WashU weekly Neuroscience publications

Untangling a canopy of spinal itch circuits
(2019) Pain, 160 (5), pp. 987-988. 

Grajales-Reyes, J.G.^{a b c} , Samineni, V.K.^{a c}

^a Division of Basic Research, Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO, United States
^b Medical Scientist Training Program, Washington University in St. Louis, St. Louis, MO, United States
^c Washington University Pain Center, Washington University in St. Louis, St. Louis, MO, United States

Document Type: Article
Publication Stage: Final
Source: Scopus

Mutant huntingtin enhances activation of dendritic Kv4 K + channels in striatal spiny projection neurons
(2019) eLife, 8, . 

Carrillo-Reid, L.^{a b} , Day, M.^a , Xie, Z.^a , Melendez, A.E.^a , Kondapalli, J.^a , Plotkin, J.L.^{a c} , Wokosin, D.L.^a , Chen, Y.^a , Kress, G.J.^{a d} , Kaplitt, M.^e , Ilijic, E.^a , Guzman, J.N.^a , Chan, S.S.^a , Surmeier, D.J.^a

^a Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, United States
^b Department of Developmental Neurobiology and Neurophysiology, Neurobiology Institute, National Autonomous University of MexicoQueretaro, Mexico
^c Department of Neurobiology & Behavior, Stony Brook University School of Medicine, Stony Brook, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, United States
^e Department of Neurological Surgery, Weill Cornell Medical CollegeNY, United States

Abstract
Huntington’s disease (HD) is initially characterized by an inability to suppress unwanted movements, a deficit attributable to impaired synaptic activation of striatal indirect pathway spiny projection neurons (iSPNs). To better understand the mechanisms underlying this deficit, striatal neurons in ex vivo brain slices from mouse genetic models of HD were studied using electrophysiological, optical and biochemical approaches. Distal dendrites of iSPNs from symptomatic HD mice were hypoexcitable, a change that was attributable to increased association of dendritic Kv4 potassium channels with auxiliary KChIP subunits. This association was negatively modulated by TrkB receptor signaling. Dendritic excitability of HD iSPNs was rescued by knocking-down expression of Kv4 channels, by disrupting KChIP binding, by restoring TrkB receptor signaling or by lowering mutant-Htt (mHtt) levels with a zinc finger protein. Collectively, these studies demonstrate that mHtt induces reversible alterations in the dendritic excitability of iSPNs that could contribute to the motor symptoms of HD. © 2019, Carrillo-Reid et al.

Author Keywords
calcium imaging;  dendrite;  Huntington’s disease;  KChIP;  Kv4;  mouse;  neuroscience;  zinc finger protein

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

Additional Approaches to Treatment of Depression
(2019) JAMA – Journal of the American Medical Association, 321 (16), pp. 1634-1635. 

Carney, R.M.

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

Document Type: Letter
Publication Stage: Final
Source: Scopus

Detection of Pediatric Upper Extremity Motor Activity and Deficits With Accelerometry
(2019) JAMA network open, 2 (4), p. e192970. 

Hoyt, C.R.^{a b} , Van, A.N.^a , Ortega, M.^a , Koller, J.M.^c , Everett, E.A.^a , Nguyen, A.L.^a , Lang, C.E.^{a b d} , Schlaggar, B.L.^{a c e f g h} , Dosenbach, N.U.F.^{a b g h i}

^a Department of Neurology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Program in Occupational Therapy, Washington University School of Medicine in St Louis, St Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
^d Program in Physical Therapy, Washington University School of Medicine in St Louis, St Louis, MO, United States
^e Department of Anatomy and Neurobiology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^f Kennedy Krieger Institute, Baltimore, MD, United States
^g Department of Radiology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^h Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, MO, United States
ⁱ Department of Biomedical Engineering, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: Affordable, quantitative methods to screen children for developmental delays are needed. Motor milestones can be an indicator of developmental delay and may be used to track developmental progress. Accelerometry offers a way to gather real-world information about pediatric motor behavior. Objective: To develop a referent cohort of pediatric accelerometry from bilateral upper extremities (UEs) and determine whether movement can accurately distinguish those with and without motor deficits. Design, Setting, and Participants: Children aged 0 to 17 years participated in a prospective cohort from December 8, 2014, to December 29, 2017. Children were recruited from Ranken Jordan Pediatric Bridge Hospital, Maryland Heights, Missouri, and Washington University School of Medicine in St Louis, St Louis, Missouri. Typically developing children were included as a referent cohort if they had no history of motor or neurological deficit; consecutive sampling and matching ensured equal representation of sex and age. Children with diagnosed asymmetric motor deficits were included in the motor impaired cohort. Exposures: Bilateral UE motor activity was measured using wrist-worn accelerometers for a total of 100 hours in 25-hour increments. Main Outcomes and Measures: To characterize bilateral UE motor activity in a referent cohort for the purpose of detecting irregularities in the future, total activity and the use ratio between UEs were used to describe typically developing children. Asymmetric impairment was classified using the mono-arm use index (MAUI) and bilateral-arm use index (BAUI) to quantify the acceleration of unilateral movements. Results: A total of 216 children enrolled, and 185 children were included in analysis. Of these, 156 were typically developing, with mean (SD) age 9.1 (5.1) years and 81 boys (52.0%). There were 29 children in the motor impaired cohort, with mean (SD) age 7.4 (4.4) years and 16 boys (55.2%). The combined MAUI and BAUI (mean [SD], 0.86 [0.005] and use ratio (mean [SD], 0.90 [0.008]) had similar F1 values. The area under the curve was also similar between the combined MAUI and BAUI (mean [SD], 0.98 [0.004]) and the use ratio (mean [SD], 0.98 [0.004]). Conclusions and Relevance: Bilateral UE movement as measured with accelerometry may provide a meaningful metric of real-world motor behavior across childhood. Screening in early childhood remains a challenge; MAUI may provide an effective method for clinicians to measure and visualize real-world motor behavior in children at risk for asymmetrical deficits.

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

A heteroscedastic hidden Markov mixture model for responses and categorized response times
(2019) Behavior research methods, 51 (2), pp. 676-696. 

Molenaar, D.^a , Rózsa, S.^b , Bolsinova, M.^c

^a Department of Psychology, University of Amsterdam, Amsterdam, Netherlands
^b Washington University School of Medicine, St. Louis, MO, United States
^c Iowa City, IA, United States

Abstract
Various mixture modeling approaches have been proposed to identify within-subjects differences in the psychological processes underlying responses to psychometric tests. Although valuable, the existing mixture models are associated with at least one of the following three challenges: (1) A parametric distribution is assumed for the response times that-if violated-may bias the results; (2) the response processes are assumed to result in equal variances (homoscedasticity) in the response times, whereas some processes may produce more variability than others (heteroscedasticity); and (3) the different response processes are modeled as independent latent variables, whereas they may be related. Although each of these challenges has been addressed separately, in practice they may occur simultaneously. Therefore, we propose a heteroscedastic hidden Markov mixture model for responses and categorized response times that addresses all the challenges above in a single model. In a simulation study, we demonstrated that the model is associated with acceptable parameter recovery and acceptable resolution to distinguish between various special cases. In addition, the model was applied to the responses and response times of the WAIS-IV block design subtest, to demonstrate its use in practice.

Author Keywords
Hidden Markov models;  Item response theory;  Mixture models;  Response times

Document Type: Article
Publication Stage: Final
Source: Scopus

Use of magnetic resonance imaging in severe pediatric traumatic brain injury: Assessment of current practice
(2019) Journal of Neurosurgery: Pediatrics, 23 (4), pp. 471-479. 

