a Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400, United States
b Department of Biomedical Engineering, Center for Biological Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
c Graduate Program in Biochemistry and Structural Biology, Graduate Program in Biophysics, State University of New York at Stony Brook, Stony Brook, NY 11794, United States

Abstract
The sizes of unfolded proteins under highly denaturing conditions scale as N0.59 with chain length. This suggests that denaturing conditions mimic good solvents, whereby the preference for favorable chain-solvent interactions causes intrachain interactions to be repulsive, on average. Beyond this generic inference, the broader implications of N0.59 scaling for quantitative descriptions of denatured state ensembles (DSEs) remain unresolved. Of particular interest is the degree to which N0.59 scaling can simultaneously accommodate intrachain attractions and detectable long-range contacts. Here we present data showing that the DSE of the N-terminal domain of the L9 (NTL9) ribosomal protein in 8.3Murea lacks detectable secondary structure and forms expanded conformations in accord with the expected N0.59 scaling behavior. Paramagnetic relaxation enhancements, however, indicate the presence of detectable long-range contacts in the denatured-state ensemble of NTL9. To explain these observations we used atomistic thermal unfolding simulations to identify ensembles whose properties are consistent with all of the experimental observations, thus serving as useful proxies for the DSE of NTL9 in 8.3 M urea. Analysis of these ensembles shows that residual attractions are present under mimics of good solvent conditions, and for NTL9 they result from low-likelihood, medium/longrange contacts between hydrophobic residues. Our analysis provides a quantitative framework for the simultaneous observation of N0.59 scaling and low-likelihood long-range contacts for the DSE of NTL9. We propose that such low-likelihood intramolecular hydrophobic clusters might be a generic feature of DSEs that play a gatekeeping role to protect against aggregation during protein folding.

Author Keywords
Atomistic simulations;  Denatured proteins;  Paramagnetic relaxation

Document Type: Article
Source: Scopus

Yttri, E.A., Liu, Y., Snyder, L.H.
Lesions of cortical area LIP affect reach onset only when the reach is accompanied by a saccade, revealing an active eye-hand coordination circuit
(2013) Proceedings of the National Academy of Sciences of the United States of America, 110 (6), pp. 2371-2376. 

Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
The circuits that drive visually guided eye and arm movements transform generic visual inputs into effector-specific motor commands. As part of the effort to elucidate these circuits, the primate lateral intraparietal area (LIP) has been interpreted as a priority map for saccades (oculomotor-specific) or a saliencemap of space (not effector-specific). It has also been proposed as a locus for eye-hand coordination. We reversibly inactivated LIP while monkeys performed memory-guided saccades and reaches. Coordinated saccade and reach reaction times were similarly impaired, consistent with a nonspecific role. However, reaches made without an accompanying saccade remained intact, and the relative temporal coupling of saccades and reaches was unchanged. These results suggest that LIP contributes to saccade planning but not to reach planning. Coordinated reaches are delayed as a result of an eye-hand coordination mechanism, located outside of LIP, that actively delays reaches until shortly after the onset of an associated saccade. We conclude with a discussion of how to reconcile specificity for saccades with a possible role in directing attention.

Author Keywords
Intraparietal sulcus;  Muscimol;  Visuomotor

Document Type: Article
Source: Scopus

Olsen, S.L.a , DeJonge, M.b , Kline, A.c , Liptsen, E.d , Song, D.e , Anderson, B.f , Mathur, A.a b 
Optimizing therapeutic hypothermia for neonatal encephalopathy
(2013) Pediatrics, 131 (2), pp. e591-e603. 

a Section of Neonatal-Perinatal Medicine, Department of Pediatrics, University of Missouri-Kansas, 2401 Gillham Rd, Kansas City, MO 64108, United States
b Department of Pediatrics, Helen DeVos Children's Hospital, Grand Rapids, MO, United States
c Department of Pediatrics and Neonatology, Inova Fairfax Hospital for Children, Falls Church, VA, United States
d Colorado Permanente Medical Group, Department of Pediatrics, Exempla St Joseph Hospital, Denver, CO, United States
e Department of Pediatrics, Santa Clara Valley Medical Center, San Jose, CA, United States
f Department of Pediatrics, St Louis Children's Hospital, Washington University, St Louis, MO, United States

Abstract
OBJECTIVE: Therapeutic hypothermia (TH) for neonatal encephalopathy is becoming widely available in clinical practice. The goal of this collaborative was to create and implement an evidence-based standard-of-care approach to neonatal encephalopathy, deliver consistent care, and optimize outcomes. METHODS: The quality improvement process identified and used the Model for Improvement as a framework for improvement efforts. This was a Vermont Oxford Network Collaborative focused on optimizing TH in the treatment of neonatal encephalopathy. By using an evidencebased approach, Potentially Better Practices were developed by the topic expert, modified by the collaborative, and implemented at each hospital. These included the following: timely identification of at-risk infants, coordination with referring hospitals to ensure TH was available within 6 hours after birth, staff education for both local and referring hospitals, nonsedated MRI, incorporating amplitude-integrated EEG into a TH protocol, and ensuring standard neurodevelopmental follow-up of infants. Each center used these practices to develop a matrix for implementation. RESULTS: Local self-assessments directed the implementation and adaptation of the Potentially Better Practices at each center. Resources, based on common identified barriers, were developed and shared among the group. CONCLUSIONS: The implementation of a TH program to improve the consistency of care for patients in NICUs is feasible using standardquality improvement methodology. The successful introduction of new interventions such as TH to the NICU culture requires a collaborative multidisciplinary team, use of a systematic quality improvement process, and perseverance. Copyright © 2013 by the American Academy of Pediatrics.

