WashU weekly Neuroscience publications

Seizures as an early symptom of autosomal dominant Alzheimer’s disease
(2019) Neurobiology of Aging, 76, pp. 18-23. 

Vöglein, J.^{a b} , Noachtar, S.^b , McDade, E.^c , Quaid, K.A.^d , Salloway, S.^e , Ghetti, B.^f , Noble, J.^g , Berman, S.^h , Chhatwal, J.ⁱ , Mori, H.^j , Fox, N.^k , Allegri, R.^l , Masters, C.L.^m , Buckles, V.^c , Ringman, J.M.ⁿ , Rossor, M.^k , Schofield, P.R.^{o p} , Sperling, R.ⁱ , Jucker, M.^{q r} , Laske, C.^{q s} , Paumier, K.^c , Morris, J.C.^c , Bateman, R.J.^c , Levin, J.^{a b} , Danek, A.^{a b} , Dominantly Inherited Alzheimer Network^t

^a German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^b Department of Neurology, Ludwig-Maximilians-Universität München, München, Germany
^c Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN, United States
^e Butler Hospital, Providence, RI, United States
^f Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^g Columbia University, New York, NY, United States
^h University of Pittsburgh, Pittsburgh, PA, United States
ⁱ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^j Osaka City University Medical School, Asahi Machi, Abenoku, Osaka, Japan
^k Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
^l FLENI, Buenos Aires, Argentina
^m Florey Institute, University of Melbourne, Parkville, Victoria, Australia
ⁿ Center for the Health Professionals, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States
^o Neuroscience Research Australia, Randwick, New South Wales, Australia
^p School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia
^q German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^r Hertie Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany
^s Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany

Abstract
Our objective was to assess the reported history of seizures in cognitively asymptomatic mutation carriers for autosomal dominant Alzheimer’s disease (ADAD) and the predictive value of seizures for mutation carrier status in cognitively asymptomatic first-degree relatives of ADAD patients. Seizure occurrence in the Dominantly Inherited Alzheimer Network observational study was correlated with mutation carrier status in cognitively asymptomatic subjects. Of 276 cognitively asymptomatic individuals, 11 (4%) had experienced seizures, and nine of these carried an ADAD mutation. Thus, in the Dominantly Inherited Alzheimer Network population, seizure frequency in mutation carriers was significantly higher than in noncarriers (p = 0.04), and the positive predictive value of seizures for the presence of a pathogenic mutation was 81.8%. Among cognitively asymptomatic ADAD family members, the occurrence of seizures increases the a priori risk of 50% mutation-positive status to about 80%. This finding suggests that ADAD mutations increase the risk of seizures. © 2018 Elsevier Inc.

Author Keywords
Alzheimer’s disease;  Autosomal dominant;  Dementia;  Genetics;  Positive predictive value;  Seizures

Document Type: Article
Publication Stage: Final
Source: Scopus

Inhibitory mechanisms shaping delay-tuned combination-sensitivity in the auditory cortex and thalamus of the mustached bat
(2019) Hearing Research, 373, pp. 71-84. 

Butman, J.A., Suga, N.

Department of Biology, Washington University, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
Delay-tuned auditory neurons of the mustached bat show facilitative responses to a combination of signal elements of a biosonar pulse-echo pair with a specific echo delay. The subcollicular nuclei produce latency-constant phasic on-responding neurons, and the inferior colliculus produces delay-tuned combination-sensitive neurons, designated “FM-FM” neurons. The combination-sensitivity is a facilitated response to the coincidence of the excitatory rebound following glycinergic inhibition to the pulse (1st harmonic) and the short-latency response to the echo (2nd–4th harmonics). The facilitative response of thalamic FM-FM neurons is mediated by glutamate receptors (NMDA and non-NMDA receptors). Different from collicular FM-FM neurons, thalamic ones respond more selectively to pulse-echo pairs than individual signal elements. A number of differences in response properties between collicular and thalamic or cortical FM-FM neurons have been reported. However, differences between thalamic and cortical FM-FM neurons have remained to be studied. Here, we report that GABAergic inhibition controls the duration of burst of spikes of facilitative responses of thalamic FM-FM neurons and sharpens the delay tuning of cortical ones. That is, intra-cortical inhibition sharpens the delay tuning of cortical FM-FM neurons that is potentially broad because of divergent/convergent thalamo-cortical projections. Compared with thalamic neurons, cortical ones tend to show sharper delay tuning, longer response duration, and larger facilitation index. However, those differences are statistically insignificant. © 2019 Elsevier B.V.

Author Keywords
Distance information;  Echolocation;  FM-FM neurons;  GABAergic inhibition;  Hierarchical processing

Document Type: Article
Publication Stage: Final
Source: Scopus

Reply to barton and montgomery: A case for preferential prefrontal cortical expansion
(2019) Proceedings of the National Academy of Sciences of the United States of America, 116 (1), pp. 5-6. 