Ferrazzano, P.A.^{a be} , Rosario, B.L.^d , Wisniewski, S.R.^d , Shaf, N.I.^e , Siefkes, H.M.^f , Miles, D.K.^{g bb} , Alexander, A.L.^{b c} , Bell, M.J.^h , Sarnaik, A.^bg , Agrawal, S.ⁱ , Mahoney, S.^j , Gupta, D.^k , Beca, J.^l , Loftis, L.^m , Morris, K.ⁿ , Piper, L.^o , Slater, A.^p , Walson, K.^q , Bennett, T.^r , Kilbaugh, T.^s , Iqbal O’Meara, A.M.^t , Dean, N.^u , Chima, R.S.^v , Biagas, K.^w , Wildschut, E.^x , Peters, M.^y , LaRovere, K.^z , Balcells, J.^aa , Robertson, C.^ab , Gertz, S.^ac , Deep, A.^ad , Cooper, S.^ae , Wainwright, M.^af , Murphy, S.^ag , Kuluz, J.^ah , Butt, W.^ai , O’Brien, N.^aj , Thomas, N.^ak , Buttram, S.^al , Erickson, S.^am , Mahil Samuel, J.^an , Agbeko, R.^ao , Edwards, R.^ap , Ramakrishnan, K.A.^aq , Winkler, M.^ar , Borasino, S.^ar , Natale, J.^as , Giza, C.^at , Hilfiker, M.^au , Shellington, D.^au , Figaji, A.^av , Newell, E.^aw , Truemper, E.^ax , Clark, R.^ay , Newth, K.^az , Shafi, N.^ba , Schober, M.^bc , Zimmerman, J.^bd , Pineda, J.^bf

^a Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^b Department of Medical Physics, University of Wisconsin, Madison, Wisconsin, United States
^c Department of Psychiatry, University of Wisconsin, Madison, Wisconsin, United States
^d Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
^e Department of Pediatrics, University of Tennessee, Memphis, Tennessee, United States
^f Department of Pediatrics, University of California-Davis, Sacramento, California, United States
^g Department of Pediatrics, University of Texas-Southwestern, Dallas, Texas, United States
^h Department of Pediatrics, Children’s National Medical Center, Washington, DC, United States
ⁱ Addenbrookes Hospital, Cambridge, United Kingdom
^j Alder Hey Children’s NHS Foundation Trust, Liverpool, United Kingdom
^k All India Institute of Medical Sciences, New Delhi, India
^l Auckland DHB Charitable Trust, Starship Children’s Hospital, Auckland, New Zealand
^m Baylor College of Medicine, Houston, TX, United States
ⁿ Birmingham Children’s Hospital NHS Foundation Trust, Birmingham, United Kingdom
^o Levine Children’s Hospital, Charlotte, NC, United States
^p Children’s Health Queensland Hospital and Health Service, Brisbane, Australia
^q Children’s Healthcare of Atlanta, Atlanta, GA, United States
^r Children’s Hospital Colorado, Aurora, CO, United States
^s Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^t Children’s Hospital of Richmond, Richmond, VA, United States
^u Children’s National Medical Center, Washington, DC, United States
^v Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^w Columbia University, New York, NY, United States
^x Erasmus Medical Center, Rotterdam, Netherlands
^y Great Ormond St. Hospital NHS Foundation Trust, London, United Kingdom
^z Boston Children’s Hospital, Boston, MA, United States
^aa Hospital Vall d’Hebron, Barcelona, Spain
^ab John Hopkins University, Baltimore, MD, United States
^ac Joseph M. Sanzari Children’s Hospital, Hackensack University Medical Center, Hackensack, NJ, United States
^ad King’s College Hospital NHS Foundation Trust, London, United Kingdom
^ae Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
^af Lurie Children’s Hospital, Chicago, IL, United States
^ag Massachusetts General Hospital, Boston, MA, United States
^ah Miami Children’s Hospital, Miami, FL, United States
^ai Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia
^aj Nationwide Children’s Hospital, Columbus, OH, United States
^ak Pennsylvania State University, Hershey, PA, United States
^al Phoenix Children’s Hospital, Phoenix, AZ, United States
^am Princess Margaret Hospital, Perth, Australia
^an Royal Manchester Children’s Hospital NHS Foundation Trust, Manchester, United Kingdom
^ao Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom
^ap University Hospital Bristol NHS Foundation Trust, Bristol, United Kingdom
^aq University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
^ar University of Alabama at Birmingham, Birmingham, AL, United States
^as University of California, Davis, Sacramento, CA, United States
^at University of California, Los Angeles, Los Angeles, CA, United States
^au University of California, San Diego, San Diego, CA, United States
^av Red Cross War Memorial Children’s Hospital, Cape Town, South Africa
^aw University of Iowa Children’s Hospital, Iowa City, IA, United States
^ax University of Nebraska Medical Center, Nebraska Medical Center, Omaha, NE, United States
^ay University of Pittsburgh, Pittsburgh, PA, United States
^az Children’s Hospital of Los Angeles, Los Angeles, CA, United States
^ba Le Bon heur Children’s Hospital, Memphis, TN, United States
^bb University of Texas Southwestern Medical Center, Dallas, TX, United States
^bc University of Utah, Salt Lake City, UT, United States
^bd University of Washington, Seattle, WA, United States
^be University of Wisconsin, Madison, WI, United States
^bf Washington University-St. Louis, St. Louis, MO, United States
^bg Wayne State University, Detroit, MI, United States

Abstract
OBJECTIVE There is no consensus on the optimal timing and specific brain MRI sequences in the evaluation and management of severe pediatric traumatic brain injury (TBI), and information on current practices is lacking. The authors performed a survey of MRI practices among sites participating in a multicenter study of severe pediatric TBI to provide information for designing future clinical trials using MRI to assess brain injury after severe pediatric TBI. METHODS Information on current imaging practices and resources was collected from 27 institutions participating in the Approaches and Decisions after Pediatric TBI Trial. Multiple-choice questions addressed the percentage of patients with TBI who have MRI studies, timing of MRI, MRI sequences used to investigate TBI, as well as the magnetic feld strength of MR scanners used at the participating institutions and use of standardized MRI protocols for imaging after severe pediatric TBI. RESULTS Overall, the reported use of MRI in pediatric patients with severe TBI at participating sites was high, with 40% of sites indicating that they obtain MRI studies in > 95% of this patient population. Differences were observed in the frequency of MRI use between US and international sites, with the US sites obtaining MRI in a higher proportion of their pediatric patients with severe TBI (94% of US vs 44% of international sites reported MRI in at least 70% of patients with severe TBI). The reported timing and composition of MRI studies was highly variable across sites. Sixty percent of sites reported typically obtaining an MRI study within the first 7 days postinjury, with the remainder of responses distributed throughout the first 30-day postinjury period. Responses indicated that MRI sequences sensitive for diffuse axonal injury and ischemia are frequently obtained in patients with TBI, whereas perfusion imaging and spectroscopy techniques are less common. CONCLUSIONS Results from this survey suggest that despite the lack of consensus or guidelines, MRI is commonly obtained during the acute clinical setting after severe pediatric TBI. The variation in MRI practices highlights the need for additional studies to determine the utility, optimal timing, and composition of clinical MRI studies after TBI. The information in this survey describes current clinical MRI practices in children with severe TBI and identifies important challenges and objectives that should be considered when designing future studies. © AANS 2019.

Author Keywords
Magnetic resonance imaging;  Pediatric traumatic brain injury;  Survey;  Trauma

Document Type: Article
Publication Stage: Final
Source: Scopus

Lithium chloride corrects weakness and myopathology in a preclinical model of LGMD1D
(2019) Neurology: Genetics, 5 (2), art. no. e318, . 

