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Neuroscience Publications Archive - March 2016

March 21, 2016
Mendez, J.S.a , Govindan, A.b , Leong, J.b , Gao, F.c , Huang, J.d , Campian, J.L.b 
Association between treatment-related lymphopenia and overall survival in elderly patients with newly diagnosed glioblastoma
(2016) Journal of Neuro-Oncology, 127 (2), pp. 329-335. 

DOI: 10.1007/s11060-015-2037-1

a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Department of Medicine, Oncology Division, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, St Louis, MO, United States
c Department of Surgery, Division of Public Health Sciences, Washington University School of Medicine, St Louis, MO, United States
d Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, United States

Management of patients with glioblastoma (GBM) often includes radiation (RT) and temozolomide (TMZ). The association between severe treatment-related lymphopenia (TRL) after the standard chemoradiation and reduced survival has been reported in GBM patients with the median age of 57. Similar findings were described in patients with head and neck, non-small cell lung, and pancreatic cancers. This retrospective study is designed to evaluate whether elderly GBM patients (age ≥65) develop similar TRL after RT/TMZ and whether such TRL is associated with decreased survival. Serial total lymphocyte counts (TLC) were retrospectively reviewed in patients (age ≥65) with newly diagnosed GBM undergoing RT/TMZ and associated with treatment outcomes. Seventy-two patients were eligible: median KPS 70, median age 71 years (range 65–86) with 56 % of patients >70 years, 53 % female, 31 % received RT ≤45 Gy. Baseline median TLC was 1100 cells/mm3 which fell by 41 % to 650 cells/mm3 2 months after initiating RT/TMZ (p < 0.0001). Patients with TLC <500 cells/mm3 at 2 months had a shorter survival than those with higher TLCs with a median overall survival of 4.6 versus 11.6 months, respectively. Multivariate analysis revealed a significant association between TRL and survival (HR 2.76, 95 % CI 1.30–5.86, p = 0.008). Treatment-related lymphopenia is frequent, severe, and an independent predictor for survival in elderly patients with GBM. These findings add to the body of evidence that immunosuppression induced by chemoradiation is associated with inferior clinical outcomes. Prospective studies are needed to confirm these findings suggesting that immune preservation is important in this cancer. © 2016, Springer Science+Business Media New York.

Author Keywords
Chemotherapy;  Glioblastoma;  Lymphopenia;  Radiation;  Treatment-related toxicities

Document Type: Article
Source: Scopus


Sood, A.B.a , Hudziak, J.b c d 
Prevention of Mental Health Disorders: Principles and Implementation
(2016) Child and Adolescent Psychiatric Clinics of North America, 25 (2), pp. xiii-xv. 

DOI: 10.1016/j.chc.2016.01.001

a Virginia Treatment Center for Children, Virginia Commonwealth University, 515 North 10th Street, Richmond, VA, United States
b University of Vermont, College of Medicine/Fletcher Allen Health Care, Erasmus MC, Sophia Children's Hospital, Rotterdam, Netherlands
c Washington University School of Medicine, St Louis, MO, United States
d Geisel School of Medicine at Dartmouth, UHC Campus, St. Joe's, Box 364SJ 3, 1 South Prospect, Burlington, VT, United States

Document Type: Editorial
Source: Scopus


Conner, K.R.a b , Wyman, P.a , Goldston, D.B.c , Bossarte, R.M.a b , Lu, N.d , Kaukeinen, K.d , Tu, X.M.d , Houston, R.J.e , Lamis, D.A.f , Chan, G.g , Bucholz, K.K.h , Hesselbrock, V.M.g 
Two Studies of Connectedness to Parents and Suicidal Thoughts and Behavior in Children and Adolescents
(2016) Journal of Clinical Child and Adolescent Psychology, 45 (2), pp. 129-140. 

DOI: 10.1080/15374416.2014.952009

a Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, United States
b VA VISN 2 Center of Excellence for Suicide Prevention, Canandaigua VA Medical Center, Canandaigua, NY, United States
c Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC, United States
d Department of Biostatistics, University of Rochester Medical Center, Rochester, NY, United States
e Research Institute on Addictions, State University of New York at Buffalo, Buffalo, NY, United States
f Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
g Department of Psychiatry, University of Connecticut Health Center, Farmington, CT, United States
h Department of Psychiatry and Midwest Alcoholism Research Center, Washington University School of Medicine, Washington University, St. Louis, MO, United States

We tested hypotheses that greater connectedness to parent(s) is associated with lower risk for nonlethal suicidal thoughts and behavior (STB), termed direct protective effects, and that parent connectedness serves to moderate (lower) the risk for STB associated with psychopathology including major depressive episode (MDE), termed moderating protective effects. Independent samples of children and adolescents recruited for a multicenter study of familial alcoholism were studied. Generalized estimating equation models were used that adjusted for age, sex, and youth psychopathology variables. The sample for Study 1 was assessed at baseline and about 2- and 4-year follow-ups, with baseline characteristics of n = 921, M age = 14.3 ± 1.8 years, and 51.8% female. The sample for Study 2 was assessed at baseline and about 5-year follow-up, with baseline characteristics of n = 867, M age = 12.0 ± 3.2 years, and 51.0% female. In both studies, increased perceived connectedness to father but not mother was associated with lower risk for measures of STB, consistent with direct protective effects. In Study 1, measures of parent connectedness were associated with lower risk for STB but only for youth that did not experience MDE (or alcohol use disorder), inconsistent with moderating protective effects. Study 2 showed that connectedness to fathers was associated with lower risk for suicide plans or attempts (severe STB) but not frequent thoughts of death or dying (nonsevere STB). Improved connectedness to fathers may lower risk for STB in children and adolescents, consistent with direct protective effects. Hypotheses about moderating protective effects were not supported. © Taylor & Francis Group, LLC.

Document Type: Article
Source: Scopus


Salminen, L.E.a , Conturo, T.E.b , Laidlaw, D.H.c , Cabeen, R.P.c , Akbudak, E.b , Lane, E.M.d , Heaps, J.M.e , Bolzenius, J.D.a , Baker, L.M.a , Cooley, S.a , Scott, S.a , Cagle, L.M.a , Phillips, S.a , Paul, R.H.a e 
Regional age differences in gray matter diffusivity among healthy older adults
(2016) Brain Imaging and Behavior, 10 (1), pp. 203-211. 

DOI: 10.1007/s11682-015-9383-7

a Department of Psychology, University of Missouri- Saint Louis, 1 University Boulevard, Stadler Hall 442 A, Saint Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway, St. Louis, MO, United States
c Computer Science Department, Brown University, Providence, RI, United States
d Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, United States
e Missouri Institute of Mental Health, 4633 World Parkway Circle, Berkeley, MO, United States

Aging is associated with microstructural changes in brain tissue that can be visualized using diffusion tensor imaging (DTI). While previous studies have established age-related changes in white matter (WM) diffusion using DTI, the impact of age on gray matter (GM) diffusion remains unclear. The present study utilized DTI metrics of mean diffusivity (MD) to identify age differences in GM/WM microstructure in a sample of healthy older adults (N = 60). A secondary aim was to determine the functional significance of whole-brain GM/WM MD on global cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Participants were divided into three age brackets (ages 50–59, 60–69, and 70+) to examine differences in MD and cognition by decade. MD was examined bilaterally in the frontal, temporal, parietal, and occipital lobes for the primary analyses and an aggregate measure of whole-brain MD was used to test relationships with cognition. Significantly higher MD was observed in bilateral GM of the temporal and parietal lobes, and in right hemisphere WM of the frontal and temporal lobes of older individuals. The most robust differences in MD were between the 50–59 and 70+ age groups. Higher whole-brain GM MD was associated with poorer RBANS performance in the 60–69 age group. Results suggest that aging has a significant and differential impact on GM/WM diffusion in healthy older adults, which may explain a modest degree of cognitive variability at specific time points during older adulthood. © 2015, Springer Science+Business Media New York.

Author Keywords
Aging;  Cognition;  Diffusivity;  DTI;  Gray matter;  White matter

Document Type: Article
Source: Scopus


Fox, I.K.
Nerve Transfers in Tetraplegia
(2016) Hand Clinics, . Article in Press. 

DOI: 10.1016/j.hcl.2015.12.013

Division of Plastic Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8238, Saint Louis, MO 63110, USA

Hand and upper extremity function is instrumental to basic activities of daily living and level of independence in cervical spinal cord injury (SCI). Nerve transfer surgery is a novel and alternate approach for restoring function in SCI. This article discusses the biologic basis of nerve transfers in SCI, patient evaluation, management, and surgical approaches. Although the application of this technique is not new; recent case reports and case series in the literature have increased interest in this field. The challenges are to improve function, achieve maximal gains in function, avoid complications, and to primum non nocere. © 2015 Elsevier Inc.

Author Keywords
Nerve transfer;  Spinal cord injury;  Tetraplegia

Document Type: Article in Press
Source: Scopus


Bentley, W.J.a , Li, J.M.a , Snyder, A.Z.b c , Raichle, M.E.a b c , Snyder, L.H.a 
Oxygen Level and LFP in Task-Positive and Task-Negative Areas: Bridging BOLD fMRI and Electrophysiology
(2016) Cerebral Cortex, 26 (1), pp. 346-357. 

DOI: 10.1093/cercor/bhu260

a Department of Anatomy and Neurobiology, Washington University, School of Medicine, 660 S Euclid Ave., St. Louis, MO, United States
b Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States

The human default mode network (DMN) shows decreased blood oxygen level dependent (BOLD) signals in response to a wide range of attention-demanding tasks. Our understanding of the specifics regarding the neural activity underlying these "task-negative" BOLD responses remains incomplete. We paired oxygen polarography, an electrode-based oxygen measurement technique, with standard electrophysiological recording to assess the relationship of oxygen and neural activity in task-negative posterior cingulate cortex (PCC), a hub of the DMN, and visually responsive task-positive area V3 in the awake macaque. In response to engaging visual stimulation, oxygen, LFP power, and multi-unit activity in PCC showed transient activation followed by sustained suppression. In V3, oxygen, LFP power, and multi-unit activity showed an initial phasic response to the stimulus followed by sustained activation. Oxygen responses were correlated with LFP power in both areas, although the apparent hemodynamic coupling between oxygen level and electrophysiology differed across areas. Our results suggest that oxygen responses reflect changes in LFP power and multi-unit activity and that either the coupling of neural activity to blood flow and metabolism differs between PCC and V3 or computing a linear transformation from a single LFP band to oxygen level does not capture the true physiological process. © The Author 2014. Published by Oxford University Press. All rights reserved.

Author Keywords
default mode network;  neurohemodynamic coupling;  oxygen polarography;  power spectrum;  transfer function

Document Type: Article
Source: Scopus


Smyser, C.D.a b , Snyder, A.Z.a c , Shimony, J.S.c , Mitra, A.c , Inder, T.E.d , Neil, J.J.e 
Resting-State Network Complexity and Magnitude Are Reduced in Prematurely Born Infants
(2016) Cerebral Cortex, 26 (1), pp. 322-333. 

DOI: 10.1093/cercor/bhu251

a Department of Neurology, Washington University, School of Medicine, 660 South Euclid Avenue, Saint Louis, MO, United States
b Department of Pediatrics, Washington University, School of Medicine, Saint Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University, School of Medicine, Saint Louis, MO, United States
d Department of Pediatric Newborn Medicine, Brigham and Women's Hospital, Boston, MA, United States
e Department of Neurology, Boston Children's Hospital, Boston, MA, United States

Premature birth is associated with high rates of motor and cognitive disability. Investigations have described resting-state functional magnetic resonance imaging (rs-fMRI) correlates of prematurity in older children, but comparable data in the neonatal period remain scarce. We studied 25 term-born control infants within the first week of life and 25 very preterm infants (born at gestational ages ranging from 23 to 29 weeks) without evident structural injury at term equivalent postmenstrual age. Conventional resting-state network (RSN) mapping revealed only modest differences between the term and prematurely born infants, in accordance with previous work. However, clear group differences were observed in quantitative analyses based on correlation and covariance matrices representing the functional MRI time series extracted from 31 regions of interest in 7 RSNs. In addition, the maximum likelihood dimensionality estimates of the group-averaged covariance matrices in the term and preterm infants were 5 and 3, respectively, indicating that prematurity leads to a reduction in the complexity of rs-fMRI covariance structure. These findings highlight the importance of quantitative analyses of rs-fMRI data and suggest a more sensitive method for delineating the effects of preterm birth in infants without evident structural injury. © The Author 2014. Published by Oxford University Press. All rights reserved.