Donahue, C.J.^a , Glasser, M.F.^{a b} , Preuss, T.M.^{c d e} , Rilling, J.K.^{d e f g h} , Van Essen, D.C.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Division of Neuropharmacology and Neurologic Diseases, Emory University, Atlanta, GA 30329, United States
^d Center for Translational Social Neuroscience, Emory University, Atlanta, GA 30329, United States
^e Yerkes National Primate Research Center, Emory University, Atlanta, GA 30329, United States
^f Department of Anthropology, Emory University, Atlanta, GA 30329, United States
^g Center for Behavioral Neuroscience, Emory University, Atlanta, GA 30329, United States
^h Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

Special issue on stem cell and tissue engineering in development, disease, and repair
(2019) Developmental Dynamics, 248 (1), pp. 7-9. 

Shcheglovitov, A.^a , Rao, M.^b , Yoo, A.^c

^a Departments of Neurobiology and Anatomy University of Utah, Salt Lake City, UT, United States
^b Q Therapeutics, Salt Lake City, UT, United States
^c Department of Developmental Biology, Washington University, St. Louis, MO, United States

Document Type: Editorial
Publication Stage: Final
Source: Scopus

Facilitation of MrgprD by TRP-A1 promotes neuropathic pain
(2019) FASEB Journal, 33 (1), pp. 1360-1373. Cited 1 time.

Wang, C.^{a b c d} , Gu, L.^{a b c d} , Ruan, Y.^{a b c d} , Geng, X.^{a b c d} , Xu, M.^e , Yang, N.^{a f} , Yu, L.^{a b} , Jiang, Y.^{a b} , Zhu, C.^{a b c d} , Yang, Y.^{a b c d} , Zhou, Y.^{a b c d} , Guan, X.^{a b c d} , Luo, W.^g , Liu, Q.^{h i j} , Dong, X.^{k l} , Yu, G.^{a b c d} , Lan, L.^e , Tang, Z.^{a b c d}

^a School of Medicine and Life Sciences, United States
^b Key Laboratory of Chinese Medicine for Prevention and Treatment of Neurological Diseases, United States
^c State Key Laboratory Cultivation Base for Traditional Chinese Medicine Quality and Efficacy, China
^d Key Laboratory of Drug Target and Drug for Degenerative Disease of Jiangsu Province, Nanjing University of Chinese Medicine, 138 Xianlin Rd., Nanjing, Jiangsu, 210023, China
^e Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
^f Department of Traditional Chinese and Western Medicine, Jiangsu Key Lab. of Intgd. Traditional Chinese and W. Med. for Prev. and Treatm. of Senile Diseases, Yangzhou University, Yangzhou, China
^g Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^h Department of Anesthesiology, United States
ⁱ Center for the Study of Itch, United States
^j Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^k Solomon H. Snyder Department of Neuroscience, Center for Sensory Biology, United States
^l Howard Hughes Medical Institute, School of Medicine, Johns Hopkins University, Baltimore, MD, United States

Abstract
Neuropathic pain remains a therapeutic challenge because of its complicated mechanisms. Mas-related GPCR D (MrgprD) is specifically expressed in small-diameter, nociceptive neurons of dorsal root ganglia (DRGs) and is implicated in pain modulation. However, the underlying mechanism of MrgprD involved in neuropathic pain remains elusive. In this study, we used behavioral experiments and physiologic examination methods to investigate the role of MrgprD in chronic constriction injury (CCI)-induced neuropathic pain. We found that MrgprD is necessary for the initiation of mechanical hypersensitivity and cold allodynia, but not for heat allodynia. Moreover, we demonstrated that transient receptor potential cation channel (TRP)-A1 was the ion channel downstream of MrgprD, and the b-alanine-induced calcium signal was attributed mostly to TRP-A1 function.We further showed that PKA serves as a downstream mediator of b-alanine-activated MrgprD signaling to activate TRP-A1 in DRG neurons and in human embryonic kidney 293 cells, to coexpress MrgprD and TRP-A1 plasmids. Finally, we found that the b-alanine-induced pain behavior was increased, whereas theitching behavior was unchangedin CCI models compared with sham-injured animals. Knockout of TRPA1 also attenuated the b-alanine-induced pain behavior in CCI models. In conclusion, MrgprD is essential in cold allodynia in CCI-induced neuropathic pain through the PKA-TRP-A1 pathway. TRP-A1 facilitates MrgprD to development of neuropathic pain. Our findings reveal a novel mechanism of neuropathic pain formation and highlight MrgprD as a promising drug target for the treatment of neuropathic pain. © FASEB.

Author Keywords
Dorsal root ganglia (DRG);  MrgprA1;  Protein kinase A (PKA)

Document Type: Article
Publication Stage: Final
Source: Scopus

Sex-specific gene and pathway modeling of inherited glioma risk
(2019) Neuro-oncology, 21 (1), pp. 71-82. 

