WashU weekly Neuroscience publications

Evidence for altered neurodevelopment and neurodegeneration in Wolfram syndrome using longitudinal morphometry
(2019) Scientific Reports, 9 (1), art. no. 6010, . 

Lugar, H.M.^a , Koller, J.M.^a , Rutlin, J.^a , Eisenstein, S.A.^a , Neyman, O.^a , Narayanan, A.^a , Chen, L.^c , Shimony, J.S.^b , Hershey, T.^{a b}

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Wolfram syndrome is a rare disease caused by mutations in the WFS1 gene leading to symptoms in early to mid-childhood. Brain structural abnormalities are present even in young children, but it is not known when these abnormalities arise. Such information is critical in determining optimal outcome measures for clinical trials and in understanding the aberrant neurobiological processes in Wolfram syndrome. Using voxel-wise and regional longitudinal analyses, we compared brain volumes in Wolfram patients (n = 29; ages 5–25 at baseline; mean follow-up = 3.6 years), to age and sex-equivalent controls (n = 52; ages 6–26 at baseline; mean follow-up = 2.0 years). Between groups, white and gray matter volumes were affected differentially during development. Controls had uniformly increasing volume in white matter, whereas the Wolfram group had stable (optic radiations) or decreasing (brainstem, ventral pons) white matter volumes. In gray matter, controls had stable (thalamus, cerebellar cortex) or decreasing volumes (cortex), whereas the Wolfram group had decreased volume in thalamus and cerebellar cortex. These patterns suggest that there may be early, stalled white matter development in Wolfram syndrome, with additional degenerative processes in both white and gray matter. Ideally, animal models could be used to identify the underlying mechanisms and develop specific interventions. © 2019, The Author(s).

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

RNA editing is abundant and correlates with task performance in a social bumblebee
(2019) Nature Communications, 10 (1), art. no. 1605, . 

Porath, H.T.^a , Hazan, E.^b , Shpigler, H.^b , Cohen, M.^b , Band, M.^{c d} , Ben-Shahar, Y.^e , Levanon, E.Y.^a , Eisenberg, E.^f , Bloch, G.^b

^a The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat-Gan, 52900, Israel
^b Department of Ecology, Evolution & Behavior, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel
^c Roy J Carver Biotechnology Center, The University of Illinois at Urbana-Champaign, Champaign, IL 61801, United States
^d Institute of Evolution, University of Haifa, Haifa, 3498838, Israel
^e Department of Biology, Washington University in St. Louis, St. Louis, MO 63130-4899, United States
^f Raymond and Beverly Sackler School of Physics and Astronomy and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel

Abstract
Colonies of the bumblebee Bombus terrestris are characterized by wide phenotypic variability among genetically similar full-sister workers, suggesting a major role for epigenetic processes. Here, we report a high level of ADAR-mediated RNA editing in the bumblebee, despite the lack of an ADAR1-homolog. We identify 1.15 million unique genomic sites, and 164 recoding sites residing in 100 protein coding genes, including ion channels, transporters, and receptors predicted to affect brain function and behavior. Some edited sites are similarly edited in other insects, cephalopods and even mammals. The global editing level of protein coding and non-coding transcripts weakly correlates with task performance (brood care vs. foraging), but not affected by dominance rank or juvenile hormone known to influence physiology and behavior. Taken together, our findings show that brain editing levels are high in naturally behaving bees, and may be regulated by relatively short-term effects associated with brood care or foraging activities. © 2019, The Author(s).

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

Oxytocin in the tumor microenvironment is associated with lower inflammation and longer survival in advanced epithelial ovarian cancer patients
(2019) Psychoneuroendocrinology, 106, pp. 244-251. 

Cuneo, M.G.^a , Szeto, A.^b , Schrepf, A.^c , Kinner, E.M.^a , Schachner, B.I.^d , Ahmed, R.^d , Thaker, P.H.^e , Goodheart, M.^{f g} , Bender, D.^f , Cole, S.W.^h , McCabe, P.M.^b , Sood, A.K.ⁱ , Lutgendorf, S.K.^{a f g} , Mendez, A.J.^d

^a Department of Psychological & Brain Sciences, University of Iowa, United States
^b Department of Psychology, University of Miami, United States
^c Department of Anesthesiology and Chronic Pain and Fatigue Research Center, University of Michigan, United States
^d Diabetes Research Institute, Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, United States
^e Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, United States
^f Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, United States
^g Holden Comprehensive Cancer Center, University of Iowa, United States
^h Department of Medicine, Division of Hematology/Oncology and Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, United States
ⁱ Departments of Gynecologic Oncology, Cancer Biology and Center for RNA Interference and Noncoding RNA, University of Texas M.D. Anderson Cancer Center, United States

Abstract
Background: Prior research demonstrates a protective role for oxytocin in ovarian cancer based on its anti-proliferative, anti-migratory, and anti-invasive effects in vitro and in vivo. However, the role of endogenous oxytocin has not been examined in ovarian cancer patients. Oxytocin also has anti-inflammatory properties that have not been examined in cancer. The purpose of this investigation was to examine relationships between endogenous oxytocin, tumor-associated inflammation (interleukin-6), and survival in advanced epithelial ovarian cancer patients. Methods: Tumor microenvironment (ascites) and plasma oxytocin levels were analyzed via ELISA on extracted samples obtained from 79 patients. In vitro models were used to characterize oxytocin and oxytocin receptor expression in four ovarian cancer cell lines and to investigate direct anti-inflammatory effects of oxytocin on tumor cell secretion of interleukin-6. High and variable levels of oxytocin were observed in ascites, up to 200 times greater than in plasma. Higher levels of ascites oxytocin were associated with lower levels of systemic and tumor-associated interleukin-6, an inflammatory cytokine implicated in ovarian tumor progression. Oxytocin also attenuated interleukin-6 secretion from multiple ovarian tumor cell lines in vitro. Higher levels of ascites oxytocin were associated with a significant survival advantage and statistical mediation analyses suggested this effect was partially mediated by interleukin-6. Conclusions: These data identify a previously unacknowledged hormone in the ovarian tumor microenvironment and provide initial evidence that oxytocin has protective effects in ovarian cancer via anti-inflammatory mechanisms. Future studies should examine the therapeutic utility of oxytocin. © 2019 Elsevier Ltd

Author Keywords
Ascites;  interleukin-6;  Ovarian neoplasms;  Oxytocin;  Tumor microenvironment

Document Type: Article
Publication Stage: Final
Source: Scopus

Incorporating non-linear alignment and multi-compartmental modeling for improved human optic nerve diffusion imaging
(2019) NeuroImage, 196, pp. 102-113. 

