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“Challenges and Opportunities with Causal Discovery Algorithms: Application to Alzheimer’s Pathophysiology” (2020) Scientific Reports

Challenges and Opportunities with Causal Discovery Algorithms: Application to Alzheimer’s Pathophysiology
(2020) Scientific Reports, 10 (1), art. no. 2975, .

Shen, X.^a , Ma, S.^a , Vemuri, P.^b , Simon, G.^a , Weiner, M.W.^c , Aisen, P.^d , Petersen, R.^b , Jack, C.R.^b , Saykin, A.J.^e , Jagust, W.^f , Trojanowki, J.Q.^g , Toga, A.W.^d , Beckett, L.^h , Green, R.C.ⁱ , Morris, J.^j , Shaw, L.M.^g , Khachaturian, Z.^k , Sorensen, G.^l , Carrillo, M.^m , Kuller, L.ⁿ , Raichle, M.^j , Paul, S.^o , Davies, P.^p , Fillit, H.^q , Hefti, F.^r , Holtzman, D.^j , Mesulam, M.M.^s , Potter, W.^t , Snyder, P.^u , Schwartz, A.^v , Montine, T.^w , Thomas, R.G.^x , Donohue, M.^x , Walter, S.^x , Gessert, D.^x , Sather, T.^x , Jiminez, G.^x , Balasubramanian, A.B.^x , Mason, J.^x , Sim, I.^x , Harvey, D.^h , Bernstein, M.^b , Fox, N.^y , Thompson, P.^z , Schuff, N.^c , DeCArli, C.^h , Borowski, B.^b , Gunter, J.^b , Senjem, M.^b , Jones, D.^b , Kantarci, K.^b , Ward, C.^b , Koeppe, R.A.^aa , Foster, N.^ab , Reiman, E.M.^ac , Chen, K.^ac , Mathis, C.ⁿ , Landau, S.^f , Cairns, N.J.^j , Franklin, E.^j , Taylor-Reinwald, L.^j , Lee, V.^g , Korecka, M.^g , Figurski, M.^g , Crawford, K.^d , Neu, S.^d , Foroud, T.M.^e , Potkin, S.^ad , Faber, K.^e , Kim, S.^e , Nho, K.^e , Thal, L.^x , Buckholtz, N.^ae , Albert, M.^af , Frank, R.^ag , Hsiao, J.^ae , Kaye, J.^ah , Quinn, J.^ah , Silbert, L.^ah , Lind, B.^ah , Carter, R.^ah , Dolen, S.^ah , Schneider, L.S.^d , Pawluczyk, S.^d , Beccera, M.^d , Teodoro, L.^d , Spann, B.M.^d , Brewer, J.^x , Vanderswag, H.^x , Fleisher, A.^x , Heidebrink, J.L.^aa , Lord, J.L.^aa , Mason, S.S.^e , Albers, C.S.^b , Knopman, D.^b , Johnson, K.^b , Doody, R.S.^ai , Villanueva-Meyer, J.^ai , Pavlik, V.^ai , Shibley, V.^ai , Chowdhury, M.^ai , Rountree, S.^ai , Dang, M.^ai , Stern, Y.^aj , Honig, L.S.^aj , Bell, K.L.^aj , Ances, B.^j , Carroll, M.^j , Creech, M.L.^j , Franklin, E.^j , Mintun, M.A.^j , Schneider, S.^j , Oliver, A.^j , Marson, D.^ak , Geldmacher, D.^ak , Love, M.N.^ak , Griffith, R.^ak , Clark, D.^ak , Brockington, J.^ak , Roberson, E.^ak , Grossman, H.^al , Mitsis, E.^al , Shah, R.C.^am , deToledo-Morrell, L.^am , Duara, R.^an , Greig-Custo, M.T.^an , Barker, W.^an , Onyike, C.^af , D’Agostino, D.^af , Kielb, S.^af , Sadowski, M.^ao , Sheikh, M.O.^ao , Ulysse, A.^ao , Gaikwad, M.^ao , Doraiswamy, P.M.^ap , Petrella, J.R.^ap , Borges-Neto, S.^ap , Wong, T.Z.^ap , Coleman, E.^ap , Arnold, S.E.^g , Karlawish, J.H.^g , Wolk, D.A.^g , Clark, C.M.^g , Smith, C.D.^aq , Jicha, G.^aq , Hardy, P.^aq , Sinha, P.^aq , Oates, E.^aq , Conrad, G.^aq , Lopez, O.L.ⁿ , Oakley, M.A.ⁿ , Simpson, D.M.ⁿ , Porsteinsson, A.P.^ar , Goldstein, B.S.^ar , Martin, K.^ar , Makino, K.M.^ar , Ismail, M.S.^ar , Brand, C.^ar , Preda, A.^ad , Nguyen, D.^ad , Womack, K.^as , Mathews, D.^as , Quiceno, M.^as , Levey, A.I.^at , Lah, J.J.^at , Cellar, J.S.