Author Keywords
developmental neuroimaging;  functional MRI;  infant;  prematurity;  resting-state networks

Document Type: Article
Source: Scopus


Dubis, J.W.a , Siegel, J.S.a , Neta, M.a , Visscher, K.M.g , Petersen, S.E.a b c d e f 
Tasks Driven by Perceptual Information Do Not Recruit Sustained BOLD Activity in Cingulo-Opercular Regions
(2016) Cerebral Cortex, 26 (1), pp. 192-201. 

DOI: 10.1093/cercor/bhu187

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 Anatomy and Neurobiology, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Neurosurgery, Washington University, School of Medicine, 4525 Scott Avenue, St. Louis, MO, United States
e Department of Psychology, Washington University in Saint Louis, St. Louis, MO, United States
f Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO, United States
g Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States

Sustained blood oxygen level dependent (BOLD) signal in the dorsal anterior cingulate cortex/medial superior frontal cortex (dACC/msFC) and bilateral anterior insula/frontal operculum (aI/fO) is found in a broad majority of tasks examined and is believed to function as a putative task set maintenance signal. For example, a meta-analysis investigating task-control signals identified the dorsal anterior cingulate cortex and anterior insula as exhibiting sustained activity across a variety of task types. Re-analysis of tasks included in that meta-analysis showed exceptions, suggesting that tasks where the information necessary to determine a response was present in the stimulus (i.e., perceptually driven) does not show strong sustained cingulo-opercular activity. In a new experiment, we tested the generality of this observation while addressing alternative explanations about sustained cingulo-opercular activity (including task difficulty and verbal vs. non-verbal task demands). A new, difficult, perceptually driven task was compared with 2 new tasks that depended on information beyond that provided by the stimulus. The perceptually driven task showed a lack of cingulo-opercular activity in contrast to the 2 newly constructed tasks. This finding supports the idea that sustained cingulo-opercular activity contributes to maintenance of task set in only a subset of tasks. © The Author 2014. Published by Oxford University Press. All rights reserved.

Author Keywords
cognitive control;  fMRI;  sustained BOLD;  task set;  task-control signals

Document Type: Article
Source: Scopus


Bales, K.R.a , O'Neill, S.M.a , Pozdnyakov, N.a , Pan, F.a , Caouette, D.a , Pi, Y.a , Wood, K.M.a , Volfson, D.a , Cirrito, J.R.b c d , Han, B.-H.e , Johnson, A.W.e , Zipfel, G.J.b e c e , Samad, T.A.a 
Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity
(2015) Brain, 139 (2), pp. 563-577. 

DOI: 10.1093/brain/awv313

a Pfizer Neuroscience and Pain Research Unit, 610 Main Street, Cambridge, MA, United States
b Department of Neurology, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
c Hope Center for Neurological Disorders, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
d Knight Alzheimer's Disease Research Center, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States
e Department of Neurological Surgery, Washington University, School of Medicine, 660 South Euclid Avenue, St. Louis, MO, United States

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity. Chronic administration of ponezumab to transgenic mice led to a significant reduction in amyloid and amyloid-β accumulation both in leptomeningeal and brain vessels when measured by intravital multiphoton imaging and immunohistochemistry. By enriching for cerebral vascular elements, we also measured a significant reduction in the levels of soluble amyloid-β biochemically. We hypothesized that the reduction in vascular amyloid-β40 after ponezumab administration may reflect the ability of ponezumab to mobilize an interstitial fluid pool of amyloid-β40 in brain. Acutely, ponezumab triggered a significant and transient increase in interstitial fluid amyloid-β40 levels in old plaque-bearing transgenic mice but not in young animals. We also measured a beneficial effect on vascular reactivity following acute administration of ponezumab, even in vessels where there was a severe cerebral amyloid angiopathy burden. Taken together, the beneficial effects ponezumab administration has on reducing the rate of cerebral amyloid angiopathy deposition and restoring cerebral vascular health favours a mechanism that involves rapid removal and/or neutralization of amyloid-β species that may otherwise be detrimental to normal vessel function. © 2015 The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

Author Keywords
Alzheimer;  amyloid-β;  CAA;  vascular reactivity

Document Type: Article
Source: Scopus

March 10, 2016

Ciurria, M.
A virtue ethical approach to decisional capacity and mental health
(2016) Philosophical Psychology, 29 (3), pp. 462-475. 

DOI: 10.1080/09515089.2015.1100719

Department of Philosophy, Washington University in Saint Louis, St. Louis, MO, United States

It is a common assumption that lack of autonomy is incompatible with decisional capacity and mental health. However, there are two general conceptions of autonomy, one value-neutral and the other value-laden, which imply different notions of mental health. I argue that the value-neutral notion of autonomy is independently inadequate and that it also provides an inadequate foundation for judging whether someone is decisionally incapable or mentally disordered. I propose an alternative, value-laden account which posits ten capabilities required for basic human functioning. I then defend this account against objections and highlight its practical utility in designing optimal treatment. © 2016 Taylor & Francis.

Author Keywords
Autonomy;  capability approach;  decisional capacity;  mental health;  psychological disorder;  virtue ethics

Document Type: Article
Source: Scopus


Moore, R.C.a b c , Depp, C.A.a b c , Wetherell, J.L.a c , Lenze, E.J.d 
Ecological momentary assessment versus standard assessment instruments for measuring mindfulness, depressed mood, and anxiety among older adults
(2016) Journal of Psychiatric Research, 75, pp. 116-123. 

DOI: 10.1016/j.jpsychires.2016.01.011

a Department of Psychiatry, University of California San Diego, 9500 Gilman Drive 0993, La Jolla, CA, United States
b The Sam and Rose Stein Institute for Research on Aging, University of California San Diego, 9500 Gilman Drive 0664, La Jolla, CA, United States
c VA San Diego Healthcare System, 3550 La Jolla Village Drive, San Diego, CA, United States
d Washington University School of Medicine, Department of Psychiatry, 660 So. Euclid Ave, Campus Box 8134, St. Louis, MO, United States

As mobile data capture tools for patient-reported outcomes proliferate in clinical research, a key dimension of measure performance is sensitivity to change. This study compared performance of patient-reported measures of mindfulness, depression, and anxiety symptoms using traditional paper-and-pencil forms versus real-time, ambulatory measurement of symptoms via ecological momentary assessment (EMA). Sixty-seven emotionally distressed older adults completed paper-and-pencil measures of mindfulness, depression, and anxiety along with two weeks of identical items reported during ambulatory monitoring via EMA before and after participation in a randomized trial of Mindfulness-Based Stress Reduction (MBSR) or a health education intervention. We calculated effect sizes for these measures across both measurement approaches and estimated the Number-Needed-to-Treat (NNT) in both measurement conditions. Study outcomes greatly differed depending on which measurement method was used. When EMA was used to measure clinical symptoms, older adults who participated in the MBSR intervention had significantly higher mindfulness and significantly lower depression and anxiety than participants in the health education intervention at post-treatment. However, these significant changes in symptoms were not found when outcomes were measured with paper-and-pencil measures. The NNT for mindfulness and depression measures administered through EMA were approximately 25-50% lower than NNTs derived from paper-and-pencil administration. Sensitivity to change in anxiety was similar across administration modes. In conclusion, EMA measures of depression and mindfulness substantially outperformed paper-and-pencil measures with the same items. The additional resources associated with EMA in clinical trials would seem to be offset by its greater sensitivity to detect change in key outcome variables. © 2016 Published by Elsevier Ltd.

Author Keywords
Ecological momentary assessment;  Mindfulness-based stress reduction;  Mobile assessment;  Patient reported outcomes;  Psychometrics;  Randomized clinical trial

Document Type: Article
Source: Scopus


Rajagopal, R., Apte, R.S.
Seeing through thick and through thin: Retinal manifestations of thrombophilic and hyperviscosity syndromes
(2016) Survey of Ophthalmology, 61 (2), pp. 236-247. 

DOI: 10.1016/j.survophthal.2015.10.006

Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, United States

The presence of retinal vasculopathy in the absence of typical predisposing factors should suggest a possible underlying hematologic abnormality. In such cases, a systemic investigation may reveal a potentially fatal hypercoagulability or hyperviscosity syndrome. Retinal vein occlusion is the most commonly encountered ophthalmic finding in such syndromes; however, abnormalities of the arterial system, the choroid, and the macula are also possible. Visual symptoms may be the only manifestation of the underlying process, making timely diagnosis by the ophthalmologist critical for both treatment and thrombotic prophylaxis. Moreover, as newer ophthalmic diagnostic technologies arise, there is an increasingly important role for eye physicians in the management of such syndromes. © 2016 Elsevier Inc.

Author Keywords
Factor V Leiden;  Hyperhomocysteinemia;  Indocyanine green angiography;  Lymphoplasmacytic leukemia;  Macular edema;  Polycythemia;  Prothrombin G20210A;  Retinal vein occlusion;  Serous choroidal detachment

Document Type: Review
Source: Scopus


Lenze, E.J.a , Farber, N.B.a , Kharasch, E.a , Schweiger, J.a , Yingling, M.a , Olney, J.a , Newcomer, J.W.b 
Ninety-six hour ketamine infusion with co-administered clonidine for treatment-resistant depression: A pilot randomised controlled trial
(2016) World Journal of Biological Psychiatry, pp. 1-9. Article in Press. 

DOI: 10.3109/15622975.2016.1142607

a Washington University School of Medicine, St. Louis, MO 63110, USA
b Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, USA

Objectives We examined the feasibility of a high-dose, 96-h infusion of ketamine in treatment-resistant depression. Methods Ten participants were randomised to receive a 96-h ketamine infusion, titrated as tolerated to a target rate of 0.6 mg/kg/h, while 10 received a 40-min ketamine infusion (0.5 mg/kg). Both groups received clonidine, titrated to a maximum of 0.6 mg orally daily, during the infusion to mitigate side effects of ketamine. Participants were followed for 8 weeks to examine potential antidepressant effects. Results All 20 participants completed the infusion. Most participants tolerated the infusion well, with minimal psychotomimetic symptoms or blood pressure elevation despite achieving high ketamine concentrations (mean 424 ng/ml for 96-h arm, 156 ng/ml for 40-min arm). There was no rebound hypertension upon discontinuing clonidine. Rapid and sustained improvement in depressive symptoms was observed in both study groups. Higher ketamine concentration was associated with sustained antidepressant response, and was not with greater psychotomimetic side effects, in the 96-h arm. Conclusions This study provides evidence for the feasibility of prolonged ketamine infusions in treatment-resistant depression. Co-administration of clonidine appeared to mitigate ketamine’s psychotomimetic effects. Further study is required to investigate the extent to which prolonged ketamine infusions could provide both rapid and sustained improvements in treatment-resistant depression. identifier NCT01179009 © 2016 Taylor & Francis

Author Keywords
Affective disorders;  antidepressants;  major depressive disorder;  psychopharmacology

Document Type: Article in Press
Source: Scopus


Colonna, M., Wang, Y.
TREM2 variants: new keys to decipher Alzheimer disease pathogenesis
(2016) Nature Reviews Neuroscience, . Article in Press. 

DOI: 10.1038/nrn.2016.7

Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63108, USA.

Genome-wide association studies have identified rare variants of the gene that encodes triggering receptor expressed on myeloid cells 2 (TREM2) — an immune receptor that is found in brain microglia — as risk factors for non-familial Alzheimer disease (AD). Furthermore, animal studies have indicated that microglia have an important role in the brain response to amyloid-β (Aβ) plaques and that TREM2 variants may have an impact on such a function. We discuss how TREM2 may control the microglial response to Aβ and its impact on microglial senescence, as well as the interaction of TREM2 with other molecules that are encoded by gene variants associated with AD and the hypothetical consequences of the cleavage of TREM2 from the cell surface. © 2016 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

Document Type: Article in Press
Source: Scopus


Milchenko, M.a , Snyder, A.Z.a , LaMontagne, P.a , Shimony, J.S.a , Benzinger, T.L.a , Fouke, S.J.b , Marcus, D.S.a 
Heterogeneous Optimization Framework: Reproducible Preprocessing of Multi-Spectral Clinical MRI for Neuro-Oncology Imaging Research
(2016) Neuroinformatics, pp. 1-13. Article in Press. 