Kim, J.-W.^{a b c} , Andersson, J.L.^d , Seifert, A.C.^{a b c} , Sun, P.^e , Song, S.-K.^e , Dula, C.^f , Naismith, R.T.^f , Xu, J.^{a b c g}

^a Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^b Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^c Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^d Wellcome Center for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom
^e Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States

Abstract
In vivo human optic nerve diffusion magnetic resonance imaging (dMRI) is technically challenging with two outstanding issues not yet well addressed: (i) non-linear optic nerve movement, independent of head motion, and (ii) effect from partial-volumed cerebrospinal fluid or interstitial fluid such as in edema. In this work, we developed a non-linear optic nerve registration algorithm for improved volume alignment in axial high resolution optic nerve dMRI. During eyes-closed dMRI data acquisition, optic nerve dMRI measurements by diffusion tensor imaging (DTI) with and without free water elimination (FWE), and by diffusion basis spectrum imaging (DBSI), as well as optic nerve motion, were characterized in healthy adults at various locations along the posterior-to-anterior dimension. Optic nerve DTI results showed consistent trends in microstructural parametric measurements along the posterior-to-anterior direction of the entire intraorbital optic nerve, while the anterior portion of the intraorbital optic nerve exhibited the largest spatial displacement. Multi-compartmental dMRI modeling, such as DTI with FWE or DBSI, was less subject to spatially dependent biases in diffusivity and anisotropy measurements in the optic nerve which corresponded to similar spatial distributions of the estimated fraction of isotropic diffusion components. DBSI results derived from our clinically feasible (∼10 min) optic nerve dMRI protocol in this study are consistent with those from small animal studies, which provides the basis for evaluating the utility of multi-compartmental dMRI modeling in characterizing coexisting pathophysiology in human optic neuropathies. © 2019

Author Keywords
Diffusion MRI;  Motion correction;  Multi-compartmental modeling;  Non-linear registration;  Optic nerve

Document Type: Article
Publication Stage: Final
Source: Scopus

Quantitative ultrasound and apoptotic death in the neonatal primate brain
(2019) Neurobiology of Disease, 127, pp. 554-562. 

Rosado-Mendez, I.M.^{a b} , Noguchi, K.K.^c , Castañeda-Martinez, L.^a , Kirvassilis, G.^d , Wang, S.H.^c , Manzella, F.^e , Swiney, B.S.^c , Masuoka, K.^c , Capuano, S., III2^f , Brunner, K.G.^f , Crosno, K.^f , Guerrero, Q.W.^b , Whitson, H.^b , Brambrink, A.^g , Simmons, H.S.^f , Mejia, A.F.^f , Zagzebski, J.A.^b , Hall, T.J.^b , Ikonomidou, C.^h

^a Instituto de Física, Universidad Nacional Autónoma de MéxicoCDMX, Mexico
^b Department of Medical Physics, University of Wisconsin, School of Medicine, Madison, WI, United States
^c Department of Psychiatry, Washington University, School of Medicine, St Louis, United States
^d Department of Anesthesiology, University of Wisconsin, School of Medicine, Madison, WI, United States
^e Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
^f Wisconsin National Primate Research Center, Madison, WI, United States
^g Department of Anesthesiology, Columbia University, New York, United States
^h Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, United States

Abstract
Apoptosis is triggered in the developing mammalian brain by sedative, anesthetic or antiepileptic drugs during late gestation and early life. Whether human children are vulnerable to this toxicity mechanism remains unknown, as there are no imaging techniques to capture it. Apoptosis is characterized by distinct structural features, which affect the way damaged tissue scatters ultrasound compared to healthy tissue. We evaluated whether apoptosis, triggered by the anesthetic sevoflurane in the brains of neonatal rhesus macaques, can be detected using quantitative ultrasound (QUS). Neonatal (n = 15) rhesus macaques underwent 5 h of sevoflurane anesthesia. QUS images were obtained through the sagittal suture at 0.5 and 6 h. Brains were collected at 8 h and examined immunohistochemically to analyze apoptotic neuronal and oligodendroglial death. Significant apoptosis was detected in white and gray matter throughout the brain, including the thalamus. We measured a change in the effective scatterer size (ESS), a QUS biomarker derived from ultrasound echo signals obtained with clinical scanners, after sevoflurane-anesthesia in the thalamus. Although initial inclusion of all measurements did not reveal a significant correlation, when outliers were excluded, the change in the ESS between the pre- and post-anesthesia measurements correlated strongly and proportionally with the severity of apoptotic death. We report for the first time in vivo changes in QUS parameters, which may reflect severity of apoptosis in the brains of infant nonhuman primates. These findings suggest that QUS may enable in vivo studies of apoptosis in the brains of human infants following exposure to anesthetics, antiepileptics and other brain injury mechanisms. © 2019 Elsevier Inc.

Author Keywords
Apoptosis;  Brain injury;  Development;  Imaging;  Neonatal;  Primate;  Quantitative ultrasound;  Sevoflurane;  Thalamus

Document Type: Article
Publication Stage: Final
Source: Scopus

Heritability and genetic variance of dementia with Lewy bodies
(2019) Neurobiology of Disease, 127, pp. 492-501. 

Guerreiro, R.^{a b} , Escott-Price, V.^c , Hernandez, D.G.^{d e} , Kun-Rodrigues, C.^a , Ross, O.A.^f , Orme, T.^{a b} , Neto, J.L.^{a b} , Carmona, S.^{a b} , Dehghani, N.^{a b} , Eicher, J.D.^g , Shepherd, C.^h , Parkkinen, L.ⁱ , Darwent, L.^b , Heckman, M.G.^j , Scholz, S.W.^{k l} , Troncoso, J.C.^m , Pletnikova, O.^m , Dawson, T.^l , Rosenthal, L.^l , Ansorge, O.ⁱ , Clarimon, J.ⁿ , Lleo, A.ⁿ , Morenas-Rodriguez, E.^{n ap} , Clark, L.^o , Honig, L.S.^o , Marder, K.^o , Lemstra, A.^p , Rogaeva, E.^q , St. George-Hyslop, P.^{q r} , Londos, E.^s , Zetterberg, H.^t , Barber, I.^u , Braae, A.^u , Brown, K.^u , Morgan, K.^u , Troakes, C.^v , Al-Sarraj, S.^v , Lashley, T.^w , Holton, J.^w , Compta, Y.^{w x} , Van Deerlin, V.^y , Serrano, G.E.^z , Beach, T.G.^z , Lesage, S.^aa , Galasko, D.^ab , Masliah, E.^ac , Santana, I.^ad , Pastor, P.^ae , Diez-Fairen, M.^ae , Aguilar, M.^ae , Tienari, P.J.^af , Myllykangas, L.^ag , Oinas, M.^ah , Revesz, T.^w , Lees, A.^w , Boeve, B.F.^ai , Petersen, R.C.^ai , Ferman, T.J.^aj , Graff-Radford, N.^ak , Cairns, N.J.^al , Morris, J.C.^al , Pickering-Brown, S.^am , Mann, D.^am , Halliday, G.M.^{h an} , Hardy, J.^a , Trojanowski, J.Q.^y , Dickson, D.W.^f , Singleton, A.^d , Stone, D.J.^ao , Bras, J.^{a b} , for the International Parkinson’s Disease Genomics Consortium^aq