^at , Burns, J.M.^au , Swerdlow, R.H.^au , Brooks, W.M.^au , Apostolova, L.^z , Tingus, K.^z , Woo, E.^z , Silverman, D.H.S.^z , Lu, P.H.^z , Bartzokis, G.^z , Graff-Radford, N.R.^av , Parfitt, F.^av , Poki-Walker, K.^av , Farlow, M.R.^e , Hake, A.M.^e , Matthews, B.R.^e , Brosch, J.R.^e , Herring, S.^e , van Dyck, C.H.^aw , Carson, R.E.^aw , MacAvoy, M.G.^aw , Varma, P.^aw , Chertkow, H.^ax , Bergman, H.^ax , Hosein, C.^ax , Black, S.^ay , Stefanovic, B.^ay , Caldwell, C.^ay , Hsiung, G.-Y.R.^az , Mudge, B.^az , Sossi, V.^az , Feldman, H.^az , Assaly, M.^az , Finger, E.^ba , Pasternack, S.^ba , Rachisky, I.^ba , Rogers, J.^ba , Trost, D.^ba , Kertesz, A.^ba , Bernick, C.^bb , Munic, D.^bb , Rogalski, E.^s , Lipowski, K.^s , Weintraub, S.^s , Bonakdarpour, B.^s , Kerwin, D.^s , Wu, C.-K.^s , Johnson, N.^s , Sadowsky, C.^bc , Villena, T.^bc , Turner, R.S.^bd , Johnson, K.^bd , Reynolds, B.^bd , Sperling, R.A.ⁱ , Johnson, K.A.ⁱ , Marshall, G.ⁱ , Yesavage, J.^be , Taylor, J.L.^be , Lane, B.^be , Rosen, A.^be , Tinklenberg, J.^be , Sabbagh, M.N.^bf , Belden, C.M.^bf , Jacobson, S.A.^bf , Sirrel, S.A.^bf , Kowall, N.^bg , Killiany, R.^bg , Budson, A.E.^bg , Norbash, A.^bg , Johnson, P.L.^bg , Obisesan, T.O.^bh , Wolday, S.^bh , Allard, J.^bh , Lerner, A.^bi , Ogrocki, P.^bi , Tatsuoka, C.^bi , Fatica, P.^bi , Fletcher, E.^h , Maillard, P.^h , Olichney, J.^h , DeCarli, C.^h , Carmichael, O.^h , Kittur, S.^bj , Borrie, M.^bk , Lee, T.-Y.^bk , Bartha, R.^bk , Johnson, S.^bl , Asthana, S.^bl , Carlsson, C.M.^bl , Tariot, P.^ac , Burke, A.^ac , Milliken, A.M.^ac , Trncic, N.^ac , Fleisher, A.^ac , Reeder, S.^ac , Bates, V.^bm , Capote, H.^bm , Rainka, M.^bm , Scharre, D.W.^bn , Kataki, M.^bn , Kelly, B.^bn , Zimmerman, E.A.^bo , Celmins, D.^bo , Brown, A.D.^bo , Pearlson, G.D.^bp , Blank, K.^bp , Anderson, K.^bp , Flashman, L.A.^bq , Seltzer, M.^bq , Hynes, M.L.^bq , Santulli, R.B.^bq , Sink, K.M.^br , Gordineer, L.^br , Williamson, J.D.^br , Garg, P.^br , Watkins, F.^br , Ott, B.R.^bs , Tremont, G.^bs , Daiello, L.A.^bs , Salloway, S.^bt , Malloy, P.^bt , Correia, S.^bt , Rosen, H.J.^c , Miller, B.L.^c , Perry, D.^c , Mintzer, J.^bu , Spicer, K.^bu , Bachman, D.^bu , Pomara, N.^bv , Hernando, R.^bv , Sarrael, A.^bv , Schultz, S.K.^bw , Smith, K.E.^bw , Koleva, H.^bw , Nam, K.W.^bw , Shim, H.^bw , Relkin, N.^o , Chaing, G.^o , Lin, M.^o , Ravdin, L.^o , Smith, A.^bx , Raj, B.A.^bx , Fargher, K.^bx , the Alzheimer’s Disease Neuroimaging Initiative^by

^a Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, United States
^b Mayo Clinic, Rochester, MN 55905, United States
^c University of California, San Francisco, United States
^d University of Southern California, Los Angeles, United States
^e Indiana University, Bloomington, United States
^f University of California, Berkeley, Berkeley, United States
^g University of Pennsylvania, Philadelphia, United States
^h University of California, Davis, Davis, United States
ⁱ Brigham and Women’s Hospital/Harvard Medical School, Boston, United States
^j Washington University St. Louis, St. Louis, United States