DOI: 10.1007/s12021-016-9296-7

a Neuroinformatics Research Group, Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, Swedish Medical Center, Seattle, WA, United States

Neuroimaging research often relies on clinically acquired magnetic resonance imaging (MRI) datasets that can originate from multiple institutions. Such datasets are characterized by high heterogeneity of modalities and variability of sequence parameters. This heterogeneity complicates the automation of image processing tasks such as spatial co-registration and physiological or functional image analysis. Given this heterogeneity, conventional processing workflows developed for research purposes are not optimal for clinical data. In this work, we describe an approach called Heterogeneous Optimization Framework (HOF) for developing image analysis pipelines that can handle the high degree of clinical data non-uniformity. HOF provides a set of guidelines for configuration, algorithm development, deployment, interpretation of results and quality control for such pipelines. At each step, we illustrate the HOF approach using the implementation of an automated pipeline for Multimodal Glioma Analysis (MGA) as an example. The MGA pipeline computes tissue diffusion characteristics of diffusion tensor imaging (DTI) acquisitions, hemodynamic characteristics using a perfusion model of susceptibility contrast (DSC) MRI, and spatial cross-modal co-registration of available anatomical, physiological and derived patient images. Developing MGA within HOF enabled the processing of neuro-oncology MR imaging studies to be fully automated. MGA has been successfully used to analyze over 160 clinical tumor studies to date within several research projects. Introduction of the MGA pipeline improved image processing throughput and, most importantly, effectively produced co-registered datasets that were suitable for advanced analysis despite high heterogeneity in acquisition protocols. © 2016 Springer Science+Business Media New York

Author Keywords
Data modeling;  Diffusion imaging;  DSC imaging;  Knowledge representation;  MRI;  Neuro-oncology imaging;  Spatial co-registration

Document Type: Article in Press
Source: Scopus


Kahle, K.T.a , Kulkarni, A.V.b , Limbrick, D.D., Jr.c , Warf, B.C.a 
Hydrocephalus in children
(2016) The Lancet, 387 (10020), pp. 788-799. 

DOI: 10.1016/S0140-6736(15)60694-8

a Department of Neurosurgery, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
b Division of Neurosurgery, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
c Division of Neurosurgery, St Louis Children's Hospital, Washington University School of Medicine, St Louis, MO, United States

Hydrocephalus is a common disorder of cerebral spinal fluid (CSF) physiology resulting in abnormal expansion of the cerebral ventricles. Infants commonly present with progressive macrocephaly whereas children older than 2 years generally present with signs and symptoms of intracranial hypertension. The classic understanding of hydrocephalus as the result of obstruction to bulk flow of CSF is evolving to models that incorporate dysfunctional cerebral pulsations, brain compliance, and newly characterised water-transport mechanisms. Hydrocephalus has many causes. Congenital hydrocephalus, most commonly involving aqueduct stenosis, has been linked to genes that regulate brain growth and development. Hydrocephalus can also be acquired, mostly from pathological processes that affect ventricular outflow, subarachnoid space function, or cerebral venous compliance. Treatment options include shunt and endoscopic approaches, which should be individualised to the child. The long-term outcome for children that have received treatment for hydrocephalus varies. Advances in brain imaging, technology, and understanding of the pathophysiology should ultimately lead to improved treatment of the disorder. © 2016 Elsevier Ltd.

Document Type: Conference Paper
Source: Scopus


Barch, D.M.a , Verfaellie, M.b , Rao, S.M.c 
Introduction to JINS special issue on human brain connectivity in the modern era: Relevance to understanding health and disease
(2016) Journal of the International Neuropsychological Society, 22 (2), pp. 101-104. 

DOI: 10.1017/S1355617716000047

a Washington University in St. Louis, St. Louis, MO, United States
b VA Boston Healthcare System, Boston University, School of Medicine, Boston, MA, United States
c Cleveland Clinic, Cleveland, OH, United States

Document Type: Review
Source: Scopus


Lugar, H.M.a , Koller, J.M.a , Rutlin, J.a , Marshall, B.A.d e , Kanekura, K.f , Urano, F.f , Bischoff, A.N.a , Shimony, J.S.c , Hershey, T.a b c 
Neuroimaging evidence of deficient axon myelination in Wolfram syndrome
(2016) Scientific Reports, 6, art. no. 21167, . 

DOI: 10.1038/srep21167

a Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
c Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Cell Biology, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States

Wolfram syndrome is a rare autosomal recessive genetic disease characterized by insulin dependent diabetes and vision, hearing and brain abnormalities which generally emerge in childhood. Mutations in the WFS1 gene predispose cells to endoplasmic reticulum stress-mediated apoptosis and may induce myelin degradation in neuronal cell models. However, in vivo evidence of this phenomenon in humans is lacking. White matter microstructure and regional volumes were measured using magnetic resonance imaging in children and young adults with Wolfram syndrome (n = 21) and healthy and diabetic controls (n = 50). Wolfram patients had lower fractional anisotropy and higher radial diffusivity in major white matter tracts and lower volume in the basilar (ventral) pons, cerebellar white matter and visual cortex. Correlations were found between key brain findings and overall neurological symptoms. This pattern of findings suggests that reduction in myelin is a primary neuropathological feature of Wolfram syndrome. Endoplasmic reticulum stress-related dysfunction in Wolfram syndrome may interact with the development of myelin or promote degeneration of myelin during the progression of the disease. These measures may provide objective indices of Wolfram syndrome pathophysiology that will be useful in unraveling the underlying mechanisms and in testing the impact of treatments on the brain.

Document Type: Article
Source: Scopus


Choi, D.a , Fox, Z.a , Albert, T.b c , Arts, M.d , Balabaud, L.e , Bunger, C.f , Buchowski, J.M.g , Coppes, M.H.h , Depreitere, B.i , Fehlings, M.G.j , Harrop, J.b c , Kawahara, N.k , Martin-Benlloch, J.A.l , Massicotte, E.M.j , Mazel, C.e , Oner, F.C.m , Peul, W.c n , Quraishi, N.o , Tokuhashi, Y.p , Tomita, K.q , Verlaan, J.J.m , Wang, M.f , Wang, M.r , Crockard, H.A.a 
Rapid improvements in pain and quality of life are sustained after surgery for spinal metastases in a large prospective cohort
(2016) British Journal of Neurosurgery, pp. 1-8. Article in Press. 

DOI: 10.3109/02688697.2015.1133802

a Department of Neurosurgery, National Hospital for Neurology and Neurosurgery, University College London, London, UK
b Departments of Neurosurgery, Thomas Jefferson University and Hospitals, PA, USA
c Department of Orthopedic Surgery, Thomas Jefferson University and Hospitals, PA, USA
d Department of Neurosurgery, Medical Center Haaglanden, Haaglanden, the Netherlands
e Department of Orthopedic Surgery, L’institut Mutualiste Montsouris, Paris, France
f Department of Orthopedic Surgery, University Hospital of Aarhus, Aarhus, Denmark
g Departments of Orthopedic and Neurological Surgery, Washington University, MO, USA
h Department of Neurosurgery, Groningen, the Netherlands
i Division of Neurosurgery, University Hospital Leuven, Leuven, Belgium
j Department of Neurosurgery, Toronto Western Hospital, Toronto, Canada
k Department of Orthopedic Surgery, Kanazawa Medical University Hospital, Kanazawa, Japan
l Spinal Unit, Hospital Universitario Dr Peset, Valencia, Spain
m Department of Orthopedic Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
n Department of Neurosurgery, Leiden University Medical Centre, Leiden, the Netherlands
o Centre for Spine Studies and Surgery, Queens Medical Centre, Nottingham, UK
p Department of Orthopedic Surgery, Nihon University School of Medicine, Japan
q Department of Orthopedic Surgery, Kanazawa University, Kanazawa, Japan
r Department of Neurosurgery, Jackson Memorial Hospital, University of Miami, FL, USA

Introduction Metastatic spinal cancer is a common condition that may lead to spinal instability, pain and paralysis. In the 1980s, surgery was discouraged because results showed worse neurological outcomes and pain compared with radiotherapy alone. However, with the advent of modern imaging and spinal stabilisation techniques, the role of surgery has regained centre stage, though few studies have assessed quality of life and functional outcomes after surgery. Objective We investigated whether surgery provides sustained improvement in quality of life and pain relief for patients with symptomatic spinal metastases by analysing the largest reported surgical series of patients with epidural spinal metastases. Methods A prospective cohort study of 922 consecutive patients with spinal metastases who underwent surgery, from the Global Spine Tumour Study Group database. Pre- and post-operative EQ-5D quality of life, visual analogue pain score, Karnofsky physical functioning score, complication rates and survival were recorded. Results Quality of life (EQ-5D), VAS pain score and Karnofsky physical functioning score improved rapidly after surgery and these improvements were sustained in those patients who survived up to 2 years after surgery. In specialised spine centres, the technical intra-operative complication rate of surgery was low, however almost a quarter of patients experienced post-operative systemic adverse events. Conclusion Surgical treatment for spinal metastases produces rapid pain relief, maintains ambulation and improves good quality of life. However, as a group, patients with cancer are vulnerable to post-operative systemic complications, hence the importance of appropriate patient selection. © 2016 Taylor & Francis

Author Keywords
Metastasis;  outcome;  quality of life;  spine;  surgery

Document Type: Article in Press
Source: Scopus


Zipes, D.P.a k , Neuzil, P.b , Theres, H.c , Caraway, D.d , Mann, D.L.e , Mannheimer, C.f , Van Buren, P.g , Linde, C.h , Linderoth, B.h , Kueffer, F.i , Sarazin, S.A.i , DeJongste, M.J.L.j 
Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Systolic Heart Failure: The DEFEAT-HF Study
(2016) JACC: Heart Failure, 4 (2), pp. 129-136. Cited 1 time.

DOI: 10.1016/j.jchf.2015.10.006

a Indiana University School of Medicine, Indianapolis, IN, United States
b Na Homolce Hospital, Prague, Czech Republic
c Charité Universitätsmedizin Berlin, Berlin, Germany
d St. Mary's Medical Center, Huntington, WV, United States
e Washington University School of Medicine, St. Louis, MO, United States
f Sahlgrenska University Hospital, Göteborg, Sweden
g Fletcher Allen Healthcare, Burlington, VT, United States
h Karolinska University Hospital, Stockholm, Sweden
i Medtronic, Minneapolis, MN, United States
j Universitair Medisch Centrum Groningen and University of Groningen, Groningen, Netherlands

Objectives: The primary objective of the study was a change in left ventricular end-systolic volume index (LVESVi) from baseline to 6 months of spinal cord stimulation (SCS) therapy in the treatment arm compared to the control arm as measured by echocardiography. Secondary objectives were changes in peak oxygen uptake and N-terminal pro-B-type natriuretic peptide (NT-proBNP) between the treatment arm and control arm from baseline through 6 months. Background: Abnormal neurohormonal activation is often responsible for progression of heart failure (HF). Treatment has often included drug therapy to modulate the neurohormonal axis. The purpose of the DEFEAT-HF (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure) clinical study was to evaluate whether direct modulation of the nervous system through SCS improved HF metrics, including heart size, biomarkers, functional capacity, and symptoms. Methods: The DEFEAT-HF study was a prospective, multicenter randomized (3:2), parallel, single-blind, controlled study to investigate whether SCS was a feasible therapy for the treatment of systolic HF for patients with New York Heart Association functional class III HF, left ventricular ejection fraction (LVEF) ≤35%, QRS duration <120 ms, and left ventricular end-diastolic dimension ≥55 mm. The primary objective of the DEFEAT-HF study was to evaluate the reduction in LVESVi after 6 months of SCS therapy in the treatment arm compared to the control arm. Results: In total, 81 patients were enrolled, with 66 successfully randomized and implanted with the SCS device system. Seventy-six percent (50 of 66) had an implantable cardioverter-defibrillator at the baseline visit. Among randomized patients, the mean age was 61 years, 79% were male, mean LVEF was 27%, and mean QRS duration was 105 ms. The change in LVESVi over 6 months was not significantly different between randomization arms (SCS OFF: -2.2 [95% confidence interval: -9.1 to 4.6] vs. SCS ON: 2.1 [95% confidence interval: -2.7 to 6.9]; p = 0.30). Analyses of secondary endpoints for the study were also not significantly different. Conclusions: The present study does not provide evidence to support a meaningful change in clinical outcomes for HF patients receiving SCS. (Determining the Feasibility of Spinal Cord Neuromodulation for the Treatment of Chronic Heart Failure [DEFEAT-HF]; NCT01112579). © 2016 American College of Cardiology Foundation.

Author Keywords
Clinical trial results;  Heart failure;  Randomized;  Spinal cord stimulation

Document Type: Article
Source: Scopus


Geers, A.E.a , Nicholas, J.b , Tobey, E.a , Davidson, L.b 
Persistent language delay versus late language emergence in children with early cochlear implantation
(2016) Journal of Speech, Language, and Hearing Research, 59 (1), pp. 155-170. 