^a Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, United Kingdom
^b UK Dementia Research Institute (UK DRI) at UCL, London, United Kingdom
^c UK Dementia Research Institute (UK DRI) at Cardiff, MRC Centre for Neuropsychiatric Genetics and Genomics, School of Medicine, Cardiff University, Cardiff, United Kingdom
^d Laboratory of Neurogenetics, National Institutes on Aging, NIH, Bethesda, MD, United States
^e German Center for Neurodegenerative Diseases (DZNE), Tubingen, Germany
^f Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
^g Genetics and Pharmacogenomics, Merck Research Laboratories, Boston, MA, United States
^h Neuroscience Research Australia, Sydney, Australia and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, Australia
ⁱ Nuffield Department of Clinical Neurosciences, Oxford Parkinsons Disease Centre, University of Oxford, Oxford, United Kingdom
^j Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, United States
^k Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^l Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
^m Department of Pathology (Neuropathology), Johns Hopkins University School of Medicine, Baltimore, MD, United States
ⁿ Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain
^o Taub Institute for Alzheimer Disease and the Aging Brain, Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
^p Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands
^q Tanz Centre for Research in Neurodegenerative Diseases and department of Medicine, University of TorontoOntario, Canada
^r Department of Clinical Neurosciences, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
^s Clinical Memory Research Unit, Institution of Clinical Sciences Malmo, Lund University, Sweden
^t UK Dementia Research Institute at UCL, London UK, Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Molndal, Sweden
^u Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, United Kingdom
^v Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, United Kingdom
^w Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom
^x Queen Square Brain Bank, Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, Movement Disorders Unit, Neurology Service, Clinical Neuroscience Institute (ICN), Hospital Clinic, University of Barcelona, IDIBAPS, Barcelona, Catalonia, Spain
^y Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, 3600 Spruce Street, Philadelphia, United States
^z Banner Sun Health Research Institute, 10515 W Santa Fe Drive, Sun City, AZ 85351, United States
^aa Inserm U1127, CNRS UMR7225, Sorbonne Universites, UPMC Univ Paris 06, UMR and S1127, Institut du Cerveau et de la Moelle epiniere, Paris, France
^ab Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Veterans Affairs San Diego Healthcare System, La Jolla, CA, United States
^ac Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States, Department of Pathology, University of California, San Diego, La Jolla, CA, United States
^ad Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal; Faculty of Medicine and Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
^ae Memory Unit, Department of Neurology,University Hospital Mutua de Terrassa, University of Barcelona, Fundacion de Docencia I Recerca Mutua de Terrassa, Terrassa, Barcelona, Spain, Centro de Investigacion Biomedica en Red Enfermedades Neurdegenerativas (CIBERNED), Madrid, Spain
^af Molecular Neurology, Research Programs Unit, University of Helsinki, Department of Neurology, Helsinki University Hospital, Helsinki, Finland
^ag Department of Pathology, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
^ah Department of Neuropathology and Neurosurgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
^ai Neurology Department, Mayo Clinic, Rochester, MN, United States
^aj Department of Psychiatry and Department of Psychology, Mayo Clinic, Jacksonville, FL, United States
^ak Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^al Knight Alzheimers Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^am Institute of Brain, Behaviour and Mental Health, Faculty of Medical and Human Sciences, University of Manchester, Manchester, United Kingdom
^an Brain and Mind Centre, Sydney Medical School, The University of Sydney, Sydney, Australia
^ao Genetics and Pharmacogenomics, Merck Research Laboratories, West Point, PA, United States
^ap Centro de Investigacion Biomedica en Red en Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

Abstract
Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson’s disease (PD) or Alzheimer’s disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants. © 2019 Elsevier Inc.

Author Keywords
Dementia;  Genetic correlation;  Genetic variance;  Lewy bodies

Document Type: Article
Publication Stage: Final
Source: Scopus

Response Letter Regarding “Utility of CT angiography in screening for traumatic cerebrovascular injury”
(2019) Clinical Neurology and Neurosurgery, 181, p. 53. 

Orlowski, H.L.P., Kansagra, A.P., Miller-Thomas, M.M., Vo, K.D., Goyal, M.S.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Boulevard, St. Louis, MO 63110, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

“We’re All in this Together”: Peer-specialist Contributions to a Healthy Lifestyle Intervention for People with Serious Mental Illness
(2019) Administration and Policy in Mental Health and Mental Health Services Research, 46 (3), pp. 298-310. 

Bochicchio, L.^a , Stefancic, A.^b , Gurdak, K.^b , Swarbrick, M.^c , Cabassa, L.J.^d

^a School of Social Work, Columbia University, 1255 Amsterdam Avenue, New York, NY 10027, United States
^b Department of Psychiatry, Columbia University, 1051 Riverside Dr., Rm 6203, New York, NY 10031, United States
^c Collaborative Support Programs of New Jersey, Rutgers Behavioral Health Care, 11 Spring Street, Freehold, NJ 07728, United States
^d George Warren Brown School of Social Work, Washington University in St. Louis, Campus Box 1196, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
This qualitative study explored peer specialists’ contributions to a healthy lifestyle intervention for obese/overweight individuals with serious mental illness (SMI) living in supportive housing. Intervention participants, peer specialists, and supervisors were interviewed and a grounded model emerged from the data identifying essential interpersonal attributes of the peer specialist-participant relationship. Peer specialists’ disclosure of their own experiences making health behaviors changes was critical for building participants’ motivation and ability to try lifestyle changes. Findings can inform peer specialist training and practice standards and facilitate the expansion of peer-delivered interventions to improve the physical health of people with SMI. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Mental illness;  Peer support;  Physical health;  Qualitative

Document Type: Article
Publication Stage: Final
Source: Scopus

Multiple timescale online learning rules for information maximization with energetic constraints
(2019) Neural Computation, 31 (5), pp. 943-979. 

Yi, P., Ching, S.

Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
A key aspect of the neural coding problem is understanding how representations of afferent stimuli are built through the dynamics of learning and adaptation within neural networks. The infomax paradigm is built on the premise that such learning attempts to maximize the mutual information between input stimuli and neural activities. In this letter, we tackle the problem of such information-based neural coding with an eye toward two conceptual hurdles. Specifically, we examine and then show how this form of coding can be achieved with online input processing. Our framework thus obviates the biological incompatibility of optimization methods that rely on global network awareness and batch processing of sensory signals. Central to our result is the use of variational bounds as a surrogate objective function, an established technique that has not previously been shown to yield online policies. We obtain learning dynamics for both linear-continuous and discrete spiking neural encoding models under the umbrella of linear gaussian decoders. This result is enabled by approximating certain information quantities in terms of neuronal activity via pairwise feedback mechanisms. Furthermore, we tackle the problem of how such learning dynamics can be realized with strict energetic constraints. We show that endowing networks with auxiliary variables that evolve on a slower timescale can allow for the realization of saddle-point optimization within the neural dynamics, leading to neural codes with favorable properties in terms of both information and energy. © 2019 Massachusetts Institute of Technology.

Document Type: Letter
Publication Stage: Final
Source: Scopus

Use of the confusion assessment method in multicentre delirium trials: Training and standardisation
(2019) BMC Geriatrics, 19 (1), art. no. 107, . 

Green, J.R.^a , Smith, J.^a , Teale, E.^a , Collinson, M.^b , Avidan, M.S.^c , Schmitt, E.M.^d , Inouye, S.K.^d , Young, J.^a

^a Academic Unit of Elderly Care and Rehabilitation, Bradford Institute for Health Research Temple Bank House, Bradford Royal Infirmary, Duckworth Lane, Bradford, BD96RJ, United Kingdom
^b Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, United Kingdom
^c Washington University, School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^d Institute for Aging Research Hebrew SeniorLife, Harvard Medical School, 1200 Centre Street, Boston, MA 02131, United States

Abstract
Background: Delirium occurs commonly in older adults and is associated with adverse outcomes. Multicentre clinical trials evaluating interventions to prevent delirium are needed. The Confusion Assessment Method (CAM) is a validated instrument for delirium detection. We hypothesised it would be possible for a large feasibility study to train a large number of research assistants, with varying experience levels, to conduct CAM assessments reliably in multiple hospital sites. Methods: A standardised training programme was followed, incorporating structured training at a central location and at study sites. CAM practice sessions on both delirious and non-delirious patients by research assistants were conducted and, thereafter, there was ongoing inter-rater reliability assessment on the CAM between research assistant pairs at study sites. The setting was eight acute care hospitals in England and Wales. Participants were research assistants working on a multicentre feasibility study of delirium prevention. The measurement used was the Confusion Assessment Method. Results: Thirty-seven research assistants were trained in CAM assessment and 33 returned training logs. The logs showed there was 100% overall agreement between research assistant pairs on 295 CAM assessments, of which 263 (89.2%) were negative for delirium and 32 (10.8%) were positive. In the course of the feasibility study, research assistants successfully completed 5065 (89.7%) of the 5645 expected CAM assessments, with minimal missing data. Conclusion: Using the training methods described in this study, it is possible to achieve high quality delirium assessments for large numbers of patients with little missing data across geographically dispersed sites in multicentre studies. The standardisation of multisite delirium assessments is an important contribution to research methodology, and provides a much-needed advance for the field. Trial registration: ISRCT ISRCTN01187372. Registered 13 March 2014. © 2019 The Author(s).