Author Keywords
Encephalopathy;  Hypothermia;  Neonate;  Quality improvement

Document Type: Article
Source: Scopus

Williams, M.M.a b c , Storandt, M.a d , Roe, C.M.a e , Morris, J.C.a e f g h 
Progression of Alzheimer's disease as measured by Clinical Dementia Rating Sum of Boxes scores
(2013) Alzheimer's and Dementia, 9 (1 SUPPL.), pp. S39-S44. 


a Charles F. and Joanne Knight Alzheimer's Disease Research Center, Washington University, St. Louis, MO, United States
b Department of Medicine, Washington University, St. Louis, MO, United States
c Department of Psychiatry, Washington University, St. Louis, MO, United States
d Department of Psychology, Washington University, St. Louis, MO, United States
e Department of Neurology, Washington University, St. Louis, MO, United States
f Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
g Program in Physical Therapy, Washington University, St. Louis, MO, United States
h Program in Occupational Therapy, Washington University, St. Louis, MO, United States

Abstract
Background: This study examined rates of dementia progression as ascertained by the Clinical Dementia Rating Sum of Boxes (CDR-SB) for symptomatic Alzheimer's disease (sAD), and assessed participant characteristics as predictors of CDR-SB progression. Methods: Participants (n = 792) were enrolled in longitudinal studies at an Alzheimer's Disease Research Center, received a diagnosis of sAD with a global CDR of 0.5 (n = 466) or 1 (n = 326), and had at least one follow-up assessment. Progression in CDR-SB over time as a function of baseline global CDR was examined. Results: A longitudinal increase (P <.0001) in CDR-SB was observed. The annual rate of change in CDR-SB scores was 1.43 (standard error [SE] = 0.05) in the CDR 0.5 sample and 1.91 (SE = 0.07) in the CDR 1 sample. For participants followed from the beginning of the CDR stage, time to progression to a higher global CDR was longer for individuals who were CDR 0.5 (3.75 years; 95% confidence interval [CI]: 3.18-4.33) than those who were CDR 1 at baseline (2.98 years; 95% CI: 2.75-3.22). In the total CDR 0.5 sample, the significant predictors of progression to the next global CDR stage (P <.01) were age at first sAD diagnosis and apolipoprotein E4 genotype. Conclusions: The study findings are relevant to sAD clinical trial design and accurate, reliable ascertainment of the effect of disease-modifying treatments. © 2013 The Alzheimer's Association. All rights reserved.

Author Keywords
Alzheimer's disease;  Assessment of dementia;  Clinical Dementia Rating;  Clinical Dementia Rating Sum of Boxes;  Cohort studies

Document Type: Article
Source: Scopus

Barch, D.M.
The CAINS: Theoretical and practical advances in the assessment of negative symptoms in Schizophrenia
(2013) American Journal of Psychiatry, 170 (2), pp. 133-135. 

Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, United States

Document Type: Review
Source: Scopus

Jarskog, L.F.a , Dong, Z.b , Kangarlu, A.b , Colibazzi, T.b , Girgis, R.R.b , Kegeles, L.S.b , Barch, D.M.c , Buchanan, R.W.d , Csernansky, J.G.e , Goff, D.C.f , Harms, M.P.c , Javitt, D.C.b , Keefe, R.S.g , McEvoy, J.P.g , McMahon, R.P.d , Marder, S.R.h , Peterson, B.S.b , Lieberman, J.A.b 
Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia
(2013) Neuropsychopharmacology, . Article in Press. 

a Department of Psychiatry, University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA
b New York State Psychiatric Institute and Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA
c Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA
d Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA
e Department of Psychiatry, Northwestern Feinberg School of Medicine, Chicago, IL, USA
f Nathan Kline Institute for Psychiatric Research and Department of Psychiatry, New York University Langone Medical Center, New York, NY, USA
g Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
h UCLA Semel Institute for Neuroscience and Human Behavior, Veterans Administration VISN 22 Mental Illness Research, Education and Clinical Center, Los Angeles, CA, USA

Abstract
Schizophrenia is associated with extensive neurocognitive and behavioral impairments. Studies indicate that N-acetylaspartate (NAA), a marker of neuronal integrity, and choline, a marker of cell membrane turnover and white matter integrity, may be altered in schizophrenia. Davunetide is a neurotrophic peptide that can enhance cognitive function in animal models of neurodegeneration. Davunetide has recently demonstrated modest functional improvement in a study of people with schizophrenia. In a subset of these subjects, proton magnetic resonance spectroscopy (1H-MRS) was conducted to explore the effects of davunetide on change in NAA/creatine (NAA/Cr) and choline/creatine (choline/Cr) over 12 weeks of treatment. Of 63 outpatients with schizophrenia who received randomized davunetide (5 and 30 mg/day) or placebo in the parent clinical trial, 18 successfully completed 1H-MRS in dorsolateral prefrontal cortex (DLPFC) at baseline and at 12 weeks. Cognition was assessed using the MATRICS Consensus Cognitive Battery (MCCB). NAA/Cr was unchanged for combined high- and low-dose davunetide groups (N=11). NAA/Cr in the high-dose davunetide group (N=8) suggested a trend increase of 8.0% (P=0.072) over placebo (N=7). Choline/Cr for combined high- and low-dose davunetide groups suggested a 6.4% increase (P=0.069), while the high-dose group showed a 7.9% increase (P=0.040) over placebo. Baseline NAA/Cr correlated with the composite MCCB score (R=0.52, P=0.033), as did individual cognitive domains of attention/vigilance, verbal learning, and social cognition; however, neither metabolite correlated with functional capacity. In this exploratory study, 12 weeks of adjunctive davunetide appeared to produce modest increases in NAA/Cr and choline/Cr in DLPFC in people with schizophrenia. This is consistent with a potential neuroprotective mechanism for davunetide. The data also support use of MRS as a useful biomarker of baseline cognitive function in schizophrenia. Future clinical and preclinical studies are needed to fully define the mechanism of action and cognitive effects of davunetide in schizophrenia.Neuropsychopharmacology advance online publication, 13 February 2013; doi:10.1038/npp.2013.23.