Ostrom, Q.T.^{a b c} , Coleman, W.^d , Huang, W.^e , Rubin, J.B.^f , Lathia, J.D.^g , Berens, M.E.^h , Speyer, G.^h , Liao, P.^a , Wrensch, M.R.ⁱ , Eckel-Passow, J.E.^j , Armstrong, G.^b , Rice, T.ⁱ , Wiencke, J.K.ⁱ , McCoy, L.S.ⁱ , Hansen, H.M.ⁱ , Amos, C.I.^k , Bernstein, J.L.^l , Claus, E.B.^{m n} , Houlston, R.S.^o , Il’yasova, D.^{p q r} , Jenkins, R.B.^s , Johansen, C.^t , Lachance, D.H.^u , Lai, R.K.^v , Merrell, R.T.^w , Olson, S.H.^l , Sadetzki, S.^{x y z} , Schildkraut, J.M.^aa , Shete, S.^af , Andersson, U.^ab , Rajaraman, P.^ac , Chanock, S.J.^{ac ad} , Linet, M.S.^ac , Wang, Z.^{ac ad ae} , Yeager, M.^{ac ad} , GliomaScan consortium^ag , Melin, B.^ab , Bondy, M.L.^b , Barnholtz-Sloan, J.S.^a

^a Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^b Department of Medicine, Section of Epidemiology and Population Sciences, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
^c Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^d University School, Chagrin Falls, OH, United States
^e Case Western Reserve University, Cleveland, OH, United States
^f Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA; Department of Neuroscience, Washington University School of Medicine, St Louis, Missouri, USA
^g Department of Stem Cell Biology and Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States
^h Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, United States
ⁱ Department of Neurological Surgery, School of Medicine, University of California San Francisco, San Francisco, CA, United States
^j Division of Biomedical Statistics and Informatics, Mayo Clinic College of Medicine, Rochester, MN, United States
^k Institute for Clinical and Translational Research, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States
^l Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer CenterNY, United States
^m School of Public Health, Yale University, New HavenCT, United States
ⁿ Department of Neurosurgery, Brigham and Women’s Hospital, Boston, MA, United States
^o Division of Genetics and Epidemiology, Institute of Cancer Research, Surrey, United Kingdom
^p Department of Epidemiology and Biostatistics, School of Public Health, Georgia State University, Atlanta, GA, United States
^q Cancer Control and Prevention Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, United States
^r Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States
^s Department of Laboratory Medicine and Pathology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, United States
^t Oncology Clinic, Finsen Center, Rigshospitalet and Survivorship Research Unit, Danish Cancer Society Research Center, Copenhagen, Denmark
^u Department of Neurology, Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, United States
^v Departments of Neurology and Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
^w Department of Neurology, NorthShore University HealthSystem, Evanston, IL, United States
^x Cancer and Radiation Epidemiology Unit, Gertner Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel
^y Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
^z Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
^aa Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA, United States
^ab Department of Radiation Sciences, Faculty of Medicine, Umea° University, Umea°, Sweden
^ac Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, United States
^ad Core Genotyping Facility, National Cancer Institute, SAIC-Frederick, Inc, Gaithersburg, MD, United States
^ae Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

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

Exploring the relationship between polygenic risk for cannabis use, peer cannabis use and the longitudinal course of cannabis involvement
(2019) Addiction, . Article in Press. 

Johnson, E.C.^a , Tillman, R.^a , Aliev, F.^{b c} , Meyers, J.L.^d , Salvatore, J.E.^b , Anokhin, A.P.^a , Dick, D.M.^{b e} , Edenberg, H.J.^f , Kramer, J.R.^g , Kuperman, S.^g , McCutcheon, V.V.^a , Nurnberger, J.I., Jr.^h , Porjesz, B.^d , Schuckit, M.A.ⁱ , Tischfield, J.^j , Bucholz, K.K.^a , Agrawal, A.^a

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^c Department of Actuarial and Risk Management, Faculty of Business, Karabuk University, Turkey
^d Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY, United States
^e Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
^f Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^g Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^h Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
ⁱ Department of Psychiatry, University of California San Diego Medical School, San Diego, CA, United States
^j Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ, United States