Findlay, A.R.^{a b} , Bengoechea, R.^{a b} , Pittman, S.K.^{a b} , Chou, T.-F.^c , True, H.L.^{a d} , Weihl, C.C.^{a b}

^a Washington University School of Medicine, Hope Center for Neurological Diseases, St. Louis, MO, United States
^b Department of Neurology, Hope Center for Neurological Diseases, St. Louis, MO, United States
^c Harbor-UCLA Medical Center, Department of Pediatrics, Division of Medical Genetics, Torrance, CA, United States
^d Department of Cell Biology and Physiology, Saint Louis, MO, United States

Abstract
Objective: To understand DNAJB6’s function in skeletal muscle and identify therapeutic targets for limb-girdle muscular dystrophy 1D (LGMD1D). Methods: DNAJB6 knockout (KO) myoblasts were generated with Crispr/cas9 technology, and differentially accumulated proteins were identified using stable isotope labeling, followed by quantitative mass spectrometry. Cultured KO myotubes and mouse muscle from DNAJB6b-WT or DNAJB6b-F93L mice were analyzed using histochemistry, immunohistochemistry, and immunoblot. Mouse functional strength measures included forelimb grip strength and inverted wire hang. Results: DNAJB6 inactivation leads to the accumulation of sarcomeric proteins and hypertrophic myotubes with an enhanced fusion index. The increased fusion in DNAJB6 KO myotubes correlates with diminished glycogen synthase kinase-β (GSK3β) activity. In contrast, LGMD1D mutations in DNAJB6 enhance GSK3β activation and suppress β-catenin and NFAT3c signaling. GSK3β inhibition with lithium chloride improves muscle size and strength in an LGMD1D preclinical mouse model. Conclusions: Our results suggest that DNAJB6 facilitates protein quality control and negatively regulates myogenic signaling. In addition, LGMD1D-associated DNAJB6 mutations inhibit myogenic signaling through augmented GSK3β activity. GSK3β inhibition with lithium chloride may be a therapeutic option in LGMD1D. © 2019 American Academy of Neurology.

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

Functional and structural connectivity of the cerebellar nuclei with the striatum and cerebral cortex in first-episode psychosis
(2019) Journal of Neuropsychiatry and Clinical Neurosciences, 31 (2), pp. 143-151. 

Lee, K.-H.^{a b} , Oh, H.^a , Suh, J.-H.S.^a , Cho, K.I.K.^{a c} , Yoon, Y.B.^{a e} , Shin, W.-G.^c , Lee, T.Y.^d , Kwon, J.S.^{a b}

^a Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea
^b Department of Psychiatry, Seoul National University College of Medicine, Seoul, South Korea
^c Institute of Human Behavioral Medicine, SNU-MRC, Seoul, South Korea
^d Center for Cognition and Sociality, Institute for Basic Science, Daejeon, South Korea
^e Department of Psychiatry, Washington University, St. Louis, United States

Abstract
Objective: Evidence suggests that the cortico-striatalthalamo- cortical circuitry plays an important role in schizophrenia pathophysiology. Cerebellar contribution from deep cerebellar nuclei to the circuitry has not yet been examined. The authors investigated resting-state functional connectivity (RSFC) of cerebellar output nuclei with striatal-thalamiccortical regions in relation to white-matter integrity and regional gray-matter volumes in first-episode psychosis (FEP). Methods: Forty FEP patients and 40 age- and gendermatched healthy control subjects (HCs) participated. RSFC between cerebellar nuclei and striatal-thalamic-cortical regions was examined. Diffusion tensor imaging and volumetric scans were examined for possible structural constraints on RSFC. The authors also examined relationships between neuroimaging variables and cognitive and clinical measures. Results: FEP patients, compared with HCs, exhibited decreased RSFC between the left fastigial nucleus and right putamen, which was associated with poor letter fluency performance and lower global assessment of functioning scores. By contrast, patients showed widespread increased accumbens network connectivity in the left nucleus. The authors further observed both hypo- and hyper-RSFC between the cerebellar nuclei and fronto-parietal areas in patients, independent of striatal activity. Finally, the authors found impaired integrity of the left superior cerebellar peduncle and decreased bilateral putamen volume in patients, whereas structural-functional relationships found in HCs were absent in patients. Conclusions: This study provides evidence of disordered RSFC of cerebellar output nuclei to the striatum and neocortex at the early stage of schizophrenia. Furthermore, dysfunctional cerebellar influences on fronto-parietal areas that are independent of striatal dysfunction in patients with FEP were observed. The results suggest that cortico-striatal abnormalities in patients with FEP are produced by abnormal cerebellar influences. © 2019, American Psychiatric Association. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Standing enhances cognitive control and alters visual search
(2019) Attention, Perception, and Psychophysics, . 

Smith, K.C.^a , Davoli, C.C.^b , Knapp, W.H., III^a , Abrams, R.A.^a

^a Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^b Department of Psychology, Central Michigan University, Mount Pleasant, MI, United States

Abstract
Postural changes and the maintenance of postural stability have been shown to affect many aspects of cognition. Here we examined the extent to which selective visual attention may differ between standing and seated postures in three tasks: the Stroop color-word task, a task-switching paradigm, and visual search. We found reduced Stroop interference, a reduction in switch costs, and slower search rates in the visual search task when participants stood compared to when they sat while performing the tasks. The results suggest that the postural demands associated with standing enhance cognitive control, revealing broad connections between body posture and cognitive mechanisms. © 2019, The Psychonomic Society, Inc.

Author Keywords
Attention and executive control;  Cognitive and attentional control;  Embodied perception

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

Diffusion weighted imaging evidence of extra-callosal pathways for interhemispheric communication after complete commissurotomy
(2019) Brain Structure and Function, . 

Nomi, J.S.^a , Marshall, E.^a , Zaidel, E.^{b c} , Biswal, B.^d , Castellanos, F.X.^{e f} , Dick, A.S.^g , Uddin, L.Q.^{a h} , Mooshagian, E.ⁱ

^a Department of Psychology, University of Miami, P.O. Box 248185-0751, Coral Gables, FL 33124, United States
^b Department of Psychology, University of California, Los Angeles, CA 90095, United States
^c Brain Research Institute, University of California, Los Angeles, CA 90095, United States
^d Department of Biomedical Engineering, New Jersey Institute of Technology, Newark, NJ 07102, United States
^e Department of Child and Adolescent Psychiatry, Hassenfeld Children’s Hospital at NYU Langone, New York, NY 10016, United States
^f Nathan Kline Institute for Psychiatric Research, Orangeburg, NY 10962, United States
^g Department of Psychology, Florida International University, Miami, FL 33199, United States
^h Neuroscience Program, University of Miami Miller School of Medicine, Miami, FL 33136, United States
ⁱ Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
The integrity of white matter architecture in the human brain is related to cognitive processing abilities. The corpus callosum is the largest white matter bundle interconnecting the two cerebral hemispheres. “Split-brain” patients in whom all cortical commissures have been severed to alleviate intractable epilepsy demonstrate remarkably intact cognitive abilities despite the lack of this important interhemispheric pathway. While it has often been speculated that there are compensatory alterations in the remaining interhemispheric fibers in split-brain patients several years post-commissurotomy, this has never been directly shown. Here we examined extra-callosal pathways for interhemispheric communication in the brain of a patient who underwent complete cerebral commissurotomy using diffusion weighted imaging tractography. We found that compared with a healthy age-matched comparison group, the split-brain patient exhibited increased fractional anisotropy (FA) of the dorsal and ventral pontine decussations of the cortico-cerebellar interhemispheric pathways. Few differences were observed between the patient and the comparison group with respect to FA of other long-range intrahemispheric fibers. These results point to specific cerebellar anatomical substrates that may account for the spared interhemispheric coordination and intact cognitive abilities that have been extensively documented in this unique patient. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Corpus callosum;  Epilepsy;  Hemispheric specialization;  Interhemispheric transfer;  Laterality;  Structural connectivity

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

The Experience of Chemotherapy-Induced Peripheral Neuropathy Among Childhood Cancer Survivors
(2019) Journal of Pediatric Oncology Nursing, . 