Author Keywords
Confusion assessment method;  Delirium;  Multicentre studies;  Training

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

Repetitive Transcranial Magnetic Stimulation with Resting-State Network Targeting for Treatment-Resistant Depression in Traumatic Brain Injury: A Randomized, Controlled, Double-Blinded Pilot Study
(2019) Journal of Neurotrauma, 36 (8), pp. 1361-1374. 

Siddiqi, S.H.^{a b c} , Trapp, N.T.^f , Hacker, C.D.^d , Laumann, T.O.^c , Kandala, S.^c , Hong, X.^e , Trillo, L.^c , Shahim, P.^b , Leuthardt, E.C.^d , Carter, A.R.^e , Brody, D.L.^{b e}

^a Department of Neurology, McLean Hospital, 115 Mill Street, Belmont, MA 02478, United States
^b Center for Neuroscience and Regenerative Medicine, National Institutes of Health, Uniformed Services University of Health Sciences Traumatic Brain Injury Research Group, Bethesda, MD, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Psychiatry, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IA, United States

Abstract
Repetitive transcranial magnetic stimulation (rTMS) has demonstrated antidepressant efficacy but has limited evidence in depression associated with traumatic brain injury (TBI). Here, we investigate the use of rTMS targeted with individualized resting-state network mapping (RSNM) of dorsal attention network (DAN) and default mode network (DMN) in subjects with treatment-resistant depression associated with concussive or moderate TBI. The planned sample size was 50 with first interim analysis planned at 20, but only 15 were enrolled before the study was terminated for logistical reasons. Subjects were randomized to 20 sessions of bilateral rTMS (4000 left-sided excitatory pulses, 1000 right-sided inhibitory pulses) or sham. Treatment was targeted to the dorsolateral prefrontal cluster with maximal difference between DAN and DMN correlations based on resting-state functional magnetic resonance imaging with individualized RSNM. Mean improvement in the primary outcome, Montgomery-Asberg Depression Rating Scale (MADRS), was 56% ± 14% (n = 9) with active treatment and 27% ± 25% (n = 5) with sham (Cohen’s d = 1.43). One subject randomized to sham withdrew before starting treatment. There were no seizures or other significant adverse events. MADRS improvement was inversely correlated with functional connectivity between the right-sided stimulation site and the subgenual anterior cingulate cortex (sgACC; r = -0.68, 95% confidence interval 0.03-0.925). Active treatment led to increased sgACC-DMN connectivity (d = 1.55) and increased sgACC anti-correlation with the left- and right-sided stimulation sites (d = -1.26 and -0.69, respectively). This pilot study provides evidence that RSNM-targeted rTMS is feasible in TBI patients with depression. Given the dearth of existing evidence-based treatments for depression in this patient population, these preliminarily encouraging results indicate that larger controlled trials are warranted. © Copyright 2019, Mary Ann Liebert, Inc.

Author Keywords
depression;  fMRI;  rTMS;  TBI

Document Type: Article
Publication Stage: Final
Source: Scopus

The macaque cerebellar flocculus outputs a forward model of eye movement
(2019) Frontiers in Integrative Neuroscience, 13, art. no. 12, . 

Kim, G.^a , Laurens, J.^b , Yakusheva, T.A.^a , Blazquez, P.M.^a

^a Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States

Abstract
The central nervous system (CNS) achieves fine motor control by generating predictions of the consequences of the motor command, often called forward models of the movement. These predictions are used centrally to detect not-self generated sensations, to modify ongoing movements, and to induce motor learning. However, finding a neuronal correlate of forward models has proven difficult. In the oculomotor system, we can identify neuronal correlates of forward models vs. neuronal correlates of motor commands by examining neuronal responses during smooth pursuit at eccentric eye positions. During pursuit, torsional eye movement information is not present in the motor command, but it is generated by the mechanic of the orbit. Importantly, the directionality and approximate magnitude of torsional eye movement follow the half angle rule. We use this rule to investigate the role of the cerebellar flocculus complex (FL, flocculus and ventral paraflocculus) in the generation of forward models of the eye. We found that mossy fibers (input elements to the FL) did not change their response to pursuit with eccentricity. Thus, they do not carry torsional eye movement information. However, vertical Purkinje cells (PCs; output elements of the FL) showed a preference for counter-clockwise (CCW) eye velocity [corresponding to extorsion (outward rotation) of the ipsilateral eye]. We hypothesize that FL computes an estimate of torsional eye movement since torsion is present in PCs but not in mossy fibers. Overall, our results add to those of other laboratories in supporting the existence in the CNS of a predictive signal constructed from motor command information. © 2019 Kim, Laurens, Yakusheva and Blazquez.

Author Keywords
Cerebellar interneurons;  Cerebellum;  Forward models;  Mossy fibers;  Motor control;  Oculomotor;  Purkinje cell

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

A survey of risk tolerance to multiple sclerosis therapies
(2019) Neurology, 92 (14), pp. e1634-e1642. 

Fox, R.J., Cosenza, C., Cripps, L., Ford, P., Mercer, M., Natarajan, S., Salter, A., Tyry, T., Cofield, S.S.

From the Mellen Center for Multiple Sclerosis, (R.J.F., S.N.), Department of Bioethics (P.F.), and Department of Bioethics (M.M.), Cleveland Clinic, OH; Center for Survey Research (C.C., L.C.), University of Massachusetts, Boston; Division of Biostatistics (A.S.), Washington University School of Medicine, St. Louis, MO; Dignity Health (T.T.), St. Joseph’s Hospital and Medical Center, Phoenix, AZ; and Department of Biostatistics (S.S.C.), School of Public Health, University of Alabama, Birmingham

Abstract
OBJECTIVE: To determine tolerance to various risk scenarios associated with current multiple sclerosis (MS) therapies. METHODS: People with MS from the North American Research Committee on Multiple Sclerosis Registry’s online cohort and the National Multiple Sclerosis Society were invited to complete a questionnaire on tolerance to real-world risks associated with a hypothetical therapy. Multiple risks levels were presented, including skin rash, infection, kidney injury, thyroid injury, liver injury, and progressive multifocal leukoencephalopathy (PML). RESULTS: Both PML and kidney injury had the lowest risk tolerance (RT) at 1:1,000,000, and thyroid and infection risks had the highest tolerance at 1:1,000. Men, younger individuals, and participants with greater disability reported a higher tolerance to all risk scenarios. Those who were currently taking an MS therapy reported higher tolerance than those not taking any therapy. Participants taking infusion therapies reported high tolerance to all risks, and those taking injectables reported a lower tolerance. CONCLUSION: People with MS displayed a wide range of RT for MS therapies. Our study identified sex, age, disability, and current disease-modifying therapy use to be associated with RT. Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

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

ATN profiles among cognitively normal individuals and longitudinal cognitive outcomes
(2019) Neurology, 92 (14), pp. e1567-e1579. 