Document Type: Article in Press
Source: Scopus

Dhar, R.
Commentary
(2013) Journal of Neurosciences in Rural Practice, 4 (1), pp. 49-50. 

Department of Neurology, Division of Neurocritical Care, Washington University School of Medicine, 660 S Euclid Avenue, Saint Louis, MO 63110, United States

Document Type: Note
Source: Scopus

Weinstein, Y., Gleason, M.E., Oltmanns, T.F.
Borderline but not antisocial personality disorder symptoms are related to self-reported partner aggression in late middle-age.
(2012) Journal of abnormal psychology, 121 (3), pp. 692-698. 

Department of Psychology, Washington University, St. Louis, MO 63130-4899, USA.

Abstract
We examined the relationship between personality pathology and the frequency of self-reported psychological and physical partner aggression in a community sample of 872 adults aged 55-64. Previous research suggests that antisocial and borderline personality disorder (PD) symptoms are associated with partner aggression. Controlling for gender, education, alcohol dependence, and other personality pathology, we found that borderline PD symptoms, which include abandonment fears, unstable identity, and affective instability, were significantly related to the frequency of self-reported aggression toward one's partner. This relationship was observed regardless of whether the participant's personality was described by a clinical interviewer, the participant themselves, or an informant chosen by the participant. Further, the relationship between borderline PD symptoms and self-reported partner aggression was moderated by gender such that women were driving the association. Conversely, antisocial PD symptoms, which include deceitfulness, irresponsibility, disregard for rules, and lack of remorse did not significantly account for variance in self-reported partner aggression. PsycINFO Database Record (c) 2012 APA, all rights reserved.

Document Type: Article
Source: Scopus

Trujillo, K.A.a , Smith, M.L.b c , Sullivan, B.b d , Heller, C.Y.b , Garcia, C.b e , Bates, M.b f 
The neurobehavioral pharmacology of ketamine: Implications for drug abuse, addiction, and psychiatric disorders
(2011) ILAR Journal, 52 (3), pp. 366-378. Cited 2 times.

a Office for Biomedical Research and Training, California State University (CSU), San Marcos, United States
b Department of Psychology, CSU, San Marcos, United States
c Oregon Health and Science University, United States
d University of Texas, El Paso, United States
e Washington University, St. Louis, MO, United States
f Department of P, Texas A and M University, United States

Abstract
Ketamine was developed in the early 1960s as an anesthetic and has been used for medical and veterinary procedures since then. Its unique profile of effects has led to its use at subanesthetic doses for a variety of other purposes: it is an effective analgesic and can prevent certain types of pathological pain; it produces schizophrenia-like effects and so is used in both clinical studies and preclinical animal models to better understand this disorder; it has rapid-acting and longlasting antidepressant effects; and it is popular as a drug of abuse both among young people at dance parties and raves and among spiritual seekers. In this article we summarize recent research that provides insight into the myriad uses of ketamine. Clinical research is discussed, but the focus is on preclinical animal research, including recent findings from our own laboratory. Of particular note, although ketamine is normally considered a locomotor stimulant at subanesthetic doses, we have found locomotor depressant effects at very low subanesthetic doses. Thus, rather than a monotonic dosedependent increase in activity, ketamine produces a more complex dose response. Additional work explores the mechanism of action of ketamine, ketamine-induced neuroadaptations, and ketamine reward. The findings described will inform future research on ketamine and lead to a better understanding of both its clinical uses and its abuse.

Author Keywords
Analgesia;  Anesthesia;  Animal model;  Antide-pressant;  Drug abuse;  Glutamate;  Ketamine;  Reward;  Schizo-phrenia

Document Type: Article
Source: Scopus

 

February 7, 2013

Foster, E.R.a c d , Golden, L.a , Duncan, R.P.b , Earhart, G.M.b c e
Community-based argentine tango dance program is associated with increased activity participation among individuals with parkinson's disease
(2013) Archives of Physical Medicine and Rehabilitation, 94 (2), pp. 240-249. 


a Program in Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
b Program in Physical Therapy, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Objective: To determine the effects of a 12-month community-based tango dance program on activity participation among individuals with Parkinson's disease (PD). Design: Randomized controlled trial with assessment at baseline, 3, 6, and 12 months. Setting: Intervention was administered in the community; assessments were completed in a university laboratory. Participants: Volunteers with PD (n=62) enrolled in the study and were randomized to a treatment group; 10 participants did not receive the allocated intervention, and therefore the final analyzed sample included 52 participants. Interventions: Participants were randomly assigned to the tango group, which involved 12 months of twice-weekly Argentine tango dance classes, or to the no intervention control group (n=26 per group). Main Outcome Measure: Current, new, and retained participation in instrumental, leisure, and social activities, as measured by the Activity Card Sort (with the dance activity removed). Results: Total current participation in the tango group was higher at 3, 6, and 12 months compared with baseline (Ps≤.008), while the control group did not change (Ps≥.11). Total activity retention (since onset of PD) in the tango group increased from 77% to 90% (P=.006) over the course of the study, whereas the control group remained around 80% (P=.60). These patterns were similar in the separate activity domains. The tango group gained a significant number of new social activities (P=.003), but the control group did not (P=.71). Conclusions: Individuals with PD who participated in a community-based Argentine tango class reported increased participation in complex daily activities, recovery of activities lost since the onset of PD, and engagement in new activities. Incorporating dance into the clinical management of PD may benefit participation and subsequently quality of life for this population. © 2013 American Congress of Rehabilitation Medicine.