DOI: 10.1044/2015_JSLHR-H-14-0173

a Callier Center for Advanced Hearing Research and the Southwestern Medical Center, The University of Texas, Dallas, United States
b Washington University, Saint Louis, MO, United States

Purpose: The purpose of the present investigation is to differentiate children using cochlear implants (CIs) who did or did not achieve age-appropriate language scores by midelementary grades and to identify risk factors for persistent language delay following early cochlear implantation. Materials and Method: Children receiving unilateral CIs at young ages (12–38 months) were tested longitudinally and classified with normal language emergence (n = 19), late language emergence (n = 22), or persistent language delay (n = 19) on the basis of their test scores at 4.5 and 10.5 years of age. Relative effects of demographic, audiological, linguistic, and academic characteristics on language emergence were determined. Results: Age at CI was associated with normal language emergence but did not differentiate late emergence from persistent delay. Children with persistent delay were more likely to use left-ear implants and older speech processor technology. They experienced higher aided thresholds and lower speech perception scores. Persistent delay was foreshadowed by low morph syntactic and phonological diversity in preschool. Logistic regression analysis predicted normal language emergence with 84% accuracy and persistent language delay with 74% accuracy. Conclusion: CI characteristics had a strong effect on persistent versus resolving language delay, suggesting that right-ear (or bilateral) devices, technology upgrades, and improved audibility may positively influence long-term language outcomes. © 2016 American Speech-Language-Hearing Association.

Document Type: Article
Source: Scopus


Mitchell, K.a , Lewis, R.S.b , Satterfield, J.c , Hong, B.A.d 
The new medical college admission test: Implications for teaching psychology
(2016) American Psychologist, 71 (2), pp. 125-135. Cited 1 time.

DOI: 10.1037/a0039975

a Admissions Testing Services, Association of American Medical Colleges, United States
b Psychology Department and Neuroscience Program, Pomona College, United States
c Department of Medicine, School of Medicine, University of California, San Francisco, United States
d Department of Psychiatry, Washington University School of Medicine, United States

This year's applicants to medical school took a newly revised version of the Medical College Admission Test. Unlike applicants in the past, they were asked to demonstrate their knowledge and use of concepts commonly taught in introductory psychology courses. The new Psychological, Social, and Biological Foundations of Behavior Test asked applicants to demonstrate the ways in which psychological, social, and biological factors influence perceptions and reactions to the world; behavior and behavior change; what people think about themselves and others; the cultural and social differences that influence well-being; and the relationships among social stratification, access to resources, and wellbeing. Building from the classic biopsychosocial model, this article provides the rationale for testing psychology concepts in application to medical school. It describes the concepts and skills that the new exam tests and shows how they lay the foundation for learning in medical school about the behavioral and sociocultural determinants of health. This article discusses the implications of these changes for undergraduate psychology faculty and psychology curricula as well as their importance to the profession of psychology at large. © 2016 American Psychological Association.

Author Keywords
Admissions testing;  Introductory psychology;  Prehealth education;  Standardized tests;  Undergraduate education

Document Type: Article
Source: Scopus


Kasckow, J.a b c d e , Youk, A.e , Anderson, S.J.e , Dew, M.A.d e f , Butters, M.A.d , Marron, M.M.f , Begley, A.E.d , Szanto, K.d , Dombrovski, A.Y.d , Mulsant, B.H.d g , Lenze, E.J.h , Reynolds, C.F.d 
Trajectories of suicidal ideation in depressed older adults undergoing antidepressant treatment
(2016) Journal of Psychiatric Research, 73, pp. 96-101. 

DOI: 10.1016/j.jpsychires.2015.11.004

a VA Pittsburgh Health Care System, Behavioral Health, University DR C, Pittsburgh, PA, United States
b VA Pittsburgh Health Care System, MIRECC, University DR C, Pittsburgh, PA, United States
c VA Pittsburgh Health Care System, CHERP, University DR C, Pittsburgh, PA, United States
d Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
e Biostatistics, Graduate School of Public Health, University of Pittsburgh, United States
f Epidemiology, Graduate School of Public Health, University of Pittsburgh, United States
g Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada
h Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States

Suicide is a public health concern in older adults. Recent cross sectional studies suggest that impairments in executive functioning, memory and attention are associated with suicidal ideation in older adults. It is unknown whether these neuropsychological features predict persistent suicidal ideation. We analyzed data from 468 individuals ≥ age 60 with major depression who received venlafaxine XR monotherapy for up to 16 weeks. We used latent class growth modeling to classify groups of individuals based on trajectories of suicidal ideation. We also examined whether cognitive dysfunction predicted suicidal ideation while controlling for time-dependent variables including depression severity, and age and education. The optimal model using a zero inflated Poisson link classified individuals into four groups, each with a distinct temporal trajectory of suicidal ideation: those with 'minimal suicidal ideation' across time points; those with 'low suicidal ideation'; those with 'rapidly decreasing suicidal ideation'; and those with 'high and persistent suicidal ideation'. Participants in the 'high and persistent suicidal ideation' group had worse scores relative to those in the "rapidly decreasing suicidal ideation" group on the Color-Word 'inhibition/switching' subtest from the Delis-Kaplan Executive Function Scale, worse attention index scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and worse total RBANS index scores. These findings suggest that individuals with poorer ability to switch between inhibitory and non-inhibitory responses as well as worse attention and worse overall cognitive status are more likely to have persistently higher levels of suicidal ideation. number: NCT00892047. © 2015.

Author Keywords
Antidepressant;  Depression;  Late life;  Suicide;  Trajectory

Document Type: Article
Source: Scopus


Wilson, U.S.a c , Kaf, W.A.a , Danesh, A.A.b , Lichtenhan, J.T.c 
Assessment of low-frequency hearing with narrow-band chirp-evoked 40-Hz sinusoidal auditory steady-state response
(2016) International Journal of Audiology, 55 (4), pp. 239-247. 

DOI: 10.3109/14992027.2015.1122238

a Communication Sciences and Disorders, Missouri State University, 901 South National Avenue, Springfield, MO, United States
b Communication Sciences and Disorders, Florida Atlantic University, Boca Raton, FL, United States
c Department of Otolaryngology, Washington University, School of Medicine in Saint Louis, Saint Louis, MI, United States

Objective To determine the clinical utility of narrow-band chirp-evoked 40-Hz sinusoidal auditory steady state responses (s-ASSR) in the assessment of low-frequency hearing in noisy participants. Design Tone bursts and narrow-band chirps were used to respectively evoke auditory brainstem responses (tb-ABR) and 40-Hz s-ASSR thresholds with the Kalman-weighted filtering technique and were compared to behavioral thresholds at 500, 2000, and 4000 Hz. A repeated measure ANOVA and post-hoc t-tests, and simple regression analyses were performed for each of the three stimulus frequencies. Study sample Thirty young adults aged 18-25 with normal hearing participated in this study. Results When 4000 equivalent response averages were used, the range of mean s-ASSR thresholds from 500, 2000, and 4000 Hz were 17-22 dB lower (better) than when 2000 averages were used. The range of mean tb-ABR thresholds were lower by 11-15 dB for 2000 and 4000 Hz when twice as many equivalent response averages were used, while mean tb-ABR thresholds for 500 Hz were indistinguishable regardless of additional response averaging. Conclusion Narrow-band chirp-evoked 40-Hz s-ASSR requires a ∼15 dB smaller correction factor than tb-ABR for estimating low-frequency auditory threshold in noisy participants when adequate response averaging is used. © 2016 British Society of Audiology, International Society of Audiology, and Nordic Audiological Society.

Author Keywords
auditory brainstem response;  Auditory steady-state response;  Kalman-weighted filtering

Document Type: Article
Source: Scopus


Lee, M.H.a , Miller-Thomas, M.M.a , Benzinger, T.L.a b , Marcus, D.S.a , Hacker, C.D.c , Leuthardt, E.C.b , Shimony, J.S.a 
Clinical resting-state fMRI in the preoperative setting are we ready for prime time?
(2016) Topics in Magnetic Resonance Imaging, 25 (1), pp. 11-17. 

DOI: 10.1097/RMR.0000000000000075

a Mallinckrodt Institute of Radiology, Neuroradiology Washington Univ. Medical School Queeny Tower, 16th Fl., Suite 16109 Camp. Box 8131 510 S. K. B., Louis, MO, United States
b Department of Neurosurgery, United States
c Department of Biomedical Engineering, Washington University School of Medicine, St Louis, United States

The purpose of this manuscript is to provide an introduction to resting-state functional magnetic resonance imaging (RS-fMRI) and to review the current application of this new and powerful technique in the preoperative setting using our institute's extensive experience. RS-fMRI has provided important insights into brain physiology and is an increasingly important tool in the clinical setting. As opposed to task-based functional MRI wherein the subject performs a task while being scanned, RS-fMRI evaluates low-frequency fluctuations in the blood oxygen level dependent (BOLD) signal while the subject is at rest. Multiple resting state networks (RSNs) have been identified, including the somatosensory, language, and visual networks, which are of primary importance for presurgical planning. Over the past 4 years, we have performed over 300 RS-fMRI examinations in the clinical setting and these have been used to localize eloquent somatosensory and language cortices before brain tumor resection. RS-fMRI is particularly useful in this setting for patients who are unable to cooperate with the task-based paradigm, such as young children or those who are sedated, paretic, or aphasic. Although RS-fMRI is still investigational, our experience indicates that this method is ready for clinical application in the presurgical setting. ©2016 Wolters Kluwer Health, Inc.

Author Keywords
Brain tumor;  FMRI;  Resting-state FMRI

Document Type: Review
Source: Scopus


Freedland, K.E.a , Carney, R.M.a , Rich, M.W.b , Steinmeyer, B.C.a , Skala, J.A.c , Dávila-Román, V.G.b 
Depression and Multiple Rehospitalizations in Patients With Heart Failure
(2016) Clinical Cardiology, . Article in Press. 

DOI: 10.1002/clc.22520

a Department of Psychiatry Washington University School of Medicine St. Louis, Missouri
b Department of Medicine Washington University School of Medicine St. Louis, Missouri
c Palliative Care Department Veterans Administration Medical Center St. Louis, Missouri

Background: There have been few studies of the effect of depression on rehospitalization in patients with heart failure (HF), and even fewer on its role in multiple rehospitalizations. Hypothesis: Depression is an independent risk factor for multiple readmissions in patients with HF. Methods: A cohort of 662 patients with HF who were discharged alive after hospitalization were interviewed to evaluate symptoms of depression and were followed for 1 year. All-cause readmissions were documented by chart review. A marginal proportional rates model was used to model the effect of depression on the rate of rehospitalization with adjustment for known predictors of HF outcomes. Results: Depression symptoms predicted multiple readmissions (adjusted hazard ratio [HR]: 1.08, 95% confidence interval [CI]: 1.03-1.13, P = 0.0008). Compared with patients without depression, those who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depression at index were at the highest risk for multiple rehospitalizations (HR: 1.51, 95% CI: 1.15-1.97, P = 0.003). Conclusions: Depression is an independent risk factor for multiple all-cause readmissions in patients with HF. © 2016 Wiley Periodicals, Inc. February 2016 10.1002/clc.22520 Clinical Investigations Clinical Investigations © 2016 Wiley Periodicals, Inc..

Document Type: Article in Press
Source: Scopus


Etzel, J.A.a b c , Valchev, N.a b d , Gazzola, V.a b e f , Keysers, C.a b e f 
Is brain activity during action observation modulated by the perceived fairness of the actor?
(2016) PLoS ONE, 11 (1), art. no. e0145350, . 

DOI: 10.1371/journal.pone.0145350

a Department of Neuroscience, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands
b University of Groningen, University Medical Center Groningen, Neuroimaging Centre, Groningen, Netherlands
c Cognitive Control and Psychopathology Laboratory, Washington University in St. Louis, St. Louis, United States
d Department of Otorhinolaryngology/Head and Neck Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
e Social Brain Lab, Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
f Department of Psychology, University of Amsterdam, Amsterdam, Netherlands

Perceiving other people's actions triggers activity in premotor and parietal areas, brain areas also involved in executing and sensing our own actions. Paralleling this phenomenon, observing emotional states (including pain) in others is associated with activity in the same brain areas as activated when experiencing similar emotions directly. This emotion perception associated activity has been shown to be affected by the perceived fairness of the actor, and in-group membership more generally. Here, we examine whether action observation associated brain activity is also affected by the perceived social fairness of the actors. Perceived fairness was manipulated using an alternating iterated Prisoner's Dilemma game between the participant and two confederates, one of whom played fairly and the other unfairly. During fMRI scanning the participants watched movies of the confederates performing object-directed hand actions, and then performed hand actions themselves. Massunivariate analysis showed that observing the actions triggered robust activation in regions associated with action execution, but failed to identify a strong modulation of this activation based on perceived fairness. Multivariate pattern analysis, however, identified clusters potentially carrying information about the perceived fairness of the actor in the middle temporal gyrus, left postcentral gyrus, right inferior parietal lobule, right middle cingulate cortex, right angular gyrus, and right superioroccipital gyrus. Despite being identified by a wholebrain searchlight analysis (and so without anatomical restriction), these clusters fall into areas frequently associated with action observation. We conclude that brain activity during action observation may be modulated by perceived fairness, but such modulation is subtle; robust activity is associated with observing the actions of both fair and unfair individuals. © 2016 Etzel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus


Anderson, D.M.G.a , Van de Plas, R.a b , Rose, K.L.a , Hill, S.a , Schey, K.L.a , Solga, A.C.c , Gutmann, D.H.c , Caprioli, R.M.a 
3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma
(2016) Journal of Proteomics, . Article in Press. 