Soldan, A., Pettigrew, C., Fagan, A.M., Schindler, S.E., Moghekar, A., Fowler, C., Li, Q.-X., Collins, S.J., Carlsson, C., Asthana, S., Masters, C.L., Johnson, S., Morris, J.C., Albert, M., Gross, A.L.

From the Department of Neurology (A.S., C.P., A.M., M.A.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Neurology (A.M.F., S.E.S., J.C.M.), Washington University School of Medicine, St. Louis, MO; Florey Institute of Neuroscience and Mental Health (C.F., Q.-X.L., S.J.C., C.L.M.), the University of Melbourne, Australia; Geriatric Research Education and Clinical Center (C.C., S.A., S.J.), Wm. S. Middleton Memorial VA Hospital and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison; and Center on Aging and Health and Department of Epidemiology (A.L.G.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

Abstract
OBJECTIVE: To examine the long-term cognitive trajectories of individuals with normal cognition at baseline and distinct amyloid/tau/neurodegeneration (ATN) profiles. METHODS: Pooling data across 4 cohort studies, 814 cognitively normal participants (mean baseline age = 59.6 years) were classified into 8 ATN groups using baseline CSF levels of β-amyloid 1-42 as a measure of amyloid (A), phosphorylated tau 181 as a measure of tau (T), and total tau as a measure of neurodegeneration (N). Cognitive performance was measured using a previously validated global factor score and with the Mini-Mental State Examination. We compared the cognitive trajectories across groups using growth curve models (mean follow-up time = 7 years). RESULTS: Using different model formulations and cut points for determining biomarker abnormality, only the group with abnormal levels of amyloid, tau, and neurodegeneration (A+T+N+) showed consistently greater cognitive decline than the group with normal levels of all biomarkers (A-T-N-). Replicating prior findings using the 2011 National Institute on Aging-Alzheimer’s Association/suspected non-Alzheimer disease pathophysiology schema, only individuals with abnormal levels of both amyloid and phosphorylated tau 181 or total tau (stage 2) showed greater cognitive decline than those with normal biomarker levels (stage 0). CONCLUSION: The results are consistent with the hypothesis that both elevated brain amyloid and neurofibrillary tangles are necessary to observe accelerated neurodegeneration, which in turn leads to cognitive decline. © 2019 American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Pharmacological activation of the nuclear receptor REV-ERB reverses cognitive deficits and reduces amyloid-β burden in a mouse model of Alzheimer’s disease
(2019) PLoS ONE, 14 (4), art. no. e0215004, . 

Roby, D.A.^a , Ruiz, F.^a , Kermath, B.A.^a , Voorhees, J.R.^b , Niehoff, M.^c , Zhang, J.^a , Morley, J.E.^c , Musiek, E.S.^d , Farr, S.A.^{a c} , Burris, T.P.^b

^a Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, United States
^b Center for Clinical Pharmacology, Washington University School of Medicine and St. Louis College of Pharmacy, St. Louis, MO, United States
^c Department of Internal Medicine, Saint Louis University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Alzheimer’s disease currently lacks treatment options that effectively reverse the biological/ anatomical pathology and cognitive deficits associated with the disease. Loss of function of the nuclear receptor REV-ERB is associated with reduced cognitive function in mouse models. The effect of enhanced REV-ERB activity on cognitive function has not been examined. In this study, we tested the hypothesis that enhanced REV-ERB function may enhance cognitive function in a model of Alzheimer’s disease. We utilized the REV-ERB agonist SR9009 to pharmacologically activate the activity of REV-ERB in the SAMP8 mouse model of Alzheimer’s disease. SR9009 reversed cognitive dysfunction of an aged SAMP8 mouse in several behavioral assays including novel object recognition, T-maze foot shock avoidance, and lever press operant conditioning task assessments. SR9009 treatment reduced amyloid-β 1-40 and 1-42 levels in the cortex, which is consistent with improved cognitive function. Furthermore, SR9009 treatment led to increased hippocampal PSD-95, cortical synaptophysin expression and the number of synapses suggesting improvement in synaptic function. We conclude that REV-ERB is a potential target for treatment of Alzheimer’s disease. © 2019 Roby 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

Sex differences in eating related behaviors and psychopathology among adolescent military dependents at risk for adult obesity and eating disorders
(2019) Eating Behaviors, 33, pp. 73-77. 

Quattlebaum, M.^a , Burke, N.L.^b , Higgins Neyland, M.K.^a , Leu, W.^a , Schvey, N.A.^{a c} , Pine, A.^a , Morettini, A.^a , LeMay-Russell, S.^{a c} , Wilfley, D.E.^d , Stephens, M.^e , Sbrocco, T.^a , Yanovski, J.A.^c , Jorgensen, S.^f , Olsen, C.^a , Klein, D.^{a f} , Quinlan, J.^a , Tanofsky-Kraff, M.^{a c}

^a Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814, United States
^b Psychology Department, Fordham University, 441 E. Fordham Road, Bronx, NY 10458, United States
^c Section on Growth and Obesity, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20814, United States
^d Washington University in St. Louis, 1 Brookings Drive, St. Louis, MO 63130, United States
^e Pennsylvania State University, Old Main, State College, PA 16801, United States
^f Fort Belvoir Community Hospital (FBCH), 9300 DeWitt Loop, Fort Belvoir, VA 22060, United States

Abstract
Stressors unique to military families may place dependents of military service members of both sexes at high-risk for disordered-eating. Yet, there are no data examining sex-related differences in eating pathology and distress among this population. Therefore, we examined disordered-eating attitudes and associated psychosocial characteristics in adolescent military dependents at high-risk for both eating disorders and adult obesity (i.e., BMI ≥ 85th percentile and elevated anxiety symptoms and/or loss-of-control eating). One-hundred-twenty-five (55.2% female) adolescent (12–17 y) military dependents were studied prior to entry in an eating disorder and obesity prevention trial. Youth were administered the Eating Disorder Examination interview to determine disordered-eating attitudes, and completed questionnaires to assess self-esteem, social functioning, and depression. Girls and boys did not differ in BMIz (p =.66) or race/ethnicity (p =.997/p =.55). Adjusting for relevant covariates, girls and boys did not differ significantly with regard to disordered-eating global scores (p =.38), self-esteem (p =.23), or social functioning (p =.19). By contrast, girls reported significantly more symptoms of depression (p =.001). Adolescent male and female dependents at high-risk for eating disorders and adult obesity reported comparable levels of eating-related and psychosocial stress. Data are needed to elucidate how adolescent military dependents respond to intervention and whether sex moderates outcome. © 2019 Elsevier Ltd

Author Keywords
Adolescent military dependents;  Disordered-eating;  Psychosocial functioning;  Sex

Document Type: Article
Publication Stage: Final
Source: Scopus

A Mixture of U.S. Food and Drug Administration-Approved Monoaminergic Drugs Protects the Retina From Light Damage in Diverse Models of Night Blindness
(2019) Investigative ophthalmology & visual science, 60 (5), pp. 1442-1453. 