Author Keywords
Exercise;  Parkinson disease;  Quality of life;  Rehabilitation;  Social participation

Document Type: Article
Source: Scopus

Cavallone, L.F., Vannucci, A.
Extubation of the difficult airway and extubation failure
(2013) Anesthesia and Analgesia, 116 (2), pp. 368-383. 

Department of Anesthesiology, Washington University in St. Louis, 660 South Euclid Ave, St. Louis, MO 63110, United States

Abstract
Respiratory complications after tracheal extubation are associated with significant morbidity and mortality, suggesting that process improvements in this clinical area are needed. The decreased rate of respiratory adverse events occurring during tracheal intubation since the implementation of guidelines for difficult airway management supports the value of education and guidelines in advancing clinical practice. Accurate use of terms in defining concepts and describing distinct clinical conditions is paramount to facilitating understanding and fostering education in the treatment of tracheal extubation-related complications. As an example, understanding the distinction between extubation failure and weaning failure allows one to appreciate the need for pre-extubation tests that focus on assessing airway patency in addition to evaluating the ability to breathe spontaneously. Tracheal reintubation after planned extubation is a relatively rare event in the postoperative period of elective surgeries, with reported rates of reintubation in the operating room and postanesthesia care unit between 0.1% and 0.45%, but is a fairly common event in critically ill patients (0.4%-25%). Conditions such as obesity, obstructive sleep apnea, major head/neck and upper airway surgery, and obstetric and cervical spine procedures carry significantly increased risks of extubation failure and are frequently associated with difficult airway management. Extubation failure follows loss of upper airway patency. Edema, soft tissue collapse, and laryngospasm are among the most frequent mechanisms of upper airway obstruction. Planning for tracheal extubation is a critical component of a successful airway management strategy, particularly when dealing with situations at increased risk for extubation failure and in patients with difficult airways. Adequate planning requires identification of patients who have or may develop a difficult airway, recognition of situations at increased risk of postextubation airway compromise, and understanding the causes and underlying mechanisms of extubation failure. An effective strategy to minimize postextubation airway complications should include preemptive optimization of patients' conditions, careful timing of extubation, the presence of experienced personnel trained in advanced airway management, and the availability of the necessary equipment and appropriate postextubation monitoring. Copyright © 2013 International Anesthesia Research Society.

Document Type: Review
Source: Scopus

Simpkins, J.W.a , Richardson, T.E.a , Yi, K.D.a , Perez, E.a , Covey, D.F.b
Neuroprotection with non-feminizing estrogen analogues: An overlooked possible therapeutic strategy
(2013) Hormones and Behavior, 63 (2), pp. 278-283. 

a Institute for Aging and Alzheimer's Disease Research, Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, United States
b Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
This article is part of a Special Issue "Hormones & Neurotrauma".Although many of the effects of estrogens on the brain are mediated through estrogen receptors (ERs), there is evidence that neuroprotective activity of estrogens can be mediated by non-ER mechanisms. Herein, we review the substantial evidence that estrogens neuroprotection is in large part non-ER mediated and describe in vitro and in vivo studies that support this conclusion. Also, we described our drug discovery strategy for capitalizing on enhancement in neuroprotection while at the same time, reducing ER binding of a group of synthetic non-feminizing estrogens. Finally, we offer evidence that part of the neuroprotection of these non-feminizing estrogens is due to enhancement in redox potential of the synthesized compounds. © 2012 Elsevier Inc.

Author Keywords
Estrogen receptors;  Estrogens;  Hormone therapy;  Neuroprotection;  Non-feminizing estrogens;  Stroke

Document Type: Review
Source: Scopus

Al-Kateb, H.a , Shimony, J.S.b , Vineyard, M.c , Manwaring, L.c , Kulkarni, S.a , Shinawi, M.c
NR2F1 haploinsufficiency is associated with optic atrophy, dysmorphism and global developmental delay
(2013) American Journal of Medical Genetics, Part A, 161 (2), pp. 377-381. 

a Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States

Document Type: Letter
Source: Scopus

Avidan, M.S.a , Mashour, G.A.b
Prevention of intraoperative awareness with explicit recall: Making sense of the evidence
(2013) Anesthesiology, 118 (2), pp. 449-456. 

a Department of Anesthesiology, Cardiothoracic Anesthesiology and Cardiothoracic Intensive Care, Washington University School of Medicine, 660 South Euclid Ave, St. Louis, MO 63110, United States
b Department of Anesthesiology and Neurosurgery, Faculty, Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States

Document Type: Note
Source: Scopus

Brockmole, J.R.a , Davoli, C.C.a , Abrams, R.A.b , Witt, J.K.c
The World Within Reach: Effects of Hand Posture and Tool Use on Visual Cognition
(2013) Current Directions in Psychological Science, 22 (1), pp. 38-44. 

a Department of Psychology, University of Notre Dame, 127 Haggar Hall, Notre Dame, IN 46556, United States
b Washington University in St. Louis, United States
c Colorado State University, United States

Abstract
Our mental processing of the visual world is not independent of our physical actions within it. Placing objects near one's hands and interacting with objects using tools can enhance visual perception, bias and prolong the allocation of attention, and distort memory in systematic ways. This suggests that the world within our reach is cognitively different from the world beyond reach. In this review, we examine the evidence supporting this conclusion, focusing on the cognitive and neural mechanisms that underlie these effects, the parameters that may control their emergence, and their potential practical applications. © The Author(s) 2013.