Abstract
Background and aims: Few studies have explored how polygenic propensity to cannabis use unfolds across development, and no studies have yet examined this question in the context of environmental contributions such as peer cannabis use. Outlining the factors that contribute to progression from cannabis initiation to problem use over time may ultimately provide insights into mechanisms for targeted interventions. We sought to examine the relationships between polygenic liability for cannabis use, cannabis use trajectories from ages 12–30 years and perceived peer cannabis use at ages 12–17 years. Design: Mixed-effect logistic and linear regressions were used to examine associations between polygenic risk scores, cannabis use trajectory membership and perceived peer cannabis use. Setting: United States. Participants: From the Collaborative Study on the Genetics of Alcoholism (COGA) study, a cohort of 1167 individuals aged 12–26 years at their baseline (i.e. first) interview. Measurements: Key measurements included life-time cannabis use (yes/no), frequency of past 12-month cannabis use, maximum life-time frequency of cannabis use, cannabis use disorder (using DSM-5 criteria) and perceived peer cannabis use. Polygenic risk scores (PRS) were created using summary statistics from a large (n = 162 082) genome-wide association study (GWAS) of cannabis use. Findings: Three trajectories reflecting no/low (n = 844), moderate (n = 137) and high (n = 186) use were identified. PRS were significantly associated with trajectory membership [P = 0.002–0.006, maximum conditional R2 = 1.4%, odds ratios (ORs) = 1.40–1.49]. Individuals who reported that most/all of their best friends used cannabis had significantly higher PRS than those who reported that none of their friends were users [OR = 1.35, 95% confidence interval (CI) = 1.04, 1.75, P = 0.023]. Perceived peer use itself explained up to 11.3% of the variance in trajectory class membership (OR = 1.50–4.65). When peer cannabis use and the cannabis use PRS were entered into the model simultaneously, both the PRS and peer use continued to be significantly associated with class membership (P &lt; 0.01). Conclusions: Genetic propensity to cannabis use derived from heterogeneous samples appears to correlate with longitudinal increases in cannabis use frequency in young adults. © 2018 Society for the Study of Addiction

Author Keywords
Cannabis use;  externalizing behaviors;  high-risk sample;  peer influence;  polygenic risk score;  trajectories

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

Clinicopathologic features of anaplastic myxopapillary ependymomas
(2019) Brain Pathology, 29 (1), pp. 75-84. 

Lee, J.C.^a , Sharifai, N.^b , Dahiya, S.^b , Kleinschmidt-DeMasters, B.K.^c , Rosenblum, M.K.^d , Reis, G.F.^e , Samuel, D.^f , Siongco, A.M.^g , Santi, M.^h , Storm, P.B.ⁱ , Ferris, S.P.^a , Bollen, A.W.^a , Pekmezci, M.^a , Solomon, D.A.^{a j} , Tihan, T.^a , Perry, A.^a

^a Department of Pathology, University of California, San Francisco, CA, United States
^b Division of Neuropathology, Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
^c Department of Pathology, University of Colorado, Denver, CO, United States
^d Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
^e Department of Pathology, Memorial Healthcare System, Hollywood, FL, United States
^f Neuro-oncology, Valley Children’s Hospital, Madera, CA, United States
^g Department of Pathology, Valley Children’s Hospital, Madera, CA, United States
^h Department of Pathology, The Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Panama
ⁱ Division of Neurosurgery, The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^j Clinical Cancer Genomics Laboratory, University of California, San Francisco, Canada

Abstract
Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6–57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and <3% in the foci of classic MPE. There was documented cerebrospinal fluid (CSF) dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by fluorescence in situ hybridization (FISH) showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression. © 2018 International Society of Neuropathology

Author Keywords
anaplastic transformation;  CSF dissemination;  malignant neoplasm;  metastasis;  microvascular proliferation;  myxopapillary ependymoma;  necrosis;  recurrence

Document Type: Article
Publication Stage: Final
Source: Scopus

Altered reward processing following an acute social stressor in adolescents
(2019) PLoS ONE, 14 (1), art. no. e0209361, . 

Lincoln, S.H.^{a b} , Pisoni, A.^c , Bondy, E.^d , Kumar, P.^{a b} , Singleton, P.^{a b} , Hajcak, G.^e , Pizzagalli, D.A.^{a b f} , Auerbach, R.P.^{a b g h}

^a Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^b Center for Depression, Anxiety and Stress Research, Belmont, MA, United States
^c Department of Psychology and Neuroscience, Duke University, Durham, NC, United States
^d Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^e Departments of Biomedical Sciences and Psychology, Florida State University, Tallahassee, FL, United States
^f McLean Imaging Center, Belmont, MA, United States
^g Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, NY, United States
^h Division of Clinical Developmental Neuroscience, Sackler Institute, New York, NY, United States

Abstract
Altered reward processing is a transdiagnostic factor implicated in a wide range of psychiatric disorders. While prior animal and adult research has shown that stress contributes to reward dysfunction, less is known about how stress impacts reward processing in youth. Towards addressing this gap, the present study probed neural activation associated with reward processing following an acute stressor. Healthy adolescents (n = 40) completed a clinical assessment, and fMRI data were acquired while participants completed a monetary guessing task under a no-stress condition and then under a stress condition. Based on prior literature, analyses focused on a priori defined regions-of-interest, specifically the striatum (win trials) and dorsal anterior cingulate cortex [dACC] and insula (loss trials). Two main findings emerged. First, reward-related neural activation (i.e., striatum) was blunted in the stress relative to the no-stress condition. Second, the stress condition also contributed to blunted neural response following reward in loss-related regions (i.e., dACC, anterior insula); however, there were no changes in loss sensitivity. These results highlight the importance of conceptualizing neural vulnerability within the presence of stress, as this may clarify risk for mental disorders during a critical period of development. © 2019 Lincoln 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
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Sleep regulates visual selective attention in Drosophila
(2018) The Journal of experimental biology, 221, . 