Leinonen, H.^{a b} , Choi, E.H.^{a b} , Gardella, A.^c , Kefalov, V.J.^d , Palczewski, K.^{a b}

^a Gavin Herbert Eye Institute and the Department of Ophthalmology, University of California-Irvine, Irvine, CA, United States
^b Department of Pharmacology, Case Western Reserve University, Cleveland, OH, United States
^c Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH, United States
^d Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States

Abstract
Purpose: The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors. Methods: Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and tamsulosin (α1-receptor antagonist) before bright light exposure. Light damage was primarily assessed with optical coherence tomography and inspection of cone population in retinal whole mounts. Retinal inflammation was assessed in a subset of experiments using autofluorescence imaging by scanning laser ophthalmoscopy and by postmortem inspection of microglia and astrocyte activity. Results: The Gnat1-/- mice showed slightly increased susceptibility to rod light damage, whereas the Gnat2-/- mice were very resistant. The Arr1-/- and Grk1-/- mice were sensitive for both rod and cone light damage and showed robust retinal inflammation 7 days after bright light exposure. Pretreatment with metoprolol + bromocriptine + tamsulosin rescued the retina in all genetic backgrounds, starting at doses of 0.2 mg/kg metoprolol, 0.02 mg/kg bromocriptine, and 0.01 mg/kg tamsulosin in the Gnat1-/- mice. The therapeutic drug doses increased in parallel with light-damage severity. Conclusions: Our results suggest that congenital stationary night blindness and Oguchi disease patients can be at an elevated risk of the toxic effects of bright light. Furthermore, systems pharmacology drug regimens that stimulate Gi signaling and attenuate Gs and Gq signaling present a promising disease-modifying therapy for photoreceptor degenerative diseases.

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

Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones
(2019) FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33 (4), pp. 5782-5792. 

Kiser, P.D.^{a b} , Kolesnikov, A.V.^c , Kiser, J.Z.^b , Dong, Z.^d , Chaurasia, B.^{e f} , Wang, L.^{e f} , Summers, S.A.^{e f} , Hoang, T.^g , Blackshaw, S.^g , Peachey, N.S.^{a h} , Kefalov, V.J.^c , Palczewski, K.^{b i}

^a Research Service, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, United States
^b Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^c Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
^d Polgenix Incorporated, Cleveland, OH, United States
^e Department of Nutrition and Integrative Physiology (NUIP), University of Utah, Salt Lake City, UT, United States
^f Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT, United States
^g Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Cole Eye Institute, Cleveland Clinic, Cleveland, OH, United States
ⁱ Department of Ophthalmology, Gavin Herbert Eye Institute, University of California-Irvine, School of Medicine, Irvine, CA, United States

Abstract
Cone photoreceptors are essential for vision under moderate to high illuminance and allow color discrimination. Their fast dark adaptation rate and resistance to saturation are believed to depend in part on an intraretinal visual cycle that supplies 11- cis-retinaldehyde to cone opsins. Candidate enzymes of this pathway have been reported, but their physiologic contribution to cone photoresponses remains unknown. Here, we evaluate the role of a candidate retinol isomerase of this pathway, sphingolipid δ4 desaturase 1 (Des1). Single-cell RNA sequencing analysis revealed Des1 expression not only in Müller glia but also throughout the retina and in the retinal pigment epithelium. We assessed cone functional dependence on Müller cell-expressed Des1 through a conditional knockout approach. Floxed Des1 mice, on a guanine nucleotide-binding protein subunit α transducin 1 knockout ( Gnat1-/-) background to allow isolated recording of cone-driven photoresponses, were bred with platelet-derived growth factor receptor α (Pdgfrα)-Cre mice to delete Des1 in Müller cells. Conditional knockout of Des1 expression, as shown by tissue-selective Des1 gene recombination and reduced Des1 catalytic activity, caused no gross changes in the retinal structure and had no effect on cone sensitivity or dark adaptation but did slightly accelerate the rate of cone phototransduction termination. These results indicate that Des1 expression in Müller cells is not required for cone visual pigment regeneration in the mouse.-Kiser, P. D., Kolesnikov, A.V., Kiser, J. Z., Dong, Z., Chaurasia, B., Wang, L., Summers, S. A., Hoang, T., Blackshaw, S., Peachey, N. S., Kefalov, V. J., Palczewski, K. Conditional deletion of Des1 in the mouse retina does not impair the visual cycle in cones.

Author Keywords
Müller glia;  photoreceptor;  retinoid cycle;  sphingolipidδ(4) desaturase

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluation of pediatric glioma outcomes using intraoperative MRI: a multicenter cohort study
(2019) Journal of Neuro-Oncology, . 

Karsy, M.^a , Akbari, S.H.^b , Limbrick, D.^b , Leuthardt, E.C.^b , Evans, J.^b , Smyth, M.D.^b , Strahle, J.^b , Leonard, J.^c , Cheshier, S.^a , Brockmeyer, D.L.^a , Bollo, R.J.^a , Kestle, J.R.^a , Honeycutt, J.^d , Donahue, D.J.^d , Roberts, R.A.^d , Hansen, D.R.^d , Riva-Cambrin, J.^e , Sutherland, G.^e , Gallagher, C.^e , Hader, W.^e , Starreveld, Y.^e , Hamilton, M.^e , Duhaime, A.-C.^f , Jensen, R.L.^{a g} , Chicoine, M.R.^b

^a Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^d Department of Neurosurgery, Cook Children’s Neurosciences, Forth Worth, TX, United States
^e Department of Neurosurgery, University of Calgary, Calgary, AB, Canada
^f Department of Neurosurgery, Massachusetts General Hospital for Children, Boston, MA, United States
^g Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States

Abstract
Background: The use of intraoperative MRI (iMRI) during treatment of gliomas may increase extent of resection (EOR), decrease need for early reoperation, and increase progression-free and overall survival, but has not been fully validated, particularly in the pediatric population. Objective: To assess the accuracy of iMRI to identify residual tumor in pediatric patients with glioma and determine the effect of iMRI on decisions for resection, complication rates, and other outcomes. Methods: We retrospectively analyzed a multicenter database of pediatric patients (age ≤ 18 years) who underwent resection of pathologically confirmed gliomas. Results: We identified 314 patients (mean age 9.7 ± 4.6 years) with mean follow-up of 48.3 ± 33.6 months (range 0.03–182.07 months) who underwent surgery with iMRI. There were 201 (64.0%) WHO grade I tumors, 57 (18.2%) grade II, 24 (7.6%) grade III, 9 (2.9%) grade IV, and 23 (7.3%) not classified. Among 280 patients who underwent resection using iMRI, 131 (46.8%) had some residual tumor and underwent additional resection after the first iMRI. Of the 33 tissue specimens sent for pathological analysis after iMRI, 29 (87.9%) showed positive tumor pathology. Gross total resection was identified in 156 patients (55.7%), but this was limited by 69 (24.6%) patients with unknown EOR. Conclusions: Analysis of the largest multicenter database of pediatric gliomas resected using iMRI demonstrated additional tumor resection in a substantial portion of cases. However, determining the impact of iMRI on EOR and outcomes remains challenging because iMRI use varies among providers nationally. Continued refinement of iMRI techniques for use in pediatric patients with glioma may improve outcomes. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Extent of resection;  Glioma;  iMRI;  Intraoperative MRI;  Outcome;  Pediatric;  WHO grade;  World Health of Organization

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

Fifty Shades of Microglia
(2019) Trends in Neurosciences, . 

Brioschi, S., Peng, V., Colonna, M.

Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In a recent study, Masuda and colleagues (Nature 2019;566:388–392) used single-cell RNA-sequencing (scRNA-seq) to profile microglia across different anatomical compartments, developmental stages, and types of brain pathology in mice. Moreover, the authors performed a novel transcriptomic characterization of microglia from multiple sclerosis patients and identified phenotypically conserved microglial subsets between species. These findings, together with seminal prior results from various groups, provide valuable insights into the spatiotemporal heterogeneity of microglia during brain development and disease. © 2019 Elsevier Ltd

Author Keywords
cuprizone model;  facial nerve axotomy;  microglial transcriptomic signature;  mouse and human microglia;  multiple sclerosis;  single-cell RNA sequencing

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

An integrative model and dynamic nosology of personality disorder: Part 2: Symptom-based pharmacotherapy
(2019) Psychiatria Danubina, 31 (1), pp. 2-17. 