Author Keywords
attention;  embodied cognition;  hand posture;  memory;  perception;  tool use

Document Type: Review
Source: Scopus

Villafranca, A.J.a , Arenson, B.G.a , Avidan, M.S.b , Glick, D.c , Mashour, G.A.d , Jacobsohn, E.a
Volitional delay of self-reported outcomes: Insights from a case of intraoperative awareness with explicit recall
(2013) Anesthesia and Analgesia, 116 (2), pp. 365-367. 

a Department of Anesthesia and Perioperative Medicine, University of Manitoba, 671 William Ave., Winnipeg, MB R3E 0Z2, Canada
b Department of Anesthesiology, Washington University, St. Louis, MI, United States
c Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL, United States
d Department of Anesthesiology, University of Michigan, Ann Arbor, MI, United States

Abstract
Intraoperative awareness with explicit recall (AWR) is a self-reported outcome of interest in clinical practice, quality assurance initiatives, and clinical trials.combining structured postoperative interviews with a preoperative description of AWR is assumed to ensure prompt patient disclosure. We describe a volitionally delayed reporting of AWR because of the perceived unimportance of nondistressing awareness experiences, despite preoperative education and 2 postoperative interviews. This delay had implications for a major randomized controlled trial on AWR. Volitionally delayed self-reported outcomes may affect statistical comparisons in clinical trials and quality assurance initiatives, and delay the treatment of subsequent sequelae in clinical practice. This limitation should be considered, even when using structured outcome assessment and preoperative education. Copyright © 2013 International Anesthesia Research Society.

Document Type: Article
Source: Scopus

Rosnick, C.B.a , Rawson, K.S.b , Butters, M.A.c , Lenze, E.J.d
Association of cortisol with neuropsychological assessment in older adults with generalized anxiety disorder
(2013) Aging and Mental Health, . Article in Press. 

a Department of Psychology, Southern Illinois University Edwardsville, Edwardsville, IL, USA
b School of Aging Studies, University of South Florida, Tampa, FL, USA
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

Abstract
Objectives: Older adults with generalized anxiety disorder (GAD) have elevated diurnal cortisol patterns and show an increased cortisol stress response, which may increase risk for cognitive dysfunction. The current secondary data analysis examined how neuropsychological assessment as a possible laboratory stressor affects cortisol levels in late-life GAD and, in turn, how cortisol levels affect cognitive performance.Methods: The current sample consisted of 69 individuals with late-life GAD and 39 psychiatrically healthy group-matched comparison participants. Cognitive performance was measured with a neuropsychological battery and salivary cortisol was collected at several time points. Hierarchical regressions were performed to assess the moderating role of cortisol in the relationship between GAD status and cognitive performance.Results: The results revealed that older adults with GAD showed significantly lower cortisol levels during neuropsychological assessment, compared to their baseline levels. Further, there was a significant interaction between post-neuropsychological assessment cortisol levels and GAD status on several measures of cognitive performance. The interaction indicated that there is a significant negative relationship between cortisol level and cognitive performance in the GAD participants and no such relationship in the comparison participants.Conclusions: Our results revealed that participating in a neuropsychological assessment was associated with reduced cortisol in GAD participants, suggesting that refocusing attention such as engaging in cognitive tasks had a cortisol-lowering effect. Further, a higher cortisol level appears to have a detrimental effect on cognitive performance for individuals with GAD, but not psychiatrically healthy comparison participants. The methodological and treatment implications of these findings are discussed. © 2013 Copyright Taylor and Francis Group, LLC.

Author Keywords
cortisol;  generalized anxiety disorder;  HPA axis;  neuropsychological assessment;  stress

Document Type: Article in Press
Source: Scopus

Borson, S.a , Frank, L.b , Bayley, P.J.c , Boustani, M.d , Dean, M.e , Lin, P.-J.f , McCarten, J.R.g , Morris, J.C.h , Salmon, D.P.i , Schmitt, F.A.j , Stefanacci, R.G.k , Mendiondo, M.S.l , Peschin, S.m , Hall, E.J.n , Fillit, H.o , Ashford, J.W.c p
Improving dementia care: The role of screening and detection of cognitive impairment
(2013) Alzheimer's and Dementia, . Article in Press. 

a Memory Disorders Clinic and Dementia Health Services, University of Washington School of Medicine, Seattle, WA, USA
b Engagement Research, Patient Centered Outcomes Research Institute, Washington, DC, USA
c War Related Illness and Injury Study Center, VA Palo Alto Health Care System, Palo Alto, CA, USA
d Indiana University Center for Aging Research Scientist, Regenstrief Institute, Inc, Indianapolis, IN, USA
e Associate Faculty School of Medicine, Texas Tech Health Sciences Center, Geriatric Division, Amarillo, TX, USA
f Center for the Evaluation of Value and Risk in Health, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA
g Minneapolis VA Health Care System, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA
h Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, USA
i Department of Neurosciences, University of California, San Diego, CA, USA
j Departments of Neurology, Psychiatry, Behavioral Science, Psychology and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA
k University of the Sciences, Philadelphia, PA, USA
l Department of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA
m Alliance for Aging Research, Washington, DC, USA
n Alzheimer's Foundation of America, New York, NY, USA
o The Alzheimer's Drug Discovery Foundation, New York, NY, USA
p Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine, Palo Alto, CA, USA

Abstract
The value of screening for cognitive impairment, including dementia and Alzheimer's disease, has been debated for decades. Recent research on causes of and treatments for cognitive impairment has converged to challenge previous thinking about screening for cognitive impairment. Consequently, changes have occurred in health care policies and priorities, including the establishment of the annual wellness visit, which requires detection of any cognitive impairment for Medicare enrollees. In response to these changes, the Alzheimer's Foundation of America and the Alzheimer's Drug Discovery Foundation convened a workgroup to review evidence for screening implementation and to evaluate the implications of routine dementia detection for health care redesign. The primary domains reviewed were consideration of the benefits, harms, and impact of cognitive screening on health care quality. In conference, the workgroup developed 10 recommendations for realizing the national policy goals of early detection as the first step in improving clinical care and ensuring proactive, patient-centered management of dementia. © 2012 The Alzheimer's Association.