Kirszenblat, L.^a , Ertekin, D.^a , Goodsell, J.^a , Zhou, Y.^a , Shaw, P.J.^b , van Swinderen, B.^c

^a Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia
^b Department of Anatomy and Neurobiology, Washington University in St. Louis, 660 South Euclid Avenue, St Louis, MO 63110, United States
^c Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia

Abstract
Although sleep deprivation is known to impair attention in humans and other mammals, the underlying reasons are not well understood, and whether similar effects are present in non-mammalian species is not known. We therefore sought to investigate whether sleep is important for optimizing attention in an invertebrate species, the genetic model Drosophila melanogaster We developed a high-throughput paradigm to measure visual attention in freely walking Drosophila, using competing foreground/background visual stimuli. We found that whereas sleep-deprived flies could respond normally to either stimulus alone, they were more distracted by background cues in a visual competition task. Other stressful manipulations such as starvation, heat exposure and mechanical stress had no effects on visual attention in this paradigm. In contrast to sleep deprivation, providing additional sleep using the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP) did not affect attention in wild-type flies, but specifically improved attention in the learning mutant dunce Our results reveal a key function of sleep in optimizing attention processes in Drosophila, and establish a behavioral paradigm that can be used to explore the molecular mechanisms involved. © 2018. Published by The Company of Biologists Ltd.

Author Keywords
Attention;  Behavior;  Drosophila;  Flies;  Sleep

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

Extreme Enlargement of the Cerebellum in a Clade of Teleost Fishes that Evolved a Novel Active Sensory System
(2018) Current Biology, 28 (23), pp. 3857-3863.e3. 

Sukhum, K.V., Shen, J., Carlson, B.A.

Department of Biology, Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
Brains, and the distinct regions that make up brains, vary widely in size across vertebrates [1, 2]. Two prominent hypotheses have been proposed to explain brain region scaling evolution. The mosaic hypothesis proposes that changes in the relative sizes of particular brain regions are the result of selection acting independently on those regions [2, 3]. The concerted hypothesis proposes that the brain evolves as a coordinated structure due to developmental constraints [4]. These hypotheses have been widely debated [3–7], and recent studies suggest a combination of the two best describes vertebrate brain region scaling [8–10]. However, no study has addressed how the mosaic and concerted models relate to the evolution of novel behavioral phenotypes. We addressed this question using African mormyroid fishes. The mormyroids have evolved a novel active electrosensory system and are well known for having extreme encephalization [11] and a large cerebellum [2, 12], which is cited as a possible example of mosaic evolution [2]. We found that compared to outgroups without active electrosensing, mormyroids experienced mosaic increases in the sizes of the cerebellum and hindbrain, and mosaic decreases in the sizes of the telencephalon, optic tectum, and olfactory bulb. However, the evolution of extreme encephalization within mormyroids was associated with concerted changes in the sizes of all brain regions. This suggests that mosaic evolutionary change in the regional composition of the brain is most likely to occur alongside the evolution of novel behavioral functions, but not with the evolution of extreme encephalization. © 2018 Elsevier Ltd

Sukhum et al. show that evolution of enlarged brains in osteoglossomorph fishes is associated with concerted increases in the sizes of all brain regions, but that active electrosensing evolved alongside independent changes in the sizes of different brain regions. Changes in brain structure may be most likely with the evolution of novel behaviors. © 2018 Elsevier Ltd

Author Keywords
allometry;  brain evolution;  concerted evolution;  encephalization;  Mormyridae;  mosaic evolution;  Osteoglossomorpha;  weakly electric fish

Document Type: Article
Publication Stage: Final
Source: Scopus

Guidance for switching from off-label antipsychotics to pimavanserin for Parkinson’s disease psychosis: an expert consensus
(2018) CNS spectrums, 23 (6), pp. 402-413. 