Svrakic, D.^a , Divac-Jovanovic, M.^b , Azhar, N.^a

^a Department of Psychiatry, VA medical center St Louis, Washington University School of Medicine, St Louis, MO, United States
^b Department of Psychology, Faculty for Media and Communication, Singidunum University, Belgrade, Serbia

Abstract
This paper presents an integrative model of personality and personality disorder which incorporates psychoanalytic concepts with modern neuroscience. In addition, a dynamic, personalized, and context – and time-sensitive diagnosis of personality disorder is introduced. The authors cogently argue that all clinical variants of personality disorder share the same common deficit: fragmented basic units of experience at the nonconscious core of the mind (aka “partial object relations”). The fragmentation propagates through mental faculties (thought, motivation, emotion), as they self-organize into subsystems of personality, e.g., one’s sense of self, identity, character, moral values, rendering them polarized into extreme and thus adaptively suboptimal. The syndrome of personality disorder arises as a nonconscious compensatory maneuver of the fragmented mind to organize itself through a defensive but unrealistic self-image (e.g., narcissistic, schizoid, antisocial, etc.), giving rise to a host of unique symptoms. Symptomatic pharmacotherapy of personality disorder is best organized around four empirically derived domains of symptoms, shared by all variants to a variable degree: i) mood and anxiety dysregulation; ii) impulsivity, aggression, and behavior dyscontrol; iii) emotional disinterest and detachment; and iv) cognitive distortions and brief reactive psychoses. Pharmacotherapy targeting the above domains is nonspecific, as medications affect multiple domains simultaneously. Modest empirical evidence and considerable clinical benefits continue to support the use of medications in the overall symptomatic treatment of personality disorder. © Medicinska naklada – Zagreb, Croatia.

Author Keywords
Character;  Integrative model;  Personality disorder;  Pharmacotherapy;  Temperament

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

Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma
(2019) Journal of Neuro-Oncology, . 

Kim, M.M.^a , Speers, C.^a , Li, P.^a , Schipper, M.^a , Junck, L.^b , Leung, D.^b , Orringer, D.^c , Heth, J.^c , Umemura, Y.^b , Spratt, D.E.^a , Wahl, D.R.^a , Cao, Y.^a , Lawrence, T.S.^a , Tsien, C.I.^d

^a Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, United States
^b Department of Neurology, University of Michigan, Ann Arbor, MI, United States
^c Department of Neurosurgery, University of Michigan, Ann Arbor, MI, United States
^d Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background and purpose: We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era. Materials and methods: Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66–81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan–Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression. Results: Median follow-up was 23 months (95% CI 4–124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3–11.0) and OS was 18.7 months (95% CI 13.1–25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93–0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16–0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16–0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09–0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival. Conclusion: Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Dose-escalation;  Glioblastoma;  Outcomes;  Patterns of failure;  Radiation

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

Brain Heterogeneity in Schizophrenia and Its Association with Polygenic Risk
(2019) JAMA Psychiatry, . Cited 1 time.

Alnæs, D.^a , Kaufmann, T.^a , Van Der Meer, D.^a , Córdova-Palomera, A.^a , Rokicki, J.^a , Moberget, T.^a , Bettella, F.^a , Agartz, I.^{a b} , Barch, D.M.^c , Bertolino, A.^d , Brandt, C.L.^a , Cervenka, S.^b , Djurovic, S.^{a e} , Doan, N.T.^a , Eisenacher, S.^f , Fatouros-Bergman, H.^b , Flyckt, L.^b , Di Giorgio, A.^{d g} , Haatveit, B.^a , Jönsson, E.G.^{a b} , Kirsch, P.^{f h} , Lund, M.J.^a , Meyer-Lindenberg, A.^{f h} , Pergola, G.^d , Schwarz, E.^f , Smeland, O.B.^a , Quarto, T.^d , Zink, M.^f , Andreassen, O.A.^a , Westlye, L.T.^{a i}

^a Norwegian Centre for Mental Disorders Research, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo, Norway
^b Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
^c Department of Psychological and Brain Sciences, Washington University in Saint Louis, St Louis, MO, United States
^d Psychiatric Neuroscience Group, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
^e Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
^f Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
^g Fondazione Istituto di Ricovero e Cura A Carattere Scientifico Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
^h Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
ⁱ Department of Psychology, University of Oslo, Oslo, Norway

Abstract
Importance: Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature. Objectives: To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. Design, Setting, and Participants: This case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank. Data were collected from October 27, 2004, through April 12, 2018, and analyzed from December 3, 2017, through August 1, 2018. Main Outcomes and Measures: Mean and dispersion parameters were estimated using double generalized linear models. Vertex-wise analysis was used to assess cortical thickness, and regions-of-interest analyses were used to assess total cortical volume, total surface area, and white matter, subcortical, and hippocampal subfield volumes. Follow-up analyses included within-sample analysis, test of robustness of the PRS threshold, population covariates, outlier removal, and control for image quality. Results: A comparison of 1151 patients with schizophrenia (mean [SD] age, 33.8 [10.6] years; 68.6% male [n = 790] and 31.4% female [n = 361]) with 2010 healthy controls (mean [SD] age, 32.6 [10.4] years; 56.0% male [n = 1126] and 44.0% female [n = 884]) revealed higher heterogeneity in schizophrenia for cortical thickness and area (t = 3.34), cortical (t = 3.24) and ventricle (t range, 3.15-5.78) volumes, and hippocampal subfields (t range, 2.32-3.55). In the UK Biobank sample of 12 490 participants (mean [SD] age, 55.9 [7.5] years; 48.2% male [n = 6025] and 51.8% female [n = 6465]), higher PRS was associated with thinner frontal and temporal cortices and smaller left CA2/3 (t = -3.00) but was not significantly associated with dispersion. Conclusions and Relevance: This study suggests that schizophrenia is associated with substantial brain structural heterogeneity beyond the mean differences. These findings may reflect higher sensitivity to environmental and genetic perturbations in patients, supporting the heterogeneous nature of schizophrenia. A higher PRS was associated with thinner frontotemporal cortices and smaller hippocampal subfield volume, but not heterogeneity. This finding suggests that brain variability in schizophrenia results from interactions between environmental and genetic factors that are not captured by the PRS. Factors contributing to heterogeneity in frontotemporal cortices and hippocampus are key to furthering our understanding of how genetic and environmental factors shape brain biology in schizophrenia. © 2019 AMA-AIP. All Rights Reserved.

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

Strabismus surgery in the setting of glaucoma drainage devices in the pediatric population
(2019) Journal of AAPOS, . 