Author Keywords
Alzheimer;  Annual wellness visit;  Cognitive impairment;  Cost-benefit analysis;  Dementia;  Detection;  Health care;  Management;  Medicare;  Patient-centered;  Policy;  Priority;  Quality;  Screening

Document Type: Article in Press
Source: Scopus

Tanofsky-Kraff, M.a , Bulik, C.M.b , Marcus, M.D.c , Striegel, R.H.d , Wilfley, D.E.e , Wonderlich, S.A.f , Hudson, J.I.g
Binge eating disorder: The next generation of research
(2013) International Journal of Eating Disorders, . Article in Press. 

a Department of Medical and Clinical Psychology Uniformed Services University of the Health Sciences, Bethesda, Maryland
b Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, North Carolina
c University of Pittsburgh School of Medicine, Western Psychiatric Institute Pittsburgh, Pennsylvania
d Department of Psychology, Wesleyan University, Middletown, Connecticut
e Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri
f Department of Clinical Research, Neuropsychiatric Research Institute, Fargo, North Dakota
g Department of Psychiatry, Harvard Medical School, Boston, Massachusetts

Document Type: Article in Press
Source: Scopus

Shoji-Kawata, S.a b , Sumpter, R.a b , Leveno, M.a b , Campbell, G.R.c d , Zou, Z.a b e , Kinch, L.f g , Wilkins, A.D.h , Sun, Q.a b , Pallauf, K.i , MacDuff, D.j , Huerta, C.k l , Virgin, H.W.j , Helms, J.B.m , Eerland, R.m , Tooze, S.A.n , Xavier, R.o p q , Lenschow, D.J.r s , Yamamoto, A.t , King, D.u , Lichtarge, O.h , Grishin, N.V.f g , Spector, S.A.c d , Kaloyanova, D.V.m , Levine, B.a b e v
Identification of a candidate therapeutic autophagy-inducing peptide
(2013) Nature, . Article in Press. 

a 1] Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA
b Center for Autophagy Research, UT Southwestern Medical Center, Dallas, Texas 75390, USA
c 1] Department of Pediatrics, University of California, San Diego, La Jolla, California 92093, USA
d Rady Children's Hospital, San Diego, California 92123, USA
e Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA
f 1] Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, Texas 75390, USA
g Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, USA
h Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
i Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA
j Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
k 1] Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, USA
l Reata Pharmaceuticals, Inc, Irving, Texas 75063, USA
m Department of Biochemistry and Cell Biology and Institute of Biomembranes, Utrecht University, Utrecht 3508TD, The Netherlands
n London Research Institute, Cancer Research UK, London EC1V 4AD, UK
o 1] Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
p Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
q Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
r 1] Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA
s Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
t Department of Neurology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA
u Howard Hughes Medical Institute, University of California, Berkeley, California 94720, USA
v Department of Microbiology, UT Southwestern Medical Center, Dallas, Texas 75390, USA

Abstract
The lysosomal degradation pathway of autophagy has a crucial role in defence against infection, neurodegenerative disorders, cancer and ageing. Accordingly, agents that induce autophagy may have broad therapeutic applications. One approach to developing such agents is to exploit autophagy manipulation strategies used by microbial virulence factors. Here we show that a peptide, Tat-beclin 1-derived from a region of the autophagy protein, beclin 1, which binds human immunodeficiency virus (HIV)-1 Nef-is a potent inducer of autophagy, and interacts with a newly identified negative regulator of autophagy, GAPR-1 (also called GLIPR2). Tat-beclin 1 decreases the accumulation of polyglutamine expansion protein aggregates and the replication of several pathogens (including HIV-1) in vitro, and reduces mortality in mice infected with chikungunya or West Nile virus. Thus, through the characterization of a domain of beclin 1 that interacts with HIV-1 Nef, we have developed an autophagy-inducing peptide that has potential efficacy in the treatment of human diseases.

Document Type: Article in Press
Source: Scopus

Sun, A.X.a b , Crabtree, G.R.a b , Yoo, A.S.c
MicroRNAs: regulators of neuronal fate
(2013) Current Opinion in Cell Biology, . Article in Press. 

a Howard Hughes Medical Institute and Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA
b Howard Hughes Medical Institute and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
c Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA

Abstract
Mammalian neural development has been traditionally studied in the context of evolutionarily conserved signaling pathways and neurogenic transcription factors. Recent studies suggest that microRNAs, a group of highly conserved noncoding regulatory small RNAs also play essential roles in neural development and neuronal function. A part of their action in the developing nervous system is to regulate subunit compositions of BAF complexes (ATP-dependent chromatin remodeling complexes), which appear to have dedicated functions during neural development. Intriguingly, ectopic expression of a set of brain-enriched microRNAs, miR-9/9* and miR-124 that promote the assembly of neuron-specific BAF complexes, converts the nonneuronal fate of human dermal fibroblasts towards postmitotic neurons, thereby revealing a previously unappreciated instructive role of these microRNAs. In addition to these global effects, accumulating evidence indicates that many microRNAs could also function locally, such as at the growth cone or at synapses modulating synaptic activity and neuronal connectivity. Here we discuss some of the recent findings about microRNAs' activity in regulating various developmental stages of neurons. © 2013.