Mohrmann, C.

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

Abstract
As the number of childhood cancer survivors (CCS) is increasing, it is imperative to understand the late effects of childhood cancer therapy to optimize their health and quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is an unpleasant effect of chemotherapy that affects the peripheral nervous system. This qualitative study uses narrative analysis with a phenomenological influence to understand the lived experience of CIPN among five CCS utilizing photo-elicitation. The lived experience of CIPN is characterized by “a condition of disconnection” with three subthemes: (1) disconnection between mind and body, (2) disconnection between anticipated potential and reality, and (3) disconnection between survivors and support. The condition of disconnection leads to a variety of negative physical and emotional performance outcomes. These findings support the need for refined clinical strategies for identifying this underappreciated condition and further development of interventions to “rebuild the connections” that CCS are lacking. © 2019 by Association of Pediatric Hematology/Oncology Nurses.

Author Keywords
adolescents and young adults;  AYA;  late effects of cancer;  survivorship;  symptom management

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

Transplantation of v2a interneurons and neural progenitors after cervical spinal cord injury
(2019) Transactions of the Annual Meeting of the Society for Biomaterials and the Annual International Biomaterials Symposium, 40, p. 29. 

Sakiyama-Elbert, S.^a , Thompson, R.^{a b} , Zholudeva, L.V.^c , Lane, M.^c

^a Department of Biomedical Engineering, University of Texas at Austin, United States
^b Department of Biomedical Engineering, Washington University, St Louis, United States
^c Department of Neurobiology and Anatomy, Spinal Cord Research Center, College of Medicine, Drexel University, United States

Abstract
Every year 17,000 Americans suffer a traumatic spinal cord injury (SCI) that leads to a significant, lifelong healthcare burden, which can cost from $1 to 4.5 million. One major reason for the high cost of SCI is the limited of regenerative capacity of the adult mammalian spinal cord. 1 This lack of regeneration is due, in part, to a highly organized, predominantly astrocytic glial scar that forms to limit the spread of secondary injury, but also represents a chemical and physical barrier to neuronal growth. Interestingly, it has been observed that astrocytes are also present where axons are able to cross the injury site. 2 This suggests that astrocytes are involved in both the formation of the glial scar and the creation of bridges across the scar and lesion environments. V2a interneurons are glutamatergic, ipsilaterally projecting cells that have been found to be important for local rewiring following SCI, particularly in the phrenic circuit. In this work, we used a novel hyaluronic acid (HA)-astrocyte extracellular matrix (ECM) hydrogel and demonstrate that this hydrogel can be used to deliver V2a interneurons into the injured spinal cord. © 2019 Omnipress – All rights reserved.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

Association of Patient Social, Cognitive, and Functional Risk Factors with Preventable Hospitalizations: Implications for Physician Value-Based Payment
(2019) Journal of General Internal Medicine, . 

Johnston, K.J.^a , Wen, H.^b , Schootman, M.^c , Joynt Maddox, K.E.^d

^a Department of Health Management and Policy and Center for Outcomes Research, College for Public Health and Social Justice, Saint Louis University, St. Louis, MO, United States
^b Department of Health Management and Policy, University of Kentucky, Lexington, KY, United States
^c Department of Clinical Analytics and Insights, Center for Clinical Excellence, SSM Health, St. Louis, MO, United States
^d Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Ambulatory care-sensitive condition (ACSC) hospitalizations are used to evaluate physicians’ performance in Medicare value-based payment programs. However, these measures may disadvantage physicians caring for vulnerable populations because they omit social, cognitive, and functional factors that may be important determinants of hospitalization. Objective: To determine whether social, cognitive, and functional risk factors are associated with ACSC hospitalization rates and whether adjusting for them changes outpatient safety-net providers’ performance. Design: Using data from the Medicare Current Beneficiary Survey, we conducted patient-level multivariable regression to estimate the association (as incidence rate ratios (IRRs)) between patient-reported social, cognitive, and functional risk factors and ACSC hospitalizations. We compared outpatient safety-net and non-safety-net providers’ performance after adjusting for clinical comorbidities alone and after additional adjustment for social, cognitive, and functional factors captured in survey data. Setting: Safety-net and non-safety-net clinics. Participants: Community-dwelling Medicare beneficiaries contributing 38,616 person-years from 2006 to 2013. Measurements: Acute and chronic ACSC hospitalizations. Results: After adjusting for clinical comorbidities, Alzheimer’s/dementia (IRR 1.30, 95% CI 1.02–1.65), difficulty with 3–6 activities of daily living (ADLs) (IRR 1.43, 95% CI 1.05–1.94), difficulty with 1–2 instrumental ADLs (IADLs, IRR 1.54, 95% CI 1.26–1.90), and 3–6 IADLs (IRR 1.90, 95% CI 1.49–2.43) were associated with acute ACSC hospitalization. Low income (IRR 1.28, 95% CI 1.03–1.58), lack of educational attainment (IRR 1.33, 95% CI 1.04–1.69), being unmarried (IRR 1.18, 95% CI 1.01–1.36), difficulty with 1–2 IADLs (IRR 1.30, 95% CI 1.05–1.60), and 3–6 IADLs (IRR 1.44, 95% CI 1.16–1.80) were associated with chronic ACSC hospitalization. Adding these factors to standard Medicare risk adjustment eliminated outpatient safety-net providers’ performance gap (p <.05) on ACSC hospitalization rates relative to non-safety-net providers. Conclusions: Social, cognitive, and functional risk factors are independently associated with ACSC hospitalizations. Failure to account for them may penalize outpatient safety-net providers for factors that are beyond their control. © 2019, Society of General Internal Medicine.

Author Keywords
Medicare;  physician value-based payment;  safety-net providers

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

Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint
(2019) Alzheimer’s and Dementia, . 

Staffaroni, A.M.^a , Bajorek, L.^a , Casaletto, K.B.^a , Cobigo, Y.^a , Goh, S.-Y.M.^a , Wolf, A.^a , Heuer, H.W.^a , Elahi, F.M.^a , Ljubenkov, P.A.^a , Dever, R.^a , Kornak, J.^b , Appleby, B.^c , Bove, J.^d , Bordelon, Y.^e , Brannelly, P.^f , Brushaber, D.^g , Caso, C.^h , Coppola, G.^{e i} , Dheel, C.^j , Dickerson, B.C.^k , Dickinson, S.^l , Dominguez, S.^d , Domoto-Reilly, K.^h , Faber, K.^m , Ferrall, J.ⁿ , Fields, J.A.^o , Fishman, A.^p , Fong, J.^a , Foroud, T.^m , Forsberg, L.K.^j , Gavrilova, R.^j , Gearhart, D.^j , Ghazanfari, B.^{q r} , Ghoshal, N.^s , Goldman, J.^{t u} , Graff-Radford, J.^j , Graff-Radford, N.^v , Grant, I.^w , Grossman, M.^d , Haley, D.^v , Hsiung, G.-Y.^x , Huey, E.D.^{t u} , Irwin, D.J.^d , Jones, D.T.^j , Jones, L.^y , Kantarci, K.^z , Karydas, A.^a , Kaufer, D.I.ⁿ , Kerwin, D.R.^{aa ab} , Knopman, D.S.^j , Kraft, R.^j , Kremers, W.K.^g , Kukull, W.A.^ac , Litvan, I.^ad , Lucente, D.^k , Lungu, C.^ae , Mackenzie, I.R.^af , Maldonado, M.^e , Manoochehri, M.^t , McGinnis, S.M.^k , McKinley, E.^ag , Mendez, M.F.^{e i} , Miller, B.L.^a , Multani, N.^{q r} , Onyike, C.^ah , Padmanabhan, J.^k , Pantelyat, A.^ai , Pearlman, R.^aj , Petrucelli, L.^ak , Potter, M.^m , Rademakers, R.^ak , Ramos, E.M.ⁱ , Rankin, K.P.^a , Rascovsky, K.^d , Roberson, E.D.^ag , Rogalski, E.^al , Sengdy, P.^x , Shaw, L.M.^am , Syrjanen, J.^g , Tartaglia, M.C.^{q r} , Tatton, N.^l , Taylor, J.^a , Toga, A.^an , Trojanowski, J.Q.^am , Weintraub, S.^w , Wang, P.^a , Wong, B.^k , Wszolek, Z.^v , Boxer, A.L.^a , Boeve, B.F.^j , Kramer, J.H.^a , Rosen, H.J.^a , ARTFL/LEFFTDS consortium^ao