DOI: 10.1016/j.jprot.2016.02.004

a Mass Spectrometry Research Center and Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, United States
b Delft Center for Systems and Control, Delft University of Technology, Delft, The Netherlands
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions. Biological significance: The current work addresses a number of challenges in 3-D MALDI IMS, driven by the small size of the mouse optic nerve and the need to maintain consistency across multiple 2-D IMS experiments. The 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions, which could then be targeted for identification and related back to the biology observed in gliomas of the optic nerve. © 2016 Elsevier B.V.

Author Keywords
3-D imaging;  Bottom-up proteomics;  Imaging mass spectrometry;  MALDI;  Optic glioma;  Top-down proteomics

Document Type: Article in Press
Source: Scopus


Ben-Shahar, Y.
Editorial overview: Neuroscience: How nervous systems generate behavior: Lessons from insects
(2015) Current Opinion in Insect Science, 12, pp. v-vii. 

DOI: 10.1016/j.cois.2015.10.005

Department of Biology, Washington University, St. Louis, MO, United States
Document Type: Editorial
Source: Scopus

March 3, 2016

Treiman, R.a , Kessler, B.a , Decker, K.a , Pollo, T.C.b
How do prephonological writers link written words to their objects?
(2016) Cognitive Development, 38, pp. 89-98. 

DOI: 10.1016/j.cogdev.2016.02.002

a Department of Psychological and Brain Sciences, Washington University in St. Louis, Campus Box 1125, St. Louis, MO, United States
b Department of Psychology, Universidade Federal de São João del-Rei, Praça Frei Orlando, 170-Centro São João del-Rei, Minas Gerais, Brazil

Two experiments studied prephonological writers, namely children who do not yet use letters to represent phonemes. The experiments tested the hypothesis that these children link elements of writing not to the phonological forms of spoken words but to physical characteristics of the words' referents. In Experiment 1, prephonological spellers (n= 36, mean age 4 years, 3 months) used more elements on average to write plural nouns such as cows than singular nouns such as cow. Prephonological spellers in Experiment 2 (n= 42, mean age 4 years, 4 months) did not use more elements to write longer verbs such as buying than shorter ones such as buy. Thus, the results of Experiment 1 suggest that prephonological spellers are sensitive to the quantity of the referent rather than the number of phonemes, syllables, or morphemes in the word. That is, prephonological spellers have some tendency to treat writing as iconic. © 2016 Elsevier Inc.

Author Keywords
Iconicity;  Morphology;  Phonology;  Prephonological spellers;  Spelling;  Syllables;  Symbols;  Writing

Document Type: Article
Source: Scopus

Ayer, L.a , Kohl, P.b , Malsberger, R.a , Burgette, L.a
The impact of fathers on maltreated youths' mental health
(2016) Children and Youth Services Review, 63, pp. 16-20. 

DOI: 10.1016/j.childyouth.2016.02.006

a The RAND Corporation, 1200 South Hayes Street, Arlington, VA, United States
b George Warren Brown School of Social Work, Washington University, Campus Box 1196, One Brookings Drive, St. Louis, MO, United States

Men are increasingly the heads of single parent households, yet are often excluded from child welfare research and practice. To better serve all families in the child welfare system, it is necessary to understand the impact of primary caregiving men on children's wellbeing. In this study we investigated the longitudinal effects of primary caregiving fathers' mental health and substance use on child mental health, and examined possible differences by child age and gender. Regression analyses were conducted with the sample of 322 youth living with a male primary caregiver at the first wave of data collection from the National Survey of Child and Adolescent Wellbeing-II (NSCAW-II). We found that father depression at baseline consistently predicted child mental health outcomes three years later, even after accounting for demographics and baseline child mental health. Surprisingly, fathers' substance use did not predict child mental health, and interactions with child age and gender were not significant. Our findings are consistent with a small but growing literature suggesting that efforts to improve engagement of and attention to fathers within research, clinical and policy efforts are likely to be worthwhile. © 2016 Elsevier Ltd.

Author Keywords
Child mental health;  Child welfare;  Depression;  Fathers;  Substance use

Document Type: Article
Source: Scopus

Pekny, M.a b c , Pekna, M.a b c , Messing, A.d , Steinhäuser, C.e , Lee, J.-M.f , Parpura, V.g , Hol, E.M.h i j , Sofroniew, M.V.k , Verkhratsky, A.l m n o
Astrocytes: a central element in neurological diseases
(2016) Acta Neuropathologica, 131 (3), pp. 323-345. 

DOI: 10.1007/s00401-015-1513-1

a Department of Clinical Neuroscience and Rehabilitation, Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
b Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
c University of Newcastle, New South Wales, Australia
d Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI, United States
e Institute of Cellular Neurosciences, University of Bonn, Bonn, Germany
f Department of Neurology, The Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, United States
g Department of Neurobiology, Civitan International Research Center, Center for Glial Biology in Medicine, Evelyn F. McKnight Brain Institute, Atomic Force Microscopy and Nanotechnology Laboratories, University of Alabama at Birmingham, 1719 6th Avenue South, CIRC 429, Birmingham, AL, United States
h Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, Netherlands
i Netherlands Institute for Neuroscience, An Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands
j Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, Amsterdam, Netherlands
k Department of Neurobiology, University of California, Los Angeles, CA, United States
l The University of Manchester, Oxford Road, Manchester, United Kingdom
m Achucarro Center for Neuroscience, IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
n Department of Neurosciences, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain
o University of Nizhny Novgorod, Nizhny Novgorod, Russian Federation

The neurone-centred view of the past disregarded or downplayed the role of astroglia as a primary component in the pathogenesis of neurological diseases. As this concept is changing, so is also the perceived role of astrocytes in the healthy and diseased brain and spinal cord. We have started to unravel the different signalling mechanisms that trigger specific molecular, morphological and functional changes in reactive astrocytes that are critical for repairing tissue and maintaining function in CNS pathologies, such as neurotrauma, stroke, or neurodegenerative diseases. An increasing body of evidence shows that the effects of astrogliosis on the neural tissue and its functions are not uniform or stereotypic, but vary in a context-specific manner from astrogliosis being an adaptive beneficial response under some circumstances to a maladaptive and deleterious process in another context. There is a growing support for the concept of astrocytopathies in which the disruption of normal astrocyte functions, astrodegeneration or dysfunctional/maladaptive astrogliosis are the primary cause or the main factor in neurological dysfunction and disease. This review describes the multiple roles of astrocytes in the healthy CNS, discusses the diversity of astroglial responses in neurological disorders and argues that targeting astrocytes may represent an effective therapeutic strategy for Alexander disease, neurotrauma, stroke, epilepsy and Alzheimer’s disease as well as other neurodegenerative diseases. © 2015, Springer-Verlag Berlin Heidelberg.

Author Keywords
Alexander disease;  Alzheimer’s disease;  Astrocytes;  Astrocytopathies;  Astroglial cells;  Epilepsy;  Huntington disease;  Neurological diseases;  Neurotrauma;  Reactive astrogliosis;  Reactive gliosis;  Stroke

Document Type: Review
Source: Scopus

Gilbert, K.E.a , Nolen-Hoeksema, S.b , Gruber, J.c
I don't want to come back down: Undoing versus maintaining of reward recovery in older adolescents
(2016) Emotion, 16 (2), pp. 214-225. 

DOI: 10.1037/emo0000128

a Department of Psychiatry, Washington University in St. Louis, United States
b Department of Psychology, Yale University, United States
c Department of Psychology and Neuroscience, University of Colorado Boulder, United States

Adolescence is characterized by heightened and sometimes impairing reward sensitivity, yet less is known about how adolescents recover from highly arousing positive states. This is particularly important given high onset rates of psychopathology associated with reward sensitivity during late adolescence and early adulthood. The current study thus utilized a novel reward sensitivity task in order to examine potential ways in which older adolescent females (ages 18-21; N = 83) might recover from high arousal positive reward sensitive states. Participants underwent a fixed incentive reward sensitivity task and subsequently watched a neutral, sad, or a low approach-motivated positive emotional film clip during which subjective and physiological recovery was assessed. Results indicated that the positive and negative film conditions were associated with maintained physiological arousal while the neutral condition facilitated faster physiological recovery from the reward sensitivity task. It is interesting to note that individual differences in self-reported positive emotion during the reward task were associated with faster recovery in the neutral condition. Findings suggest elicited emotion (regardless of valence) may serve to maintain reward sensitivity whereas self-reported positive emotional experience may be a key ingredient facilitating physiological recovery or undoing. Understanding the nuances of reward recovery provides a critical step in understanding the etiology and persistence of reward dysregulation more generally. © 2015 American Psychological Association.

Author Keywords
Adolescents;  Emotional recovery;  Positive emotion;  Reward;  Undoing hypothesis

Document Type: Article
Source: Scopus

Vesoulis, Z.A., Ters, N.E., Foster, A., Trivedi, S.B., Liao, S.M., Mathur, A.M.
Response to dopamine in prematurity: a biomarker for brain injury?
(2016) Journal of Perinatology, . Article in Press. 

DOI: 10.1038/jp.2016.5

Division of Newborn Medicine, Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA

Objective:To identify factors associated with responsiveness to dopamine therapy for hypotension and the relationship to brain injury in a cohort of preterm infants.Study Design:The pharmacy database at St Louis Children’s Hospital was retrospectively queried to identify infants who (a) were born &lt;28 weeks gestation between 2012 and 2014, (b) received dopamine and (c) had blood pressure measurements from an umbilical arterial catheter. A control group was constructed from contemporaneous infants who did not receive dopamine. Mean arterial blood pressure (MABP) at baseline, 1 h and 3 h after initiating dopamine were obtained for each dopamine-exposed infant. MABP measurements at matched time points were obtained in the control group.Result:Sixty-nine dopamine-treated and 45 control infants were included. Mean ΔMABP at 3 h was 4.5±6.3 mm of Hg for treated infants vs 1±2.9 for the control. Median dopamine starting dose was 2.5 μg kg-1 min-1. Dopamine-treated infants were less mature and of lower birth weight while also more likely to be intubated at 72 h, diagnosed with intraventricular hemorrhage (IVH) and to die. Failure to respond to dopamine was associated with greater likelihood of developing IVH (odds ratio (OR) 5.8, 95% confidence interval (CI) 1.1–42.3), while a strong response (ΔMABP&gt;10 mm Hg) was associated with a reduction in risk of IVH (OR 0.1, 95% CI 0.01–0.8).Conclusion:Low–moderate dose dopamine administration results in modest blood pressure improvements. A lack of response to dopamine is associated with a greater risk of IVH, whereas a strong response is associated with a decreased risk. Further research into underlying mechanisms and management strategies is needed.Journal of Perinatology advance online publication, 18 February 2016; doi:10.1038/jp.2016.5. © 2016 Nature America, Inc.

Document Type: Article in Press
Source: Scopus

Goyal, M.S., Hoff, B.G., Williams, J., Khoury, N., Wiesehan, R., Heitsch, L., Panagos, P., Vo, K.D., Benzinger, T., Derdeyn, C.P., Lee, J.-M., Ford, A.L.
Streamlined Hyperacute Magnetic Resonance Imaging Protocol Identifies Tissue-Type Plasminogen Activator–Eligible Stroke Patients When Clinical Impression Is Stroke Mimic
(2016) Stroke, . Article in Press. 

DOI: 10.1161/STROKEAHA.115.011913

From the Mallinckrodt Institute of Radiology (M.S.G., K.D.V., T.B., C.P.D., J.-M.L.), Department of Neurology (R.W., C.P.D., J.-M.L., A.L.F.), Division of Emergency Medicine (L.H., P.P.), and Department of Neurological Surgery (C.P.D.), Washington University School of Medicine, St Louis, MO; Department of Operational Excellence (B.G.H.) and Department of Emergency Services (J.W.), Barnes-Jewish Hospital, St Louis, MO; Department of Neuroradiology, University of Montreal, Montreal, Quebec, Canada (N.K.); and Department of Biomedical Engineering, Washington University, St Louis, MO (J.-M.L.).