Document Type: Article in Press
Source: Scopus

Jennum, P.a , Mayer, G.b c , Ju, Y.-E.d , Postuma, R.e
Morbidities in Rapid Eye Movement Sleep Behavior Disorders
(2013) Sleep Medicine, . Article in Press. 

a Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, University of Copenhagen, Glostrup, Copenhagen, Denmark
b Hephata-Klinik, Schwalmstadt-Treysa, Germany
c Department of Neurology, University of Marburg, Germany
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
e Department of Neurology, McGill University, Montreal General Hospital, Quebec, Canada

Abstract
Idiopathic Rapid Eye Movement (REM) Sleep Behavior Disorder (iRBD, RBD without any obvious comorbid major neurological disease), is strongly associated with numerous comorbid conditions. The most prominent is that with neurodegenerative disorders, especially synuclein-mediated disorders, above all Parkinson Disease (PD). Idiopathic RBD is an important risk factor for the development of synucleinopathies. Comorbidity studies suggest that iRBD is associated with a number of other potential pre-motor manifestations of synucleinopathies such as, cognitive and olfactory impairment, reduced autonomic function, neuropsychiatric manifestations and sleep complaints. Furthermore, patients with PD and RBD may have worse prognosis in terms of impaired cognitive function and overall morbidity/mortality; in dementia, the presence of RBD is strongly associated with clinical hallmarks and pathological findings of dementia with Lewy bodies. These findings underline the progressive disease process, suggesting involvement of more brain regions in patients with a more advanced disease stage. RBD is also associated with narcolepsy, and it is likely that RBD associated with narcolepsy is a distinct subtype associated with different comorbidities. RBD is also associated with antidepressant medications, autoimmune conditions, and, in rare cases, brainstem lesions. © 2012 Elsevier B.V.

Author Keywords
Comorbidity;  Morbidity;  Narcolepsy;  Neurodegenerative disorder;  Parkinsonism;  REM Sleep Behavior Disorder

Document Type: Article in Press
Source: Scopus

Izumi, Y.a c , Svrakic, N.a , O'Dell, K.a c , Zorumski, C.F.a b c
Ammonia inhibits long-term potentiation via neurosteroid synthesis in hippocampal pyramidal neurons
(2013) Neuroscience, . Article in Press. 

a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
b Department of Neurobiology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
c The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States

Abstract
Neurosteroids are a class of endogenous steroids synthesized in the brain that are believed to be involved in the pathogenesis of neuropsychiatric disorders and memory impairment. Ammonia impairs long-term potentiation (LTP), a synaptic model of learning, in the hippocampus, a brain region involved in memory acquisition. Although mechanisms underlying ammonia-mediated LTP inhibition are not fully understood, we previously found that the activation of N-methyl-d-aspartate receptors (NMDARs) is important. Based on this, we hypothesize that metabolic stressors, including hyperammonemia, promote untimely NMDAR activation and result in neural adaptations that include the synthesis of allopregnanolone (alloP) and other GABA-potentiating neurosteroids that dampen neuronal activity and impair LTP and memory formation. Using an antibody against 5α-reduced neurosteroids, we found that 100 μM ammonia acutely enhanced neurosteroid immunostaining in pyramidal neurons in the CA1 region of rat hippocampal slices. The enhanced staining was blocked by finasteride, a selective inhibitor of 5α-reductase, a key enzyme required for alloP synthesis. Finasteride also overcame LTP inhibition by 100 μM ammonia, as did picrotoxin, an inhibitor of GABA-A receptors. These results indicate that GABA-enhancing neurosteroids, synthesized locally within pyramidal neurons, contribute significantly to ammonia-mediated synaptic dysfunction. These results suggest that the manipulation of neurosteroid synthesis could provide a strategy to improve cognitive function in individuals with hyperammonemia. © 2012 IBRO.

Author Keywords
allopregnanolone;  finasteride;  hepatic encephalopathy;  LTP;  neurosteroid;  tetrahydrodeoxycorticosterone

Document Type: Article in Press
Source: Scopus

Yang, L.a g , O'Neill, P.d , Martin, K.c , Maass, J.C.a e f , Vassilev, V.d , Ladher, R.d , Groves, A.K.a b
Analysis of FGF-Dependent and FGF-Independent Pathways in Otic Placode Induction
(2013) PLoS ONE, 8 (1), art. no. e55011, . 

a Departments of Neuroscience and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
b Program in Developmental Biology, Baylor College of Medicine, Houston, TX, United States
c Division of Cell Biology and Genetics, House Research Institute, Los Angeles, CA, United States
d RIKEN Center for Developmental Biology, Chuo-ku, Kobe, Japan
e Department of Otolaryngology, Hospital Clínico Universidad de Chile, Santiago, Chile
f Department of Otolaryngology, Clínica Alemana de Santiago, Facultad de Medicina Clínica Alemana-Universidad del Desarrollo, Santiago, Chile
g Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The inner ear develops from a patch of thickened cranial ectoderm adjacent to the hindbrain called the otic placode. Studies in a number of vertebrate species suggest that the initial steps in induction of the otic placode are regulated by members of the Fibroblast Growth Factor (FGF) family, and that inhibition of FGF signaling can prevent otic placode formation. To better understand the genetic pathways activated by FGF signaling during otic placode induction, we performed microarray experiments to estimate the proportion of chicken otic placode genes that can be up-regulated by the FGF pathway in a simple culture model of otic placode induction. Surprisingly, we find that FGF is only sufficient to induce about 15% of chick otic placode-specific genes in our experimental system. However, pharmacological blockade of the FGF pathway in cultured chick embryos showed that although FGF signaling was not sufficient to induce the majority of otic placode-specific genes, it was still necessary for their expression in vivo. These inhibitor experiments further suggest that the early steps in otic placode induction regulated by FGF signaling occur through the MAP kinase pathway. Although our work suggests that FGF signaling is necessary for otic placode induction, it demonstrates that other unidentified signaling pathways are required to co-operate with FGF signaling to induce the full otic placode program. © 2013 Yang et al.