^a Department of Neurology, Memory and Aging Center, University of California, San Francisco, San Francisco, CA, United States
^b Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
^c Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
^d Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e Department of Neurology, University of California, Los Angeles, Los Angeles, CA, United States
^f Tau Consortium, Rainwater Charitable Foundation, Fort Worth, TX, United States
^g Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^h Department of Neurology, University of Washington, Seattle, WA, United States
ⁱ Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, United States
^j Department of Neurology, Mayo Clinic, Rochester, MN, United States
^k Department of Neurology, Frontotemporal Disorders Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^l Association for Frontotemporal Degeneration, Radnor, PA, United States
^m National Cell Repository for Alzheimer’s Disease (NCRAD), Indiana University, Indianapolis, IN, United States
ⁿ Department of Neurology, University of North Carolina, Chapel Hill, NC, United States
^o Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^p School of Medicine, Department of Psychiatry, Johns Hopkins University, Baltimore, MD, United States
^q Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
^r Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
^s Departments of Neurology and Psychiatry, Washington University School of Medicine, Washington University, St. Louis, MO, United States
^t Department of Neurology, Columbia University, New York, NY, United States
^u Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
^v Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
^w Feinberg School of Medicine, Department of Neurology, Northwestern University, Chicago, IL, United States
^x Division of Neurology, Deptartment of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
^y Department of Radiology, Washington University School of Medicine, Washington University, St. Louis, MO, United States
^z Department of Radiology, Mayo Clinic, Rochester, MN, United States
^aa Department of Neurology and Neurotherapeutics, Center for Alzheimer’s and Neurodegenerative Diseases, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, United States
^ab Department of Internal Medicine, The University of Texas, Southwestern Medical Center at Dallas, Dallas, TX, United States
^ac National Alzheimer Coordinating Center (NACC), University of Washington, Seattle, WA, United States
^ad Department of Neurosciences, Parkinson and Other Movement Disorders Center, University of California, San Diego, San Diego, CA, United States
^ae National Institute of Neurological Disorders and Stroke (NINDS), Bethesda, MD, United States
^af Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
^ag Department of Neurology, Alzheimer’s Disease Center, University of Alabama at Birmingham, Birmingham, AL, United States
^ah Department of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University, Baltimore, MD, United States
^ai School of Medicine, Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
^aj Bluefield Project, San Francisco, CA, United States
^ak Department of Neurosciences, Mayo Clinic, Jacksonville, FL, United States
^al Feinberg School of Medicine, Department of Psychiatry and Behavioral Sciences, Northwestern University, Chicago, IL, United States
^am Perelman School of Medicine, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, United States
^an Departments of Ophthalmology, Neurology, Psychiatry and the Behavioral Sciences, Radiology and Engineering, Laboratory of Neuroimaging (LONI), USC, Los Angeles, CA, United States

Abstract
Introduction: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD)is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. Methods: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1)and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER)and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. Results: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. Discussion: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint. © 2019 The Authors

Author Keywords
Behavioral variant;  Cognition;  Corticobasal syndrome;  Fluency;  Genetic;  Inhibition;  Neuropsychology;  Nonfluent variant;  Primary progressive aphasia;  Progranulin;  Progressive supranuclear palsy;  Semantic variant;  Set-shifting;  Tau;  Working memory

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

Simultaneous patient presentation for endovascular thrombectomy in acute ischemic stroke
(2019) Journal of NeuroInterventional Surgery, . 

Dalsania, A.K.^a , Kansagra, A.P.^{b c d}

^a Rutgers New Jersey Medical School, Newark, NJ, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^d Department of Neurology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Increased demand for endovascular thrombectomy has increased the likelihood of simultaneous patient presentation leading to competing demand for time-critical treatment that could adversely impact patient outcomes. We aimed to quantify the occurrence of simultaneous patient presentation at different patient volumes. Methods: Empirical distributions for time of patient presentation and case duration were used to probabilistically generate arrival time and case duration for a set annual patient volume, ranging from 1 to 500 cases per year, for 16 000 independent trials at each volume. Time series were generated for each trial to represent the number of cases being performed at each minute of the year. Time series were used to calculate daily thrombectomy demand, annual concurrent demand, and hourly excess demand. Results: The patient volumes at which at least one annual occurrence of concurrent demand by two patients was 50% and 97.5% likely were 45 and 101, respectively. The volumes at which at least one annual occurrence of concurrent demand by three patients was 50% and 97.5% likely were 216 and 387, respectively. There was dramatic variation in the occurrence of excess demand by two or more patients throughout the day. Conclusions: The occurrence of simultaneous presentation by multiple patients for endovascular thrombectomy varies with annual patient volume and time of day. Understanding these trends and the associated patient impact can inform intelligent strategies at regional and national levels for optimizing patient care within real-world financial and operational constraints. © Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
brain;  economics;  intervention;  stroke;  thrombectomy

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

Patient Stakeholder Versus Physician Preferences Regarding Amyloid PET Testing
(2019) Alzheimer Disease and Associated Disorders, . 

Armstrong, M.J.^a , Gronseth, G.S.^b , Day, G.S.^c , Rheaume, C.^d , Alliance, S.^a , Mullins, C.D.^e

^a Department of Neurology, McKnight Brain Institute, University of Florida, College of Medicine, Gainesville, FL, United States
^b Department of Neurology, University of Kansas Medical Center, Kansas City, KS, United States
^c Department of Neurology, Charles F and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
^d American Academy of Neurology, Minneapolis, MN, United States
^e Pharmaceutical Health Research Department, University of Maryland School of Pharmacy, Baltimore, MD, United States

Author Keywords
amyloid PET imaging;  dementia;  guidelines as topic;  mild cognitive impairment;  patient participation;  preclinical Alzheimer disease

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

Differential Relationships of Child Anxiety and Depression to Child Report and Parent Report of Electronic Media Use
(2019) Child Psychiatry and Human Development, . 

Fors, P.Q.^a , Barch, D.M.^{a b c}

^a Department of Psychological & Brain Sciences, Washington University, Campus Box 1125, 1 Brookings Drive, St. Louis, MO 63130, United States
^b Department of Psychiatry, Washington University, St. Louis, MO, United States
^c Department of Radiology, Washington University, St. Louis, MO, United States

Abstract
Child depression and anxiety have been associated with electronic media use, but the comorbidity between the two has rarely been accounted for in analyses. We examined both child and parent reports of electronic media use in relation to parent-reported child depression and anxiety. Using survey and interview data collected for 9- to 11-year-olds from the 21-site adolescent brain cognitive development study, we conducted generalized linear mixed models. Our results demonstrated that electronic media use was more strongly associated with depression than anxiety, and that accounting for depression significantly reduced the relationship between electronic media use and anxiety. Different categories of electronic media showed differential relationships to anxiety and depression, with video gaming and video chatting related to anxiety, but video watching related to depression. These findings provide important data to ground theories of the mechanisms that contribute to these associations. © 2019, The Author(s).