Black, K.J.^a , Nasrallah, H.^b , Isaacson, S.^c , Stacy, M.^d , Pahwa, R.^e , Adler, C.H.^f , Alva, G.^g , Cooney, J.W.^h , Kremens, D.ⁱ , Menza, M.A.^j , Meyer, J.M.^k , Patkar, A.A.^l , Simuni, T.^m , Morrissette, D.A.ⁿ , Stahl, S.M.^o

^a Departments of Psychiatry, Neurology, Radiology, Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry and Behavioral Neuroscience, Saint Louis University School of Medicine, St. Louis, MO, United States
^c 3Parkinson’s Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, United States
^d 4Brody School of Medicine, East Carolina University, Greenville, NC, United States
^e Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
^f Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, United States
^g Department of Psychiatry and Neuroscience, University of California, Riverside, CA, United States
^h Department of Neurology, Duke University School of Medicine, Durham, NC, United States
ⁱ 10Comprehensive Parkinson’s Disease and Movement Disorders Center at the Vickie and Jack Farber Center for Neurosciences at the Sidney Kimmel Medical School at Jefferson University, Philadelphia, United States
^j 11Department of Psychiatry,Robert Wood Johnson Medical School,New Brunswick,New Jersey,USA
^k 12California Department of State Hospitals, Sacramento, CA, United States
^l 14Department of Psychiatry & Community and Family Medicine, Duke University Medical Center, Durham, NC, United States
^m 15Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
ⁿ 16Neuroscience Education Institute, Carlsbad, CA, United States
^o 13Department of Psychiatry, University of California, La Jolla, San Diego, CA, United States

Abstract
Patients with Parkinson’s disease psychosis (PDP) are often treated with an atypical antipsychotic, especially quetiapine or clozapine, but side effects, lack of sufficient efficacy, or both may motivate a switch to pimavanserin, the first medication approved for management of PDP. How best to implement a switch to pimavanserin has not been clear, as there are no controlled trials or case series in the literature to provide guidance. An abrupt switch may interrupt partially effective treatment or potentially trigger rebound effects from antipsychotic withdrawal, whereas cross-taper involves potential drug interactions. A panel of experts drew from published data, their experience treating PDP, lessons from switching antipsychotic drugs in other populations, and the pharmacology of the relevant drugs, to establish consensus recommendations. The panel concluded that patients with PDP can be safely and effectively switched from atypical antipsychotics used off label in PDP to the recently approved pimavanserin by considering each agent’s pharmacokinetics and pharmacodynamics, receptor interactions, and the clinical reason for switching (efficacy or adverse events). Final recommendations are that such a switch should aim to maintain adequate 5-HT2A antagonism during the switch, thus providing a stable transition so that efficacy is maintained. Specifically, the consensus recommendation is to add pimavanserin at the full recommended daily dose (34 mg) for 2-6 weeks in most patients before beginning to taper and discontinue quetiapine or clozapine over several days to weeks. Further details are provided for this recommendation, as well as for special clinical circumstances where switching may need to proceed more rapidly.

Author Keywords
antipsychotic agents;  complications;  Parkinson Disease:;  pimavanserin;  psychotic disorders:;  therapy

Document Type: Article
Publication Stage: Final
Source: Scopus

Acute and Chronic Effects of Whole-Body Vibration on Balance, Postural Stability, and Mobility in Women With Multiple Sclerosis
(2018) Dose-Response, 16 (4), . 

Freitas, E.D.S.^a , Frederiksen, C.^b , Miller, R.M.^a , Heishman, A.^a , Anderson, M.^c , Pardo, G.^d , Fjeldstad, C.^d , Bemben, D.A.^{a e} , Bemben, M.G.^{a e}

^a Department of Health and Exercise Science, Neuromuscular Laboratory, University of Oklahoma, Norman, OK, United States
^b Department of Surgery, Washington University Medical Center, St Louis, MO, United States
^c Department of Rehabilitation Sciences, University of Oklahoma Health Sciences Center, Oklahoma, OK, United States
^d Oklahoma Medical Research Foundation Multiple Sclerosis Center of Excellence, Oklahoma, OK, United States
^e Department of Health and Exercise Science, Bone Laboratory, University of Oklahoma, Norman, OK, United States

Abstract
The acute and chronic effects of whole-body vibration (WBV) on balance, postural stability, and mobility were evaluated in 21 women with relapsing-remitting multiple sclerosis (MS) randomly assigned to control (n = 9) or experimental (n = 12) groups. To assess acute responses, outcome variables were assessed before and immediately after a session of WBV (five 30-second bouts of vibration; frequency 30 Hz; amplitude 3 mm; 1-minute rest intervals) during their first visit (week 1) using field (Timed-Up and Go; 500-m walk; Berg Balance Scale) and laboratory tests (NeuroCom Balance Master and EquiTest System—Sensory Organization Test, Adaptation Test, Limits of Stability, Modified Clinical Test for Sensory Integration of Balance, Unilateral Stance, Tandem Walk, Step/Quick Turn). Acute responses were also measured after their fifth visit for only the Adaptation and Sensory Organization tests. For the chronic responses, participants were exposed to the WBV protocol once a week, for a total of 5 weeks, and then at week 5, were reassessed with the Adaptation and the Sensory Organization tests. Neither acute nor chronic exposure to the WBV protocols used in this study resulted in significant improvements (P >.05) in balance, postural stability, or mobility as assessed by either field or laboratory tests. However, based on promising results from other studies that have used WBV with other clinical populations, either alone or in conjunction with exercise, additional studies that increase the dose of vibration exposure, both acutely and chronically, should be conducted in patients with MS. © The Author(s) 2018.