Document Type: Article
Source: Scopus

Plunk, A.D., Cavazaos-Rehg, P., Bierut, L.J., Grucza, R.A.
The Persistent Effects of Minimum Legal Drinking Age Laws on Drinking Patterns Later in Life
(2013) Alcoholism: Clinical and Experimental Research, . Article in Press. 

Department of Psychiatry (ADP, PC-R, LJB, RAG) Washington University School of Medicine St. Louis, Missouri

Abstract
Background: Exposure to permissive minimum legal drinking age (MLDA) laws not only affects young adults in the short term, but also later in life; for example, individuals who could legally purchase alcohol before the age of 21 are more likely to suffer from drinking problems as older adults, long after the laws had been changed. However, it is not known how permissive MLDA exposure affects specific drinking behavior. This present study uses changes in MLDA laws during the 1970s and 1980s as a natural experiment to investigate the potential impact of permissive MLDA exposure on average alcohol consumption, frequency of drinking, and patterns of binging and more moderate, nonheavy drinking. Methods: Policy exposure data were paired with alcohol use data from the 1991 to 1992 National Longitudinal Alcohol Epidemiologic Survey and the 2001 to 2002 National Epidemiologic Survey on Alcohol and Related Conditions. Past-year drinkers born between 1949 and 1972 (n = 24,088) were included. Average daily intake, overall drinking frequency, and frequency of both binge episodes (5+ drinks) and days without a binge episode (nonheavy drinking) for the previous year at the time of interview were tracked for each respondent. Results: Exposure to permissive MLDAs was associated with higher odds to report frequent binging and lower odds to report any moderate drinking; these associations were largely driven by men and those who did not attend college. Overall drinking frequency and average alcohol consumption were not affected by MLDA exposure. Conclusions: The ability to legally purchase alcohol before the age of 21 does not seem to increase overall drinking frequency, but our findings suggest that it is associated with certain types of problematic drinking behaviors that persist into later adulthood: more frequent binge episodes and less frequent nonheavy drinking. We also propose that policymakers and critics should not focus on college drinking when evaluating the effectiveness of MLDAs. © 2013 by the Research Society on Alcoholism.

Author Keywords
Binge Drinking;  Drinking Patterns;  Minimum Legal Drinking Age;  Moderate Drinking

Document Type: Article in Press
Source: Scopus

Rastogi, R., Meek, B.D.
Management of chronic pain in elderly, frail patients: Finding a suitable, personalized method of control
(2013) Clinical Interventions in Aging, 8, pp. 37-46. 

Department of Anesthesiology, Washington University School of Medicine, Saint Louis, United States

Abstract
The elderly population is projected to make up 20% of the total United States population by the year 2030. In addition, epidemiological data suggests increasing prevalence of chronic pain and frailty with advancing age. Pain, being a subjective symptom, is challenging to manage effectively. This is more so in elderly populations with age-specific physiological changes that affect drug action and metabolism. Elderly patients are also more likely to have multiple chronic health pathologies, declining function, and frailty. The barriers present for patients, providers, and health systems also negatively impact efficient and effective pain control. These factors result in disproportionate utilization of health resources by the older population group. The scientific literature is lagging behind in age-specific studies for the elderly population. As a result, there is a lack of age-specific standardized management guidelines for various health problems, including chronic pain. Increasing efforts are now being directed to studies on pain control in the elderly. However, pain management remains inconsistent and suboptimal. This article is an attempt to suggest an informed, comprehensive guide to achieve effective pain control in the presence of these limitations. © 2013 Rastogi and Meek, publisher and licensee Dove Medical Press Ltd.

Author Keywords
Chronic pain;  Elderly;  Frailty;  Geriatric pain

Document Type: Review
Source: Scopus

Mashour, G.A.a , Avidan, M.S.b
Capturing covert consciousness
(2013) The Lancet, 381 (9863), pp. 371-372. 

a Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109-5048, United States
b Department of Anesthesiology, Washington University, St Louis, MO, United States

Document Type: Note
Source: Scopus

Meade, M.L.a , Geraci, L.D.b , Roediger III, H.L.c
Neuropsychological status in older adults influences susceptibility to false memories
(2012) American Journal of Psychology, 125 (4), pp. 449-467. 

a Montana State University, United States
b Texas A and M University, United States
c Washington University, Saint Louis, United States

Abstract
In 2 experiments we examined the influence of frontal lobe function on older adults' susceptibility to false memory in a categorized list paradigm. Using a neuropsychological battery of tests developed by Glisky, Polster, and Routhieaux (1995), we designated older adults as having high- or low-frontal function. Young and older adults studied and were tested on categorized lists using free report cued recall and forced report cued recall instructions, with the latter requiring participants to produce responses even if they had to guess. Under free report cued recall instructions, frontal lobe function was a strong predictor of false memories in older adults: Older adults who scored low on tests of frontal functioning demonstrated much higher levels of false recall than younger adults, whereas levels of false recall in high-frontal older adults were more similar to those of young adults. However, after forced report cued recall, high- and lowfrontal older adults performed similarly to each other, and both demonstrated higher levels of false recall than young adults. On a final recognition test, high-frontal older adults in both the free report cued recall and forced report cued recall conditions were more successful than lowfrontal older adults in using source information to reduce memory errors. The results indicate that older adults show higher levels of false recall than younger adults, but type of test (free report or forced report) and neuropsychological status of older adults mediate these effects. Low-frontal older adults are particularly susceptible to producing false memories on free report tests that entail source monitoring. © 2012 by the Board of Trustees of the University of Illinois.

Document Type: Article
Source: Scopus