Author Keywords
Anxiety;  Children;  Depression;  Electronic media use;  Technology

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

A pathogenic CtBP1 missense mutation causes altered cofactor binding and transcriptional activity
(2019) Neurogenetics, . 

Beck, D.B.^a , Subramanian, T.^b , Vijayalingam, S.^b , Ezekiel, U.R.^c , Donkervoort, S.^d , Yang, M.L.^e , Dubbs, H.A.^f , Ortiz-Gonzalez, X.R.^g , Lakhani, S.^h , Segal, D.ⁱ , Au, M.^j , Graham, J.M., Jr.^j , Verma, S.^k , Waggoner, D.^l , Shinawi, M.^m , Bönnemann, C.G.^d , Chung, W.K.ⁿ , Chinnadurai, G.^b

^a National Human Genome Research Institute, National Institutes of Health, 10 Center Drive, Room B3-4129, Bethesda, MD 20892, United States
^b Institute for Molecular Virology, Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, E. A. Doisy Research Center, 6th Floor, St. Louis, MO 63104, United States
^c Clinical Health Sciences, Saint Louis University, 3437 Caroline Street, Allied Health Building, Suite 3025, Saint Louis, MO 63104, United States
^d National Institute of Neurological Disorders and Stroke Neurogenetics Branch, National Institutes of Health, 10 Center Drive Room 2B39, MSC 1477, Bethesda, MD 20892, United States
^e University of Colorado Denver, 13123 E. 16th Ave; Box B155, Aurora, CO 80238, United States
^f Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^g Department of Neurology, Pereleman School of Medicine, University of Pennsylvania; Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
^h Center for Neurogenetics, Brain and Mind Research Institute, Weill Cornell Medicine, 413 E 69th Street, New York, NY 10021, United States
ⁱ Department of Pediatrics, Division of Child Neurology, Weill Cornell Medicine, 525 E. 68th St, Box 91, New York, NY 10065, United States
^j Medical Genetics, Department of Pediatrics, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90068, United States
^k Division of Pediatric Neurology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, United States
^l Department of Human Genetics, University of Chicago, Chicago, IL 60637, United States
^m Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁿ Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, United States

Abstract
We previously reported a pathogenic de novo p.R342W mutation in the transcriptional corepressor CTBP1 in four independent patients with neurodevelopmental disabilities [1]. Here, we report the clinical phenotypes of seven additional individuals with the same recurrent de novo CTBP1 mutation. Within this cohort, we identified consistent CtBP1-related phenotypes of intellectual disability, ataxia, hypotonia, and tooth enamel defects present in most patients. The R342W mutation in CtBP1 is located within a region implicated in a high affinity-binding cleft for CtBP-interacting proteins. Unbiased proteomic analysis demonstrated reduced interaction of several chromatin-modifying factors with the CtBP1 W342 mutant. Genome-wide transcriptome analysis in human glioblastoma cell lines expressing -CtBP1 R342 (wt) or W342 mutation revealed changes in the expression profiles of genes controlling multiple cellular processes. Patient-derived dermal fibroblasts were found to be more sensitive to apoptosis during acute glucose deprivation compared to controls. Glucose deprivation strongly activated the BH3-only pro-apoptotic gene NOXA, suggesting a link between enhanced cell death and NOXA expression in patient fibroblasts. Our results suggest that context-dependent relief of transcriptional repression of the CtBP1 mutant W342 allele may contribute to deregulation of apoptosis in target tissues of patients leading to neurodevelopmental phenotypes. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
C-terminal binding protein;  Chromatin modifying complex;  CtBP1;  Neurodevelopmental disease;  p.R342W mutation

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

PCH1 regulates light, temperature, and circadian signaling as a structural component of phytochrome B-photobodies in Arabidopsis
(2019) Proceedings of the National Academy of Sciences of the United States of America, 116 (17), pp. 8603-8608. 

Huang, H.^a , McLoughlin, K.E.^b , Sorkin, M.L.^{a c} , Sethe Burgie, E.^b , Bindbeutel, R.K.^a , Vierstra, R.D.^b , Nusinow, D.A.^a

^a Donald Danforth Plant Science Center, St. Louis, MO 63132, United States
^b Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
The members of the phytochrome (phy) family of bilin-containing photoreceptors are major regulators of plant photomorphogenesis through their unique ability to photointerconvert between a biologically inactive red light-absorbing Pr state and an active far-red light-absorbing Pfr state. While the initial steps in Pfr signaling are unclear, an early event for the phyB isoform after photoconversion is its redistribution from the cytoplasm into subnuclear foci known as photobodies (PBs), which dissipate after Pfr reverts back to Pr by far-red irradiation or by temperature-dependent nonphotochemical reversion. Here we present evidence that PHOTOPERIODIC CONTROL OF HYPOCOTYL 1 (PCH1) functions both as an essential structural component of phyB-containing PBs and as a direct regulator of thermal reversion that is sufficient to stabilize phyB as Pfr in vitro. By examining the genetic interaction between a constitutively active phyB Y276H -YFP allele (YHB-YFP) and PCH1, we show that the loss of PCH1 prevents YHB from coalescing into PBs without affecting its nuclear localization, whereas overexpression of PCH1 dramatically increases PB levels. Loss of PCH1, presumably by impacting phyB-PB assembly, compromises a number of events elicited in YHB-YFP plants, including their constitutive photomorphogenic phenotype, red light-regulated thermomorphogenesis, and input of phyB into the circadian clock. Conversely, elevated levels of both phyB and PCH1 generate stable, yet far-red light–reversible PBs that persisted for days. Collectively, our data demonstrate that the assembly of PCH1-containing PBs is critical for phyB signaling to multiple outputs and suggest that altering PB dynamics could be exploited to modulate plant responses to light and temperature. © 2019 National Academy of Sciences. All rights reserved.

Author Keywords
Circadian clock;  Photobodies;  Photomorphogenesis;  Phytochrome;  Thermomorphogenesis

Document Type: Article
Publication Stage: Final
Source: Scopus

Gambling in Emerging Adulthood: the Role of Adolescent Depressive Symptoms, Antisocial Behaviors, and Alcohol Use
(2019) International Journal of Mental Health and Addiction, . 

Jun, H.-J.^a , Sacco, P.^a , Cunningham-Williams, R.M.^b

^a University of Maryland School of Social Work, 525 W. Redwood Street, Baltimore, MD 21201, United States
^b Brown School, Washington University in St. Louis, One Brookings Drive, St. Louis, MO 63130, United States

Abstract
Emerging adults (ages 18–29) display higher prevalence of gambling participation and problem gambling as well as co-occurrence with other risk behaviors compared to other age groups. Consequences of these co-occurring conditions may lead to psychological symptoms, behavioral problems, and socioeconomic and medical costs. Depressive symptoms, antisocial behaviors, and alcohol use are known risk factors for gambling participation and problem gambling. However, scarce research has examined the co-occurrence of those adolescent risk factors and later gambling behaviors in emerging adulthood longitudinally. Using multiple waves of National Longitudinal Study of Adolescent to Adult Health (Add Health) data, we examined the relationship between earlier depressive symptoms, antisocial behaviors, alcohol use, and gambling behaviors at wave III, and later gambling participation and problem gambling (wave IV) in emerging adults ages 18–29, using multinomial logistic regression. Our findings suggest that earlier antisocial behaviors and gambling behaviors increased later risk for gambling participation and problem gambling. Past-year alcohol use and heavy drinking were associated with the increased risk of gambling participation but not problem gambling. Earlier depressive symptoms decreased the risk of gambling participation later among those who endorsed antisocial behaviors. Emerging adulthood may be a critical developmental period in the development of comorbid conditions of gambling and other risk behaviors. The results contribute evidence supporting the importance of early prevention and intervention for the co-occurrence of gambling and other risk behaviors in emerging adulthood. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Alcohol use;  Emerging adults;  Externalizing behaviors;  Gambling;  Internalizing behaviors

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

Frequency and Risk Factors for Prolonged Opioid Prescriptions After Surgery for Brachial Plexus Injury
(2019) Journal of Hand Surgery, . 