BACKGROUND AND PURPOSE—: Stroke mimics (SM) challenge the initial assessment of patients presenting with possible acute ischemic stroke (AIS). When SM is considered likely, intravenous tissue-type plasminogen activator (tPA) may be withheld, risking an opportunity to treat AIS. Although computed tomography is routinely used for tPA decision making, magnetic resonance imaging (MRI) may diagnose AIS when SM is favored but not certain. We hypothesized that a hyperacute MRI (hMRI) protocol would identify tPA-eligible AIS patients among those initially favored to have SM. METHODS—: A streamlined hMRI protocol was designed based on barriers to rapid patient transport, MRI acquisition, and post-MRI tPA delivery. Neurologists were trained to order hMRI when SM was favored and tPA was being withheld. The use of hMRI for tPA decision making, door-to-needle times, and outcomes were compared before hMRI implementation (pre-hMRI: August 1, 2011 to July 31, 2013) and after (post-hMRI, August 1, 2013, to January 15, 2015). RESULTS—: Post hMRI, 57 patients with suspected SM underwent hMRI (median MRI-order-to-start time, 29 minutes), of whom, 11 (19%) were diagnosed with AIS and 7 (12%) received tPA. Pre-hMRI, no tPA-treated patients were screened with hMRI. Post hMRI, 7 of 106 (6.6%) tPA-treated patients underwent hMRI to aid in decision making because of suspected SM (0% versus 6.6%; P=0.001). To ensure standard care was maintained after implementing the hMRI protocol, pre- versus post-hMRI tPA-treated cohorts were compared and did not differ: door-to-needle time (39 versus 37 minutes; P=0.63), symptomatic hemorrhage rate (4.5% versus 1.9%; P=0.32), and favorable discharge location (85% versus 89%; P=0.37). CONCLUSIONS—: A streamlined hMRI protocol permitted tPA administration to a small, but significant, subset of AIS patients initially considered to have SM. © 2016 American Heart Association, Inc.

Document Type: Article in Press
Source: Scopus

Westbrook, A.a , Braver, T.S.a b
Dopamine Does Double Duty in Motivating Cognitive Effort
(2016) Neuron, 89 (4), pp. 695-710. 

DOI: 10.1016/j.neuron.2015.12.029

a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Cognitive control is subjectively costly, suggesting that engagement is modulated in relationship to incentive state. Dopamine appears to play key roles. In particular, dopamine may mediate cognitive effort by two broad classes of functions: (1) modulating the functional parameters of working memory circuits subserving effortful cognition, and (2) mediating value-learning and decision-making about effortful cognitive action. Here, we tie together these two lines of research, proposing how dopamine serves "double duty", translating incentive information into cognitive motivation. Temporally extended, goal-directed behavior often involves subjectively effortful cognition. Westbrook and Braver review two broad, complementary roles by which DA translates incentive information into cognitive motivation: (1) modulating working memory circuit parameters and (2) training decision value functions for cognitive engagement. © 2016 Elsevier Inc.

Document Type: Review
Source: Scopus

Kim, K.X., Rutherford, M.A.
Maturation of nav and kv channel topographies in the auditory nerve spike initiator before and after developmental onset of hearing function
(2016) Journal of Neuroscience, 36 (7), pp. 2111-2118. 

DOI: 10.1523/JNEUROSCI.3437-15.2016

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

Auditory nerve excitation and thus hearing depend on spike-generating ion channels and their placement along the axons of auditory nerve fibers (ANFs). The developmental expression patterns and native axonal locations of voltage-gated ion channels in ANFs are unknown. Therefore, we examined the development of heminodes and nodes of Ranvier in the peripheral axons of type I ANFs in the rat cochlea with immunohistochemistry and confocal microscopy. Nodal structures presumably supporting presensory spiking formed between postnatal days 5 (P5) and P7, including Ankyrin-G, NaV1.6, and Caspr. These immature nodal structures lacked low-voltageactivated KV1.1 which was not enriched at juxtaparanodes until approximately P13, concurrent with the developmental onset of acoustic hearing function. Anatomical alignment of ANF spike-initiating heminodes relative to excitatory input from inner hair cell (IHC) ribbon synapses continued until approximately P30. High-voltage-activated KV3.1b and KV2.2 were expressed in mutually exclusive domains: KV3.1b was strictly localized to nodes and heminodes, whereas KV2.2 expression began at the juxtaparanodes and continued centrally along the first internode. At spike-initiating heminodes in the distal osseous spiral lamina, NaV1.1 partly overlapped NaV1.6 and ankyrin-G. ANFs displayed KV7.2 andKV7.3 at heminodes, nodes, internodes, and the unmyelinated synaptic terminal segments beneath IHCs in the organ of Corti. In response to sound, spikes are initiated at the heminode, which is tightly coupled to the IHC ribbon synapse ~ 20–40 μm away. These results show that maturation of nodal alignment and ion channel content may underlie postnatal improvements of ANF excitability and discharge synchrony. © 2016 the authors.

Author Keywords
Action potential generation;  Ankyrin-G;  Axon initial segment;  Cochlea;  Heminode;  Voltage-gated Na+ and K+ channels

Document Type: Article
Source: Scopus

Carpenter, C.R.
In acute low back pain, adding opioids or cyclobenzaprine to naproxen did not improve pain or function
(2016) Annals of Internal Medicine, 164 (4), p. JC19. 

DOI: 10.7326/ACPJC-2016-164-4-019

Washington University in St. Louis, St. Louis, MO, United States

Document Type: Note
Source: Scopus

Wallace, A.N.a , Kansagra, A.P.a , McEachern, J.a , Moran, C.J.a , Cross III, D.T.a , Derdeyn, C.P.b
Evolution of endovascular stroke therapies and devices
(2016) Expert Review of Medical Devices, pp. 1-8. Article in Press. 

DOI: 10.1586/17434440.2016.1143772

a Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, MO, USA
b Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA

Acute ischemic stroke is caused by occlusion of a cerebral artery, resulting in loss of brain tissue and neurologic deficits. However, a portion of the ischemic brain can be salvaged if blood flow is restored within an appropriate time frame. The past year has seen the publication of five positive randomized controlled trials demonstrating substantial benefit of mechanical thrombectomy in select patients with large vessel cerebrovascular occlusion. This progress is related to several factors, but most importantly, dramatic improvements in speed and rates of recanalization with the latest generation devices. In this article, we review the evolution of endovascular acute ischemic stroke therapies and key design features of the most widely used devices. © 2016 Taylor & Francis

Author Keywords
catheter;  endovascular;  stentriever;  Stroke;  technique;  thrombectomy

Document Type: Article in Press
Source: Scopus

Harris, R.A.a , Tindale, L.a , Lone, A.a , Singh, O.a , Macauley, S.L.b , Stanley, M.b , Holtzman, D.M.b , Bartha, R.c , Cumming, R.C.a
Aerobic glycolysis in the frontal cortex correlates with memory performance in wild-type mice but not the APP/PS1 mouse model of cerebral amyloidosis
(2016) Journal of Neuroscience, 36 (6), pp. 1871-1878. 

DOI: 10.1523/JNEUROSCI.3131-15.2016

a Department of Biology, University of Western Ontario, London, ON, Canada
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Physiology and Pharmacology, University of Western Ontario, Molecular Brain Research Group, Robarts Research Institute, London, ON, Canada

Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer’s disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-β. In vivo 1H-magnetic resonance spectroscopy revealed an age-dependent decline in lactate levels within the frontal cortex of control mice, whereas lactate levels remained unaltered in APP/PS1 mice from 3 to 12 months of age. Analysis of hippocampal interstitial fluid by in vivo microdialysis revealed a significant elevation in lactate levels in APP/PS1 mice relative to control mice at 12 months of age. An age-dependent decline in the levels of key aerobic glycolysis enzymes and a concomitant increase in lactate transporter expression was detected in control mice. Increased expression of lactate-producing enzymes correlated with improved memory in control mice. Interestingly, in APP/PS1 mice the opposite effect was detected. In these mice, increased expression of lactate producing enzymes correlated with poorer memory performance. Immunofluorescent staining revealed localization of the aerobic glycolysisenzymespyruvate dehydrogenase kinaseandlactate dehydrogenaseAwithin corticalandhippocampal neurons in control mice, as well as within astrocytes surrounding amyloid plaques in APP/PS1 mice. These observations collectively indicate that production of lactate, via aerobic glycolysis, is beneficial formemoryfunction during normal aging. However, elevated lactate levels in APP/PS1 mice indicate perturbed lactate processing, a factor that may contribute to cognitive decline in AD. © 2016 the authors.

Author Keywords
Aerobic glycolysis;  Alzheimer’s disease;  Amyloid;  Lactate;  Magnetic resonance spectroscopy;  Memory

Document Type: Article
Source: Scopus

Yang, G.a , Chen, L.a , Grant, G.R.a b , Paschos, G.a , Song, W.-L.a , Musiek, E.S.c , Lee, V.d , McLoughlin, S.C.a , Grosser, T.a , Cotsarelis, G.e , Fitzgerald, G.A.a
Timing of expression of the core clock gene Bmal1 influences its effects on aging and survival
(2016) Science Translational Medicine, 8 (324), art. no. 324ra16, . 

DOI: 10.1126/scitranslmed.aad3305

a Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
b Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States
c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
d Department of Ophthalmology, University of Pennsylvania Scheie Eye Institute, Philadelphia, PA, United States
e Department of Dermatology, Perelman School of Medicine, University of PennsylvaniaPA, United States

The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock.

Document Type: Article
Source: Scopus

Lim, M.M.a b , Ju, Y.-E.S.c
A reply to "to travel or not to travel: The modern day struggle of the academic researcher"
(2016) Annals of Neurology, 79 (2), p. 333. 

DOI: 10.1002/ana.24589

a VA Portland Health Care System, Portland, OR, United States
b Oregon Health and Science University, Portland, OR, United States
c Washington University, Saint Louis, MO, United States

Document Type: Letter
Source: Scopus

Lopez-Garcia, P.a b c , Lesh, T.A.c , Salo, T.c , Barch, D.M.d , MacDonald, A.W., IIIe , Gold, J.M.f , Ragland, J.D.c , Strauss, M.g , Silverstein, S.M.h , Carter, C.S.c
The neural circuitry supporting goal maintenance during cognitive control: a comparison of expectancy AX-CPT and dot probe expectancy paradigms
(2016) Cognitive, Affective and Behavioral Neuroscience, 16 (1), pp. 164-175. 

DOI: 10.3758/s13415-015-0384-1

a Universidad Autonoma de Madrid, Madrid, Spain
b CIBERSAM, Madrid, Spain
c University of California at Davis, Davis, CA, United States
d Washington University in St Louis, St Louis, MO, United States
e University of Minnesota, Minneapolis, MN, United States
f University of Maryland, College Park, MD, United States
g Case Western Reserve University, Cleveland, OH, United States
h Rutgers University, New Brunswick, NJ, United States

Goal maintenance is an aspect of cognitive control that has been identified as critical for understanding psychopathology according to criteria of the NIMH-sponsored CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) and Research Domain Criteria (RDoC) initiatives. CNTRICS proposed the expectancy AX-CPT, and its visual-spatial parallel the dot probe expectancy (DPX), as valid measures of the cognitive and neural processes thought to be relevant for goal maintenance. The goal of this study was to specifically examine the functional neural correlates and connectivity patterns of both goal maintenance tasks in the same subset of subjects to further validate their neural construct validity and clarify our understanding of the nature and function of the neural circuitry engaged by the tasks. Twenty-six healthy control subjects performed both the letter (AX) and dot pattern (DPX) variants of the CPT during fMRI. Behavioral performance was similar between tasks. The 2 tasks engaged the same brain networks including dorsolateral prefrontal cortex (DLPFC) and dorsal parietal regions, supporting their validity as complementary measures of the goal maintenance construct. Interestingly there was greater engagement of the frontal opercular insula region during the expectancy AX-CPT (letter) and greater functional connectivity between the PFC and medial temporal lobe in the DPX (dot pattern). These differences are consistent with differential recruitment of phonological and visual-spatial processes by the two tasks and suggest that additional long-term memory systems may be engaged by the dot probe version. © 2015, Psychonomic Society, Inc.

Author Keywords
Cognitive control;  Connectivity;  Context processing;  Goal maintenance

Document Type: Article
Source: Scopus

Kristjansson, S.a , Mccutcheon, V.V.a , Agrawal, A.a , Lynskey, M.T.b , Conroy, E.c , Statham, D.J.d , Madden, P.A.F.a , Henders, A.K.d , Todorov, A.A.a , Bucholz, K.K.a , Degenhardt, L.e , Martin, N.G.d , Heath, A.C.a , Nelson, E.C.a
The variance shared across forms of childhood trauma is strongly associated with liability for psychiatric and substance use disorders
(2016) Brain and Behavior, 6 (2), pp. 1-11. 