Author Keywords
balance;  mobility;  neurodegenerative disease;  posture;  vibration

Document Type: Article
Publication Stage: Final
Source: Scopus

Sequencing of Chemotherapy and Radiotherapy for Newly Diagnosed Anaplastic Oligodendroglioma and Oligoastrocytoma
(2018) American Journal of Clinical Oncology: Cancer Clinical Trials, . Article in Press. 

Ryckman, J.M.^a , Surkar, S.M.^b , Haque, W.^c , Butler, E.B.^c , Teh, B.S.^c , Verma, V.^d

^a Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, United States
^b Department of Physical Therapy, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Radiation Oncology, Houston Methodist Hospital, Houston, TX, United States
^d Department of Radiation Oncology, Allegheny General Hospital, Pittsburgh, PA, United States

Abstract
Introduction: Adjuvant management of anaplastic oligodendrogliomas (AOs) and anaplastic oligoastrocytomas (AOAs) is guided by 2 seminal phase III trials, one of which utilized radiotherapy (RT) followed by chemotherapy (CT) (RT-CT), and the other in which CT was followed by RT (CT-RT). Both paradigms are endorsed by the National Comprehensive Cancer Network because no direct comparison in the first-line (nonprogressive) setting has been performed to date. This study of a contemporary national database sought to evaluate practice patterns and outcomes between both approaches. Materials and Methods: The National Cancer Database (NCDB) was queried for newly diagnosed AO/AOA treated with postoperative sequential CT-RT or RT-CT. Multivariable logistic regression ascertained factors independently associated with delivery of a particular paradigm. Overall survival (OS) between cohorts was compared using Kaplan-Meier methodology. Univariate and multivariate Cox proportional hazards modeling evaluated factors associated with OS. Results: Of 225 patients, 19 (8.4%) received CT-RT and 206 (91.6%) underwent RT-CT. Groups were well-balanced, although CT-RT was more often administered to men (P=0.009) and AOs (P=0.037). Median follow-up was 58 months. Median OS in the CT-RT cohort was 93 months (95% confidence interval, 37-150 mo), and 107 months (95% confidence interval, 72-142 mo) in the RT-CT group (P=0.709). Therapy sequence was not associated with OS on univariate (P=0.709) or multivariate (P=0.257) assessment. Conclusions: In the United States, most AO/AOA patients receiving sequential therapy undergo RT followed by CT. No differences in survival were observed with either approach; this addresses a knowledge gap and confirms that both paradigms are appropriate in the first-line setting. © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
anaplastic;  chemotherapy;  glioma;  radiation therapy;  sequencing

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

The Human Connectome Project 7 Tesla retinotopy dataset: Description and population receptive field analysis
(2018) Journal of Vision, 18 (13), pp. 1-22. 

Benson, N.C.^a , Jamison, K.W.^{b c} , Arcaro, M.J.^d , Vu, A.T.^{b e} , Glasser, M.F.^{f g h} , Coalson, T.S.^f , Van Essen, D.C.^f , Yacoub, E.^b , Ugurbil, K.^b , Winawer, J.^a , Kay, K.^b

^a Department of Psychology and Center for Neural Science, New York University, New York, NY, United States
^b Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, MN, United States
^c Department of Radiology, Weill Cornell Medical College, New York, NY, United States
^d Department of Neurobiology, Harvard Medical School, Boston, MA, United States
^e Center for Imaging of Neurodegenerative Diseases, VA Healthcare System, San Francisco, CA, United States
^f Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^h Department of Medicine, St. Luke’s Hospital, St. Louis, MO, United States

Abstract
About a quarter of human cerebral cortex is dedicated mainly to visual processing. The large-scale spatial organization of visual cortex can be measured with functional magnetic resonance imaging (fMRI) while subjects view spatially modulated visual stimuli, also known as ”retinotopic mapping.” One of the datasets collected by the Human Connectome Project involved ultrahigh-field (7 Tesla) fMRI retinotopic mapping in 181 healthy young adults (1.6-mm resolution), yielding the largest freely available collection of retinotopy data. Here, we describe the experimental paradigm and the results of model-based analysis of the fMRI data. These results provide estimates of population receptive field position and size. Our analyses include both results from individual subjects as well as results obtained by averaging fMRI time series across subjects at each cortical and subcortical location and then fitting models. Both the group-average and individual-subject results reveal robust signals across much of the brain, including occipital, temporal, parietal, and frontal cortex as well as subcortical areas. The group-average results agree well with previously published parcellations of visual areas. In addition, split-half analyses show strong within-subject reliability, further demonstrating the high quality of the data. We make publicly available the analysis results for individual subjects and the group average, as well as associated stimuli and analysis code. These resources provide an opportunity for studying fine-scale individual variability in cortical and subcortical organization and the properties of high-resolution fMRI. In addition, they provide a set of observations that can be compared with other Human Connectome Project measures acquired in these same participants. © 2018 The Authors.