Dy, C.J.^{a b} , Peacock, K.^c , Olsen, M.A.^{b c} , Ray, W.Z.^d , Brogan, D.M.^a

^a Department of Orthopaedic Surgery, Division of Hand and Microsurgery, United States
^b Department of Surgery, Division of Public Health Sciences, United States
^c Department of Medicine, Center for Administrative Data Research, United States
^d Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Purpose: We hypothesized that patients with preoperative opioid prescriptions and diagnoses of depression and anxiety would be at increased risk for prolonged opioid prescriptions after surgery for brachial plexus injury (BPI). Methods: Using an administrative database of privately insured patients, we assembled a cohort of BPI surgery patients and a control group of non-BPI patients, matching for age, sex, and year. Pharmacy claims for prescriptions filled for opioids and neuropathic pain medications were examined 12 months before surgery to 180 days after surgery. The primary outcome was prolonged opioid prescription, defined as receiving a prescription 90 to 180 days after the index (BPI surgery or randomly selected date of service for controls). Multivariable regression was used to examine risk factors for postoperative opioid use, including diagnoses of depression, anxiety, drug abuse, tobacco use, and preoperative use of opioids and neuropathic pain medications. A subgroup analysis was performed for opioid-naive BPI patients between 30 days to 1 year before surgery. Results: Among BPI surgery patients (n = 1,936), 27.7% had prolonged opioid prescriptions. Among opioid-naive BPI patients (n = 911), 10.8% had prolonged opioid prescriptions. In controls (n = 19,360), frequency of prolonged opioid prescriptions was 0.11%. Among all BPI patients, after adjustment for age and sex, predictors of prolonged postoperative opioid prescriptions in BPI patients were preoperative opioids, preoperative neuropathic pain medication use, histories of drug abuse, tobacco use, and anxiety. Conclusions: Prolonged postoperative opioids prescriptions after BPI reconstruction are higher than previous estimates among other surgical patients. In addition to establishing normative data among this population, our findings serve to increase awareness of risk factors for prolonged opioids after BPI reconstruction and encourage coordinated multidisciplinary care. Type of study/level of evidence: Prognostic II. © 2019 American Society for Surgery of the Hand

Author Keywords
Brachial plexus;  chronic pain;  nerve injury;  neuropathic pain;  opioids

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

Research Review: Outcomes of 24- to 36-month-old children with autism spectrum disorder vary by ascertainment strategy: a systematic review and meta-analysis
(2019) Journal of Child Psychology and Psychiatry and Allied Disciplines, . 

Micheletti, M.^{a b c} , McCracken, C.^{b c} , Constantino, J.N.^d , Mandell, D.^e , Jones, W.^{a b c f} , Klin, A.^{a b c f}

^a Marcus Autism Center, Atlanta, GA, United States
^b Children’s Healthcare of Atlanta, Atlanta, GA, United States
^c Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
^d Departments of Psychiatry and Pediatrics, Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St Louis, MO, United States
^e Center for Mental Health Policy and Services Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Emory Center for Translational Social Neuroscience, Atlanta, GA, United States

Abstract
Background: Despite widespread recommendations for early surveillance of risk for autism spectrum disorder (ASD), no research to date has shown that early surveillance leads to better clinical outcomes. Preliminary research has suggested that children with ASD ascertained via prospective follow-up have better outcomes than those ascertained via community referral. Because prospective studies include early surveillance, by comparing outcomes of children with ASD across ascertainment strategies, we may gain insight into the effects of early surveillance relative to its absence. Methods: A systematic review was conducted to identify studies reporting outcomes of 24- to 36-month-olds with ASD ascertained via prospective follow-up, community referral, or universal screening. A meta-analysis using a random effects model was used to calculate overall effect size estimates for developmental level and symptom severity across ascertainment cohorts. Results: Eleven prospective, ten community referral, and eight universal screening studies were identified, reporting on 1,658 toddlers with ASD. We found no differences in outcomes between community referral and universal screening studies. Relative to both, prospective studies reported significantly higher developmental levels and lower symptom severities. Conclusions: Outcomes of young children with ASD ascertained via prospective follow-up are better than those of children with ASD recruited via community referral or universal screening. Although we discuss why sampling bias is not likely the driving force behind these findings, we cannot rule out the possibility that sampling bias contributes to the observed differences; future studies should probe the effects of sociodemographic variables on clinical outcomes as a function of ascertainment strategy. This limitation notwithstanding, our results raise the possibility that prospective follow-up may confer a ‘surveillance effect’ that contributes to improved developmental and diagnostic outcomes in children with ASD. Future research should test this hypothesis and determine the specific mechanism by which surveillance may improve outcomes. © 2019 Association for Child and Adolescent Mental Health

Author Keywords
Autism spectrum disorder;  meta-analysis;  outcomes;  sampling bias;  surveillance;  systematic review;  toddlers

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

Positive Affect and Well-Being in Huntington’s Disease Moderates the Association between Functional Impairment and HRQOL Outcomes
(2019) Journal of Huntington’s Disease, 8 (2), pp. 221-232. 

Ready, R.E.^a , Boileau, N.R.^b , Barton, S.K.^c , Lai, J.-S.^d , McCormack, M.K.^{e f} , Cella, D.^d , Fritz, N.E.^g , Paulsen, J.S.^h , Carlozzi, N.E.^b

^a Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, United States
^b Department of Physical Medicine and Rehabilitation, University of Michigan, North Campus Research Complex, Building NCRC B14, 2800 Plymouth Road, Ann Arbor, MI 48109-2800, United States
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^e Department of Psychiatry, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ, United States
^f Department of Pathology, Rowan-SOM, Stratford, NJ, United States
^g Physical Therapy Program, Wayne State University, Detroit, MI, United States
^h Departments of Neurology, Psychiatry, and Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States

Abstract
Background: Positive affect is associated with resiliency and beneficial health outcomes, but little is known about associations between positive affect and health-related quality of life (HRQOL) in Huntington’s disease (HD). Objective: This longitudinal study determined the association between positive affect and several HRQOL outcomes in persons with HD. Functional status was examined as a moderator of the association between positive affect and HRQOL. Methods: Participants, with premanifest (i.e., genetically at risk but no clinical diagnosis, n = 50) and manifest HD (earlystage n = 171; late-stage n = 101), completed a measure of positive affect and well-being and several HRQOL measures at baseline, 12-, and 24-month follow-ups. UHDRS Functional Assessment scale indicated functional status. Results: Positive affect was associated with better HRQOL for persons with premanifest and manifest HD over the 24-month time frame. These associations were moderated by functional status. For persons with higher functional status, positive affect was associated with better HRQOL, including less depression, lower anxiety, less anger, better social role satisfaction, better executive functions, greater upper extremity function, less dyscontrol, and less concern with death and dying. For persons with lower functional status, positive affect was not associated with HRQOL. Conclusions: Positive affect predicted better self-reported HRQOL over a 24-month period in persons with premanifest and manifest HD, particularly when participnats had better functional status. Interventions to enhance positive affect in HD may have beneficial effects on HRQOL. © 2019-IOS Press and the authors. All rights reserved.

Author Keywords
Functional assessment;  Huntington’s disease;  Longitudinal;  Positive affect;  Quality of life

Document Type: Article
Publication Stage: Final
Source: Scopus

Emotional response inhibition is greater in older than younger adults
(2019) Frontiers in Psychology, 10 (APR), art. no. 961, . 