DOI: 10.1002/brb3.432

a Alcoholism Research Center, Washington University School of Medicine, St. Louis, MO, United States
b Institute of Psychiatry, Psychology, and Neuroscience, King's College, London, United Kingdom
c Centre for Health Research, University of Western Sydney, Sydney, Australia
d QIMR Berghofer Medical Research Institute, Brisbane, Australia
e National Drug and Alcohol Research Center, University of New South Wales, Sydney, Australia

Introduction: Forms of childhood trauma tend to co-occur and are associated with increased risk for psychiatric and substance use disorders. Commonly used binary measures of trauma exposure have substantial limitations. Methods: We performed multigroup confirmatory factor analysis (CFA), separately by sex, using data from the Childhood Trauma (CT) Study's sample of twins and siblings (N = 2594) to derive three first-order factors (childhood physical abuse, childhood sexual abuse, and parental partner abuse) and, as hypothesized, one higher order, childhood trauma factor (CTF) representing a measure of their common variance. Results: CFA produced a good-fitting model in the CT Study; we replicated the model in the Comorbidity and Trauma (CAT) Study's sample (N = 1981) of opioid-dependent cases and controls. In both samples, first-order factors are moderately correlated (indicating they measure largely unique, but related constructs) and their loadings on the CTF suggest it provides a reasonable measure of their common variance. We examined the association of CTF score with risk for psychiatric and substance use disorders in these samples and the OZ-ALC GWAS sample (N = 1538) in which CT Study factor loadings were applied. We found that CTF scores are strongly associated with liability for psychiatric and substance use disorders in all three samples; estimates of risk are extremely consistent across samples. Conclusions: The CTF is a continuous, robust measure that captures the common variance across forms of childhood trauma and provides a means to estimate shared liability while avoiding multicollinearity. Confirmatory factor analysis was used to derive a higher order, childhood trauma factor representing a measure of the common variance across three forms of trauma: childhood physical abuse, childhood sexual abuse, and parental partner abuse. We replicated the model in a second sample. We then examined the association of childhood trauma score with risk for psychiatric and substance use disorders in these samples and a third sample in which the primary sample's factor loadings were applied finding factor scores to be strongly and consistently associated with liability for psychiatric and substance use disorders in all three samples. © 2016 Published by Wiley Periodicals, Inc.

Author Keywords
Childhood trauma;  Confirmatory factor analysis;  Substance use disorders

Document Type: Article
Source: Scopus

Chang, J.J.a , Salas, J.b , Tabet, M.a , Kasper, Z.a , Elder, K.c , Staley, H.d , Brownson, R.C.e
Changes in Body Mass Index and the Trajectory of Depressive Symptoms Among Rural Men and Women
(2016) Journal of Rural Health, . Article in Press. 

DOI: 10.1111/jrh.12170

a Department of Epidemiology Saint Louis University College for Public Health and Social Justice St. Louis Missouri
b Department of Family and Community Medicine Saint Louis University School of Medicine St. Louis Missouri
c Department of Health Management and Policy Saint Louis University College for Public Health and Social Justice St. Louis Missouri
d SSM Health Care St. Louis Missouri
e The Prevention Research Center in St. Louis, the Brown School and the Department of Surgery (Division of Public Health Sciences) and Alvin J. Siteman Cancer Center, School of Medicine Washington University St. Louis Missouri

Purpose: This study examined the association between body mass index (BMI) changes over time and the risk of elevated depressive symptoms in a cohort of Midwestern rural adults. Methods: The longitudinal study used data from a telephone survey in 2005 including 1,475 men and women enrolled in the Walk the Ozarks to Wellness Project from 12 rural communities in Missouri, Arkansas, and Tennessee. Multilevel random intercept mixed models were used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the association between BMI calculated from self-reported height and body weight and elevated depressive symptoms, adjusting for sociodemographic, behavioral, and medical variables. Findings: Elevated depressive symptoms were common in this rural population (17%-19%) and the mean BMI was 28 kg/m2. For each unit increase in BMI over time, representing an average increase of about 5.8 pounds from baseline weight, there was a 6% increased odds of elevated depressive symptoms (aOR: 1.06, 95% CI: 1.02-1.12). Conclusions: Our findings hold important public health implications given the increasing rates of overweight and obesity over the past couple of decades, particularly among rural adults. © 2016 National Rural Health Association.

Author Keywords
Body mass index;  Depression;  Obesity;  Overweight;  Rural health

Document Type: Article in Press
Source: Scopus

Barch, D.M.a , Gotlib, I.H.b , Bilder, R.M.c , Pine, D.S.d , Smoller, J.W.e , Brown, C.H.f , Huggins, W.g , Hamilton, C.g , Haim, A.h , Farber, G.K.i
Common Measures for National Institute of Mental Health Funded Research
(2016) Biological Psychiatry, . Article in Press. 

DOI: 10.1016/j.biopsych.2015.07.006

a Departments of Psychology, Psychiatry, and Radiology, Washington University, St. Louis, Missouri
b Department of Psychology, Stanford University, Stanford, California
c Departments of Psychiatry and Biobehavioral Sciences and Psychology, University of California at Los Angeles, Los Angeles, California
d National Institute of Mental Health, Intramural Research Program, Bethesda, Maryland
e Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, and Department of Psychiatry, Massachusetts General Hospital; and Stanley Center for Psychiatric Research, Broad Institute, Boston, Massachusetts
f Department of Psychiatry, Northwestern University, Chicago, Illinois
g RTI International, Research Triangle Park, Durham, North Carolina
h Office of Clinical Research and Office of Technology, Bethesda, Maryland
i Development and Coordination, National Institute of Mental Health, Bethesda, Maryland

Document Type: Article in Press
Source: Scopus

Sachet, A.B.a , Frey, S.H.a b , Jacobs, S.a , Taylor, M.a
Development of the Correspondence Between Real and Imagined Fine and Gross Motor Actions
(2016) Journal of Cognition and Development, 17 (1), pp. 162-179. 

DOI: 10.1080/15248372.2014.963585

a University of Oregon, United States
b Department of Neurology, Department of Psychological and Brain Sciences, Washington University School of Medicine, United States

The development of the correspondence between real and imagined motor actions was investigated in 2 experiments. Experiment 1 evaluated whether children imagine body position judgments of fine motor actions in the same way as they perform them. Thirty-two 8-year-old children completed a task in which an object was presented in different orientations, and children were asked to indicate the position of their hand as they grasped and imagined grasping the object. Children’s hand position was almost identical for the imagined- and real-grasping trials. Experiment 2 replicated this result with 8-year-olds as well as 6-year-olds and also assessed the development of the correspondence of the chronometry of real and imagined gross motor actions. Sixteen 6-year-old children and seventeen 8-year-old children participated in the fine motor grasping task from Experiment 1 and a gross motor task that measured the time it took for children to walk and imagine walking different distances. Six-year-olds showed more of a difference between real and imagined walking than did 8-year-olds. However, there were strong correlations between real and imagined grasping and walking for both 6- and 8-year-old children, suggesting that by at least 6 years of age, motor imagery and real action may involve common internal representations and that motor imagery is important for motor control and planning. © 2016 Taylor & Francis Group, LLC.

Document Type: Article
Source: Scopus

Glauser, T.a , Shinnar, S.b , Gloss, D.c , Alldredge, B.d , Arya, R.a , Bainbridge, J.e , Bare, M.a , Bleck, T.f , Edwin Dodson, W.g , Garrity, L.h , Jagoda, A.i , Lowenstein, D.j , Pellock, J.k , Riviello, J.l , Sloan, E.m , Treiman, D.M.n
Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults: Report of the guideline committee of the American epilepsy society
(2016) Epilepsy Currents, 16 (1), pp. 48-61. 

a Division of Neurology, Comprehensive Epilepsy Center, Cincinnati Children's Hospital Medical Ctr. and University of Cincinnati College of Medicine, Cincinnati, OH, United States
b Departments of Neurology, Pediatrics, and Epidemiology and Population Health, Comprehensive Epilepsy Management Center, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, United States
c CAMC Neurology Group, Charleston, WV, United States
d School of Pharmacy, University of California, San FranciscoCA, United States
e Department of Clinical Pharmacy, University of Colorado, Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, United States
f Departments of Neurological Sciences, Neurosurgery, Medicine, and Anesthesiology, Rush University Medical Center, Chicago, IL, United States
g Departments of Neurology and Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
h Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
i Department of Emergency Medicine, Mount Sinai Hospital, Mount Sinai School of Medicine, New York, NY, United States
j Department of Neurology, University of California, San FranciscoCA, United States
k Division of Pediatric Neurology, Virginia Commonwealth University, Richmond, VA, United States
l NYU Comprehensive Epilepsy Center, New York, NY, United States
m Department of Emergency Medicine, University of Illinois at Chicago, Chicago, IL, United States
n Division of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States

CONTEXT: The optimal pharmacologic treatment for early convulsive status epilepticus is unclear. OBJECTIVE: To analyze efficacy, tolerability and safety data for anticonvulsant treatment of children and adults with convulsive status epilepticus and use this analysis to develop an evidence-based treatment algorithm. DATA SOURCES: Structured literature review using MEDLINE, Embase, Current Contents, and Cochrane library supplemented with article reference lists. STUDY SELECTION: Randomized controlled trials of anticonvulsant treatment for seizures lasting longer than 5 minutes. DATA EXTRACTION: Individual studies were rated using predefined criteria and these results were used to form recommendations, conclusions, and an evidence-based treatment algorithm. RESULTS: A total of 38 randomized controlled trials were identified, rated and contributed to the assessment. Only four trials were considered to have class I evidence of efficacy. Two studies were rated as class II and the remaining 32 were judged to have class III evidence. In adults with convulsive status epilepticus, intramuscular midazolam, intravenous lorazepam, intravenous diazepam and intravenous phenobarbital are established as efficacious as initial therapy (Level A). Intramuscular midazolam has superior effectiveness compared to intravenous lorazepam in adults with convulsive status epilepticus without established intravenous access (Level A). In children, intravenous lorazepam and intravenous diazepam are established as efficacious at stopping seizures lasting at least 5 minutes (Level A) while rectal diazepam, intramuscular midazolam, intranasal midazolam, and buccal midazolam are probably effective (Level B). No significant difference in effectiveness has been demonstrated between intravenous lorazepam and intravenous diazepam in adults or children with convulsive status epilepticus (Level A). Respiratory and cardiac symptoms are the most commonly encountered treatment-emergent adverse events associated with intravenous anticonvulsant drug administration in adults with convulsive status epilepticus (Level A). The rate of respiratory depression in patients with convulsive status epilepticus treated with benzodiazepines is lower than in patients with convulsive status epilepticus treated with placebo indicating that respiratory problems are an important consequence of untreated convulsive status epilepticus (Level A). When both are available, fosphenytoin is preferred over phenytoin based on tolerability but phenytoin is an acceptable alternative (Level A). In adults, compared to the first therapy, the second therapy is less effective while the third therapy is substantially less effective (Level A). In children, the second therapy appears less effective and there are no data about third therapy efficacy (Level C). The evidence was synthesized into a treatment algorithm. CONCLUSIONS: Despite the paucity of well-designed randomized controlled trials, practical conclusions and an integrated treatment algorithm for the treatment of convulsive status epilepticus across the age spectrum (infants through adults) can be constructed. Multicenter, multinational efforts are needed to design, conduct and analyze additional randomized controlled trials that can answer the many outstanding clinically relevant questions identified in this guideline. © American Epilepsy Society.

Document Type: Article
Source: Scopus

Atkinson, E.G.a b , Rogers, J.c , Cheverud, J.M.a
Evolutionary and developmental implications of asymmetric brain folding in a large primate pedigree
(2016) Evolution, . Article in Press. 