Author Keywords
FMRI;  Parcellation;  Population receptive fields;  Retinotopy;  Topography;  Visual cortex

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

Tourette syndrome research highlights from 2017 [version 1; referees: 3 approved]
(2018) F1000Research, 7, art. no. 1122, . 

Hartmann, A.^a , Worbe, Y.^{a b} , Black, K.J.^c

^a Sorbonne University, National Reference Centre for Tourette Disorder, Pitié-Salpêtrière Hospital, Paris, France
^b Department of Physiology, Saint-Antoine Hospital, Paris, France
^c Psychiatry, Neurology, Radiology, and Neuroscience, Washington University School of Medicine, St. Louis, MO 63110-1093, United States

Abstract
This is the fourth yearly article in the Tourette Syndrome Research Highlights series, summarizing research from 2017 relevant to Tourette syndrome and other tic disorders. The authors briefly summarize reports they consider most important or interesting. The highlights from 2018 article is being drafted on the Authorea online authoring platform, and readers are encouraged to add references or give feedback on our selections using the comments feature on that page. After the calendar year ends, the article is submitted as the annual update for the Tics collection on F1000Research. © 2018 Hartmann A et al.

Author Keywords
Etiology;  Natural history;  Pathophysiology;  Review;  Tic disorders;  Tourette syndrome

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

“Treated me … like I was family”: Qualitative Evaluation of a Culturally-Adapted Health Care Manager Intervention for Latinos with Serious Mental Illness and at Risk for Cardiovascular Disease
(2018) Transcultural Psychiatry, . Article in Press. 

Cabassa, L.J.^a , Manrique, Y.^b , Meyreles, Q.^b , Capitelli, L.^c , Younge, R.^b , Dragatsi, D.^b , Alvarez, J.^c , Lewis-Fernández, R.^c

^a Washington University in St. Louis, United States
^b Columbia University, United States
^c New York State Psychiatric Institute, United States

Abstract
Latinos with serious mental illness (SMI) experience health and health care disparities and may benefit from interventions that improve access to, coordination of, and receipt of primary care services. The aim of this qualitative study was to examine the experiences of Latinos with SMI and at risk for cardiovascular disease participating in Bridges to Better Health and Wellness (B2BHW), a culturally-adapted health care manager intervention delivered in a public outpatient mental health clinic. A total of 29 Latino participants completed a post-intervention survey that included an open-ended question about the three things they liked most about B2BHW; a subset of 16 participants participated in one of three post-intervention focus groups. Results indicate that what mattered most to participants was the health education they received, the positive relationships they formed with their health care managers, the care coordination assistance they obtained, and the motivation and activation they gained from this intervention. Study findings suggest that key elements of the health care manager intervention (e.g., care coordination, and patient activation) shaped participants’ experiences with B2BHW and were perceived as beneficial. © The Author(s) 2018.

Author Keywords
health care disparities;  health care management;  Latinos;  patient-centered care;  serious mental illness

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

Impact of Handedness on Disability After Unilateral Upper-Extremity Peripheral Nerve Disorder
(2018) Hand, . Article in Press. 

Philip, B.A., Kaskutas, V., Mackinnon, S.E.

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

Abstract
Background: Impairment of the dominant hand should lead to greater disability than impairment of the nondominant hand, but few studies have tested this directly, especially in the domain of upper-extremity peripheral nerve disorder. The aim of this study was to identify the association between hand dominance and standardized measures of disability and health status after upper-extremity peripheral nerve disorder. Methods: An existing database was reanalyzed to identify the relationship between affected-side (dominant vs nondominant) on individuals with unilateral upper-extremity peripheral nerve disorder (N = 400). Primary measure of disability was the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Results: We found no differences in standardized measures of disability or health status between patients with affected dominant hand and patients with an affected nondominant hand. However, a post hoc exploratory analysis revealed that patients with an affected dominant hand reported substantially reduced ability to perform 2 activities in the DASH questionnaire: “write” and “turn a key.” Conclusions: Following unilateral upper-extremity peripheral nerve disorder, impairment of the dominant hand (compared with impairment of the nondominant hand) is associated with reduced ability to perform specific activities, but this reduced ability is not reflected in standardized measures of disability and health status. To adequately identify disability following unilateral impairment of the dominant hand with the DASH, individual items must be used instead of the total score. New or alternative measures are also recommended. © The Author(s) 2018.

Author Keywords
disability evaluation;  hand;  hand dominance;  handedness;  peripheral nerve injuries;  peripheral neuropathies

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