Waring, J.D.^a , Greif, T.R.^a , Lenze, E.J.^b

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

Abstract
Emotional information rapidly captures our attention and also often invokes automatic response tendencies, whereby positive information motivates approach, while negative information encourages avoidance. However, many circumstances require the need to override or inhibit these automatic responses. Control over responses to emotional information remains largely intact in late life, in spite of age-related declines in cognitive control and inhibition of responses to non-emotional information. The goal of this behavioral study was to understand how the aging process influences emotional response inhibition for positive and negative information in older adults. We examined emotional response inhibition in 36 healthy older adults (ages 60-89) and 44 younger adults (ages 18-22) using an emotional Go/No-Go task presenting happy (positive), fearful (negative), and neutral faces. In both younger and older adults, happy faces produced more approach-related behavior (i.e., fewer misses), while fearful faces produced more avoidance-related behavior, in keeping with theories of approach/avoidance-motivated responses. Calculation of speed/accuracy trade-offs between response times and false alarm rates revealed that younger and older adults both favored speed at the expense of accuracy, most robustly within blocks with fearful faces. However, there was no indication that the strength of the speed/accuracy trade-off differed between younger and older adults. Although younger adults were faster to respond to all types of faces, older adults had greater emotional response inhibition (i.e., fewer false alarms). This is the first study to directly test effects of aging on emotional response inhibition. Complementing previous literature in the domains of attention and memory, these results provide new evidence that in the domain of response inhibition older adults may more effectively employ emotion regulatory ability, albeit on a slower time course, compared to younger adults. The present study extends the literature of emotional response inhibition in younger adulthood into late life, and in doing so further elucidates how cognitive aging interacts with affective control processes. © 2019 Waring, Greif and Lenze.

Author Keywords
Aging;  Emotion;  Emotion Regulation;  Executive Function;  Facial expressions;  Go/No Go;  Older adult;  Response inhibition

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

A comparison of resting state functional magnetic resonance imaging to invasive electrocortical stimulation for sensorimotor mapping in pediatric patients
(2019) NeuroImage: Clinical, 23, art. no. 101850, . 

Roland, J.L.^a , Hacker, C.D.^a , Snyder, A.Z.^{b c} , Shimony, J.S.^b , Zempel, J.M.^c , Limbrick, D.D.^a , Smyth, M.D.^a , Leuthardt, E.C.^{a d e f g h}

^a Department of Neurological Surgery, Washington University in St. Louis, St. Louis, MO, United States
^b Mallinckrodt Institute Radiology, Washington University in St. Louis, St. Louis, MO, United States
^c Neurology, Washington University in St. Louis, St. Louis, MO, United States
^d Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^e Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^f Mechanical Engineering and Materials Science, Washington University in St. Louis, St. Louis, MO, United States
^g Center for Innovation in Neuroscience and Technology, Washington University in St. Louis, St. Louis, MO, United States
^h Brain Laser Center, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Localizing neurologic function within the brain remains a significant challenge in clinical neurosurgery. Invasive mapping with direct electrocortical stimulation currently is the clinical gold standard but is impractical in young or cognitively delayed patients who are unable to reliably perform tasks. Resting state functional magnetic resonance imaging non-invasively identifies resting state networks without the need for task performance, hence, is well suited to pediatric patients. We compared sensorimotor network localization by resting state fMRI to cortical stimulation sensory and motor mapping in 16 pediatric patients aged 3.1 to 18.6 years. All had medically refractory epilepsy that required invasive electrographic monitoring and stimulation mapping. The resting state fMRI data were analyzed using a previously trained machine learning classifier that has previously been evaluated in adults. We report comparable functional localization by resting state fMRI compared to stimulation mapping. These results provide strong evidence for the utility of resting state functional imaging in the localization of sensorimotor cortex across a wide range of pediatric patients. © 2019 The Author(s)

Author Keywords
Functional MRI;  Mapping;  Neurosurgery;  Pediatric;  Resting state

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

Additive effects of item-specific and congruency sequence effects in the vocal stroop task
(2019) Frontiers in Psychology, 10 (APR), art. no. 860, . 

Aschenbrenner, A., Balota, D.

Washington University in St. Louis, United States

Abstract
There is a growing interest in assessing how cognitive processes fluidly adjust across trials within a task. Dynamic adjustments of control are typically measured using the congruency sequence effect (CSE), which refers to the reduction in interference following an incongruent trial, relative to a congruent trial. However, it is unclear if this effect stems from a general control mechanism or a distinct process tied to cross-trial reengagement of the task set. We examine the relationship of the CSE with another measure of control referred to as the item-specific proportion congruency effect (ISPC), the finding that frequently occurring congruent items exhibit greater interference than items that are often incongruent. If the two effects reflect the same control mechanism, one should find interactive effects of CSE and ISPC. We report results from three experiments utilizing a vocal Stroop task that manipulated these two effects while controlling for variables that are often confounded in the literature. Across three experiments, we observed large CSE and ISPC effects. Importantly, these effects were robustly additive with one another (Bayes Factor for the null approaching 9). This finding indicates that the CSE and ISPC arise from independent mechanisms and suggests the CSE in Stroop may reflect a more general response adjustment process that is not directly tied to trial-by-trial changes in attentional control. © 2019 Aschenbrenner and Balota.

Author Keywords
Attention;  Attentional control;  Cognitive control;  Congruency sequence effect (CSE);  Item-specific proportion congruency

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

Detection of TAR DNA-binding protein 43 (TDP-43) oligomers as initial intermediate species during aggregate formation
(2019) Journal of Biological Chemistry, 294 (17), pp. 6696-6709. 

French, R.L.^a , Grese, Z.R.^a , Aligireddy, H.^a , Dhavale, D.D.^b , Reeb, A.N.^{a d} , Kedia, N.^c , Kotzbauer, P.T.^b , Bieschke, J.^c , Ayala, Y.M.^a

^a Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St. Louis, MO 63103, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c MRC Prion Unit, University College London, London, W1W7FF, United Kingdom
^d Dept. of Otolaryngology, Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Aggregates of the RNA-binding protein TDP-43 (TAR DNA-binding protein) are a hallmark of the overlapping neurode-generative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The process of TDP-43 aggregation remains poorly understood, and whether it includes formation of intermediate complexes is unknown. Here, we analyzed aggregates derived from purified TDP-43 under semidenaturing conditions, identifying distinct oligomeric complexes at the initial time points before the formation of large aggregates. We found that this early oligomerization stageisprimarily driven by TDP-43’s RNA-binding region. Specific binding to GU-rich RNA strongly inhibited both TDP-43 oligomerization and aggregation, suggesting that RNA interactions are critical for maintaining TDP-43 solubility. Moreover, we analyzed TDP-43 liquid-liquid phase separation and detected similar detergent-resistant oligomers upon maturation of liquid droplets into solid-like fibrils. These results strongly suggest that the oligomers form during the early steps of TDP-43 misfolding. Importantly, the ALS-linked TDP-43 mutations A315T and M337V significantly accelerate aggregation, rapidly decreasing the monomeric population and shortening the oligomeric phase. We also show that aggregates generated from purified TDP-43 seed intracellular aggregation detected by established TDP-43 pathology markers. Remarkably, cytoplasmic aggregate seeding was detected earlier for the A315T and M337V variants and was 50% more widespread than for WT TDP-43 aggregates. We provide evidence for an initial step of TDP-43 self-assembly into intermediate oligomeric complexes, whereby these complexes may provide a scaffold for aggregation. This process is altered by ALS-linked mutations, underscoring the role of perturbations in TDP-43 homeostasis in protein aggregation and ALS-FTD pathogenesis. © 2019 French et al.

Document Type: Article
Publication Stage: Final
Source: Scopus