DOI: 10.1111/evo.12867

a Department of Anatomy and Neurobiology Washington University School of Medicine St. Louis 63110Missouri
b Department of Ecology and Evolution Stony Brook University Stony Brook 11794NY
c Human Genome Sequencing Center and Department of Molecular and Human Genetics Baylor College of Medicine Houston 77030Texas

Bilateral symmetry is a fundamental property of the vertebrate central nervous system. Local deviations from symmetry provide various types of information about the development, evolution, and function of elements within the CNS, especially the cerebral hemispheres. Here, we quantify the pattern and extent of asymmetry in cortical folding within the cerebrum of Papio baboons and assess the evolutionary and developmental implications of the findings. Analyses of directional asymmetry show a population-level trend in length measurements indicating that baboons are genetically predisposed to be asymmetrical, with the right side longer than the left in the anterior cerebrum while the left side is longer than the right posteriorly. We also find a corresponding bias to display a right frontal petalia (overgrowth of the anterior pole of the cerebral cortex on the right side). By quantifying fluctuating asymmetry, we assess canalization of brain features and the susceptibility of the baboon brain to developmental perturbations. We find that features are differentially canalized depending on their ontogenetic timing. We further deduce that development of the two hemispheres is to some degree independent. This independence has important implications for the evolution of cerebral hemispheres and their separate specialization. Asymmetry is a major feature of primate brains and is characteristic of both brain structure and function. © 2016, Society for the Study of Evolution

Author Keywords
Baboon;  Developmental noise;  Gyrification;  Morphological integration;  Primate brain evolution

Document Type: Article in Press
Source: Scopus

Yee, D.M., Krug, M.K., Allen, A.Z., Braver, T.S.
Humans integrate monetary and liquid incentives to motivate cognitive task performance
(2016) Frontiers in Psychology, 6 (JAN), art. no. 2037, . 

DOI: 10.3389/fpsyg.2015.02037

Cognitive Control and Psychopathology Lab, Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

It is unequivocal that a wide variety of incentives can motivate behavior. However, few studies have explicitly examined whether and how different incentives are integrated in terms of their motivational influence. The current study examines the combined effects of monetary and liquid incentives on cognitive processing, and whether appetitive and aversive incentives have distinct influences. We introduce a novel task paradigm, in which participants perform cued task-switching for monetary rewards that vary parametrically across trials, with liquid incentives serving as post-trial performance feedback. Critically, the symbolic meaning of the liquid was held constant (indicating successful reward attainment), while liquid valence was blocked. In the first experiment, monetary rewards combined additively with appetitive liquid feedback to improve subject task performance. Aversive liquid feedback counteracted monetary reward effects in low monetary reward trials, particularly in a subset of participants who tended to avoid responding under these conditions. Self-report motivation ratings predicted behavioral performance above and beyond experimental effects. A follow-up experiment replicated the predictive power of motivation ratings even when only appetitive liquids were used, suggesting that ratings reflect idiosyncratic subjective values of, rather than categorical differences between, the liquid incentives. Together, the findings indicate an integrative relationship between primary and secondary incentives and potentially dissociable influences in modulating motivational value, while informing hypotheses regarding candidate neural mechanisms. © 2016 Yee, Krug, Allen and Braver.

Author Keywords
Cognitive control;  Decision-making;  Motivation;  Primary and secondary incentives;  Reward;  Reward integration;  Subjective value

Document Type: Article
Source: Scopus

Jin, H.a , Zhang, X.a , Yue, X.a , Liu, H.a , Li, J.a , Yang, H.a , Flores, H.b , Su, Y.b , Parsons, S.M.c , Perlmutter, J.S.a b , Tu, Z.a
Kinetics modeling and occupancy studies of a novel C-11 PET tracer for VAChT in nonhuman primates
(2016) Nuclear Medicine and Biology, 43 (2), pp. 131-139. 

DOI: 10.1016/j.nucmedbio.2015.11.003

a Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, United States

Introduction: Deficits in cholinergic function have been found in the aged brain and in neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). The vesicular acetylcholine transporter (VAChT) is a reliable biomarker for the cholinergic system. We previously reported the initial in vitro and ex vivo characterization of (-)-[11C]TZ659 as a VAChT specific ligand. Here, we report the in vivo specificity, tracer kinetics, and dose-occupancy studies in the nonhuman primate brain. Methods: MicroPET brain imaging of (-)-[11C]TZ659 was performed under baseline conditions in two male macaques. Tracer kinetic modeling was carried out using a two-tissue compartment model (2TCM) and Logan plot with arterial blood input function and using a simplified reference tissue model (SRTM) and Logan plot (LoganREF) without blood input. Specificity for VAChT was demonstrated by pretreatment with (+)-pentazocine, (-)-vesamicol, or S-(-)-eticlopride. Target occupancy (Occ) was calculated following pretreatment with escalating doses of (-)-vesamicol. Results: Baseline PET imaging revealed selective retention in the striatum with rapid clearance from the cerebellar hemispheres as a reference region. Total volume of distribution (VT) values derived from both 2TCM and Logan analysis with blood input revealed ~3-fold higher levels of (-)-[11C]TZ659 in the striatum than the cerebellar hemispheres. Injection of (-)-vesamicol either as a blocking or displacing agent significantly reduced striatal uptake of (-)-[11C]TZ659. In contrast, pretreatment with the sigma-ligand (+)-pentazocine had no impact. Pretreatment with the S-(-)-eticlopride, a dopamine D2-like receptor antagonist, increased striatal uptake of (-)-[11C]TZ659. Striatal binding potential (BPND, range of 0.33-1.6 with cerebellar hemispheres as the reference region) showed good correlation (r2 = 0.97) between SRTM and LoganREF. Occupancy studies found that ~0.0057 mg/kg of (-)-vesamicol produced 50% VAChT occupancy in the striatum. Conclusion: (-)-[11C]TZ659 demonstrated specific and reversible VAChT binding and favorable pharmacokinetic properties for assessing the density of VAChT in the living brain. © 2015 Elsevier Inc.

Author Keywords
(-)-[11C]TZ659;  Binding potential;  Occupancy;  Tracer kinetics;  Vesicular acetylcholine transporter

Document Type: Article
Source: Scopus

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

DOI: 10.1159/000442424

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

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

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

Document Type: Article
Source: Scopus

Hirbe, A.C.a , Dahiya, S.b , Friedmann-Morvinski, D.c , Verma, I.M.c , Wade Clapp, D.d , Gutmann, D.H.e
Spatially- and temporally-controlled postnatal p53 knockdown cooperates with embryonic Schwann cell precursor Nf1 gene loss to promote malignant peripheral nerve sheath tumor formation
(2016) Oncotarget, 7 (7), pp. 7403-7414. 

DOI: 10.18632/oncotarget.7232

a Division of Medical Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c The Salk Institute of Biological Studies, Laboratory of Genetics, La Jolla, CA, United States
d Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
e Department of Neurology, Washington University, St. Louis, MO, United States

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive sarcomas that arise sporadically or in association with the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. In individuals with NF1, MPNSTs are hypothesized to arise from Nf1-deficient Schwann cell precursor cells following the somatic acquisition of secondary cooperating genetic mutations (e.g., p53 loss). To model this sequential genetic cooperativity, we coupled somatic lentivirus-mediated p53 knockdown in the adult right sciatic nerve with embryonic Schwann cell precursor Nf1 gene inactivation in two different Nf1 conditional knockout mouse strains. Using this approach, ~60% of mice with Periostin-Cre-mediated Nf1 gene inactivation (Periostin-Cre; Nf1flox/flox mice) developed tumors classified as low-grade MPNSTs following p53 knockdown (mean, 6 months). Similarly, ~70% of Nf1+/- mice with GFAP-Cre-mediated Nf1 gene inactivation (GFAP-Cre; Nf1flox/null mice) developed low-grade MPNSTs following p53 knockdown (mean, 3 months). In addition, wild-type and Nf1+/- mice with GFAP-Cre-mediated Nf1 loss develop MPNSTs following somatic p53 knockout with different latencies, suggesting potential influences of Nf1+/- stromal cells in MPNST pathogenesis. Collectively, this new MPNST model system permits the analysis of somatically-acquired events as well as tumor microenvironment signals that potentially cooperate with Nf1 loss in the development and progression of this deadly malignancy.

Author Keywords
Lentivirus;  Mouse models;  MPNST;  Neurofibromatosis type 1;  P53

Document Type: Article
Source: Scopus

Kamarajan, C.a , Pandey, A.K.a , Chorlian, D.B.a , Manz, N.a , Stimus, A.T.a , Anokhin, A.P.b , Bauer, L.O.c , Kuperman, S.d , Kramer, J.d , Bucholz, K.K.b , Schuckit, M.A.e , Hesselbrock, V.M.c , Porjesz, B.a
Deficient event-related theta oscillations in individuals at risk for alcoholism: A study of reward processing and impulsivity features
(2015) PLoS ONE, 10 (11), art. no. 0142659, . 

DOI: 10.1371/journal.pone.0142659

a SUNY Downstate Medical Center, Brooklyn, NY, United States
b Washington University School of Medicine, St. Louis, MO, United States
c University of Connecticut Health Center, Farmington, CT, United States
d University of Iowa, Iowa City, IA, United States
e University of California San Diego, San Diego, CA, United States

Background Individuals at high risk to develop alcoholism often manifest neurocognitive deficits as well as increased impulsivity. Event-related oscillations (EROs) have been used to effectively measure brain (dys)function during cognitive tasks in individuals with alcoholism and related disorders and in those at risk to develop these disorders. The current study examines ERO theta power during reward processing as well as impulsivity in adolescent and young adult subjects at high risk for alcoholism. Methods EROs were recorded during a monetary gambling task (MGT) in 12-25 years old participants (N = 1821; males = 48%) from high risk alcoholic families (HR, N = 1534) and comparison low risk community families (LR, N = 287) from the Collaborative Study on the Genetics of Alcoholism (COGA). Impulsivity scores and prevalence of externalizing diagnoses were also compared between LR and HR groups. Results HR offspring showed lower theta power and decreased current source density (CSD) activity than LR offspring during loss and gain conditions. Younger males had higher theta power than younger females in both groups, while the older HR females showed more theta power than older HR males. Younger subjects showed higher theta power than older subjects in each comparison. Differences in topography (i.e., frontalization) between groups were also observed. Further, HR subjects across gender had higher impulsivity scores and increased prevalence of externalizing disorders compared to LR subjects. Conclusions As theta power during reward processing is found to be lower not only in alcoholics, but also in HR subjects, it is proposed that reduced reward-related theta power, in addition to impulsivity and externalizing features, may be related in a predisposition to develop alcoholism and related disorders. © 2015 Kamarajan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Source: Scopus

Jin, S.C., Benitez, B.A., Deming, Y., Cruchaga, C.
Pooled-dna sequencing for elucidating new genomic risk factors, rare variants underlying Alzheimer's disease
(2015) Systems Biology of Alzheimer's Disease, pp. 299-314. 

DOI: 10.1007/978-1-4939-2627-5_18

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

Analyses of genome-wide association studies (GWAS) for complex disorders usually identify common variants with a relatively small effect size that only explain a small proportion of phenotypic heritability. Several studies have suggested that a significant fraction of heritability may be explained by low-frequency (minor allele frequency (MAF) of 1-5 %) and rare-variants that are not contained in the commercial GWAS genotyping arrays (Schork et al., Curr Opin Genet Dev 19:212, 2009). Rare variants can also have relatively large effects on risk for developing human diseases or disease phenotype (Cruchaga et al., PLoS One 7:e31039, 2012). However, it is necessary to perform next-generation sequencing (NGS) studies in a large population (>4,000 samples) to detect a significant rare-variant association. Several NGS methods, such as custom capture sequencing and amplicon-based sequencing, are designed to screen a small proportion of the genome, but most of these methods are limited in the number of samples that can be multiplexed (i.e. most sequencing kits only provide 96 distinct index). Additionally, the sequencing library preparation for 4,000 samples remains expensive and thus conducting NGS studies with the aforementioned methods are not feasible for most research laboratories. The need for low-cost large scale rare-variant detection makes pooled-DNA sequencing an ideally efficient and cost-effective technique to identify rare variants in target regions by sequencing hundreds to thousands of samples. Our recent work has demonstrated that pooled-DNA sequencing can accurately detect rare variants in targeted regions in multiple DNA samples with high sensitivity and specificity (Jin et al., Alzheimers Res Ther 4:34, 2012). In these studies we used a well-established pooled-DNA sequencing approach and a computational package, SPLINTER (short indel prediction by large deviation inference and nonlinear true frequency estimation by recursion) (Vallania et al., Genome Res 20:1711, 2010), for accurate identification of rare variants in large DNA pools. Given an average sequencing coverage of 30× per haploid genome, SPLINTER can detect rare variants and short indels up to 4 base pairs (bp) with high sensitivity and specificity (up to 1 haploid allele in a pool as large as 500 individuals). Step-by-step instructions on how to conduct pooled-DNA sequencing experiments and data analyses are described in this chapter. © Springer Science+Business Media New York 2015. All right reserved.

Author Keywords
Alzheimer's disease;  Next-generation sequencing;  NGS;  Pooled-DNA sequencing;  Rare variants


Document Type: Book Chapter
Source: Scopus