Lee, A.R.^a , Talsania, S.D.^b , Go, M.^c , Freedman, S.F.^c

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO, United States
^b Eye Surgery Associates, Hollywood, FL, United States
^c Department of Ophthalmology, Duke University Medical Center, Durham, NC, United States

Abstract
Purpose: To evaluate outcomes of strabismus surgery performed subequent to or concomitant with glaucoma drainage device (GDD) implantation for refractory childhood glaucoma. Methods: The medical records of children who underwent strabismus surgery after or concomitantly with GDD implantation were reviewed retrospectively. Included were surgeries with motility and alignment data measured preoperatively and ≥3 months postoperatively. The following data were collected: demographics, visual acuity, glaucoma diagnosis, GDD type/location, pre- and postoperative sensorimotor/alignment measurements, and surgical details. Motor success was defined as ≤10 Δ horizontal and ≤4 Δ vertical residual heterotropia postoperatively. Results: A total of 25 children were included: 11 in the post-GDD group and 14 in the concomitant-GDD group. In the former, peri-GDD capsule dissection was required in 9 of 11 patients (82%). All cases had preoperative motility restriction or intraoperative scarring. Mean preoperative deviation (26.7 Δ ± 14.6 Δ ) decreased by 41% postoperatively, with improved alignment in 7 patients (64%). No patients met strict motor alignment criteria for success. In the concomitant-GDD group, mean preoperative deviation (28.5 Δ ± 10.0 Δ ) decreased by 39% postoperatively, with improved alignment in 11 of 14 patients (79%). Four patients (29%) met strict criteria for success. There were no surgical complications in either group. Conclusions: Strabismus surgery in eyes with existing or planned GDDs for childhood glaucoma usually improves alignment but often does not result in success based on strict motor alignment criteria. Eyes with childhood glaucoma pose surgical technical challenges related to small orbits and exuberant GDD capsule–muscle scarring and postoperative challenges of poor vision and limited binocular function, that likely limit succcess. © 2019 American Association for Pediatric Ophthalmology and Strabismus

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

Nanoscale Organization of Vesicle Release at Central Synapses
(2019) Trends in Neurosciences, . 

Gramlich, M.W.^{a b} , Klyachko, V.A.^a

^a Department of Cell Biology and Physiology, Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, United States
^b Present address: Department of Physics, Auburn University, Auburn, AL, United States

Abstract
Presynaptic boutons support neurotransmitter release with nanoscale precision at sub-millisecond timescales. Studies over the past two decades have revealed a rich tapestry of molecular players governing synaptic vesicle fusion at highly specialized release sites in the active zone (AZ). However, the spatiotemporal organization of release at active synapses remains elusive, in part owing to the extremely small size of the AZ and the limited resolution of conventional approaches. Recent advances in fluorescence nanoscopy have revolutionized direct investigation of presynaptic release organization and dynamics. We discuss here recent nanoscopy-based studies of the molecular architecture, the spatial organization and dynamic regulation of release sites, and the mechanisms of release site replenishment. These findings have uncovered previously unknown levels of structural and functional organization at central synapses, with important implications for synaptic transmission and plasticity. © 2019

Author Keywords
nanoscopy;  neurotransmitter release;  release sites;  super-resolution microscopy;  synaptic transmission;  vesicle recycling

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

Variants in DOCK3 cause developmental delay and hypotonia
(2019) European Journal of Human Genetics, . 

Wiltrout, K.^a , Ferrer, A.^b , van de Laar, I.^c , Namekata, K.^d , Harada, T.^d , Klee, E.W.^b , Zimmerman, M.T.^e , Cousin, M.A.^b , Kempainen, J.L.^f , Babovic-Vuksanovic, D.^f , van Slegtenhorst, M.A.^c , Aarts-Tesselaar, C.D.^g , Schnur, R.E.^h , Andrews, M.ⁱ , Shinawi, M.ⁱ

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
^c Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
^d Visual Research Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
^e Genomics Sciences & Precision Medicine Center, Medical College of Wisconsin, Milwaukee, WI, United States
^f Department of Clinical Genomics, Mayo Clinic, Rochester, MN, United States
^g Department of Pediatrics, Amphia Hospital, Breda, Netherlands
^h GeneDx, Gaithersburg, MD, United States
ⁱ Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The DOCK3 gene encodes the Dedicator of cytokinesis 3 (DOCK3) protein, which belongs to the family of guanine nucleotide exchange factors and is expressed almost exclusively in the brain and spinal cord. We used whole exome sequencing (WES) to investigate the molecular cause of developmental delay and hypotonia in three unrelated probands. WES identified truncating and splice site variants in Patient 1 and compound heterozygous and homozygous missense variants in Patients 2 and 3, respectively. We studied the effect of the three missense variants in vitro by using site-directed mutagenesis and pull-down assay and show that the induction of Rac1 activation was significantly lower in DOCK3 mutant cells compared with wild type human DOCK3 (P < 0.05). We generated a protein model to further examine the effect of the two missense variants within or adjacent to the DHR-2 domain in DOCK3 and this model supports pathogenicity. Our results support a loss of function mechanism but the data on the patients with missense variants should be cautiously interpreted because of the variability of the phenotypes and limited number of cases. Prior studies have described DOCK3 bi-allelic loss of function variants in two families with ataxia, hypotonia, and developmental delay. Here, we report on three patients with DOCK3-related developmental delay, wide-based or uncoordinated gait, and hypotonia, further supporting DOCK3’s role in a neurodevelopmental syndrome and expanding the spectrum of phenotypic and genotypic variability. © 2019, European Society of Human Genetics.

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

The role of the voltage-gated potassium channel proteins Kv8.2 and Kv2.1 in vision and retinal disease: Insights from the study of mouse gene knock-out mutations
(2019) eNeuro, 6 (1), art. no. e0032-19.2019, . Cited 1 time.

Hart, N.S.^{a d} , Mountford, J.K.^{a b} , Voigt, V.^b , Fuller-Carter, P.^b , Barth, M.^{b e} , Nerbonne, J.M.^c , Hunt, D.M.^{a b} , Carvalho, L.S.^b

^a School of Biological Sciences, The University of Western Australia, Perth, WA 6009, Australia
^b Centre for Ophthalmology and Vision Science, Lions Eye Institute, The University of Western Australia, Perth, WA 6009, Australia
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Biological Sciences, Macquarie University, Sydney, NSW 2109, Australia
^e German Center for Neurodegenerative Diseases (DZNE), Bonn, 53127, Germany

Abstract
Mutations in the KCNV2 gene, which encodes the voltage-gated K + channel protein Kv8.2, cause a distinctive form of cone dystrophy with a supernormal rod response (CDSRR). Kv8.2 channel subunits only form functional channels when combined in a heterotetramer with Kv2.1 subunits encoded by the KCNB1 gene. The CDSRR disease phenotype indicates that photoreceptor adaptation is disrupted. The electroretinogram (ERG) response of affected individuals shows depressed rod and cone activity, but what distinguishes this disease is the supernormal rod response to a bright flash of light. Here, we have utilized knock-out mutations of both genes in the mouse to study the pathophysiology of CDSRR. The Kv8.2 knock-out (KO) mice show many similarities to the human disorder, including a depressed a-wave and an elevated b-wave response with bright light stimulation. Optical coherence tomography (OCT) imaging and immunohistochemistry indicate that the changes in six-month-old Kv8.2 KO retinae are largely limited to the outer nuclear layer (ONL), while outer segments appear intact. In addition, there is a significant increase in TUNEL-positive cells throughout the retina. The Kv2.1 KO and double KO mice also show a severely depressed a-wave, but the elevated b-wave response is absent. Interestingly, in all three KO genotypes, the c-wave is totally absent. The differential response shown here of these KO lines, that either possess homomeric channels or lack channels completely, has provided further insights into the role of K + channels in the generation of the a-, b-, and c-wave components of the ERG. © 2019 Hart et al.

Author Keywords
Cone dystrophy;  Electroretinogram;  Photoreceptors;  Potassium channels;  Retina;  Retinal degeneration

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