^k Prevent Alzheimer’s Disease, Rockville, 2020, United States
^l Siemens, Munich, Germany
^m Alzheimer’s AssociationIL, United States
ⁿ University of PittsburghPA, United States
^o Cornell UniversityNY, United States
^p Albert Einstein College of Medicine of Yeshiva UniversityNY, United States
^q AD Drug Discovery FoundationNY, United States
^r Acumen PharmaceuticalsCA, United States
^s Northwestern UniversityIL, United States
^t National Institute of Mental HealthMD, United States
^u Brown UniversityRI, United States
^v Eli LillyIN, United States
^w University of WashingtonWA, United States
^x University of California, San Diego, CA, United States
^y University of London, London, United Kingdom
^z University of California, Los Angeles, CA, United States
^aa University of MichiganMI, United States
^ab University of UtahUT, United States
^ac Banner Alzheimer’s InstituteAZ, United States
^ad University of California, Irvine, CA, United States
^ae National Institute on AgingMD, United States
^af Johns Hopkins UniversityMD, United States
^ag Richard Frank ConsultingNH, United States
^ah Oregon Health and Science UniversityOR, United States
^ai Baylor College of MedicineTX, United States
^aj Columbia University Medical CenterNY, United States
^ak University of Alabama-, Birmingham, AL, United States
^al Mount Sinai School of MedicineNY, United States
^am Rush University Medical Center, Rush UniversityIL, United States
^an Wien CenterFL, United States
^ao NewYork UniversityNY, United States
^ap Duke University Medical CenterNC, United States
^aq University of KentuckyKY, United States
^ar University of Rochester Medical CenterNY, United States
^as University of Texas Southwestern Medical SchoolTX, United States
^at Emory UniversityGA, United States
^au University of Kansas, Medical CenterKS, United States
^av Mayo Clinic, Jacksonville, FL, United States
^aw Yale University School of MedicineCT, United States
^ax McGill University, Montreal-Jewish General HospitalQC, Canada
^ay Sunnybrook Health SciencesON, Canada
^az U.B.C. Clinic for AD & Related DisordersBC, Canada
^ba Cognitive Neurology-St. Joseph’sON, Canada
^bb Cleveland Clinic Lou Ruvo Center for Brain HealthOH, United States
^bc Premiere Research Inst (Palm Beach Neurology)FL, United States
^bd Georgetown University Medical Center, Washington, DC, United States
^be Stanford UniversityCA, United States
^bf Banner Sun Health Research InstituteAZ, United States
^bg Boston UniversityMA, United States
^bh Howard University, Washington, DC, United States
^bi Case Western Reserve UniversityOH, United States
^bj Neurological Care of CNYNY, United States
^bk Parkwood HospitalPA, United States
^bl University of WisconsinWI, United States
^bm Dent Neurologic InstituteNY, United States
^bn Ohio State UniversityOH, United States
^bo Albany Medical CollegeNY, United States
^bp Hartford Hospital, Olin Neuropsychiatry Research CenterCT, United States
^bq Dartmouth-Hitchcock Medical CenterNH, United States
^br Wake Forest University Health SciencesNC, United States
^bs Rhode Island HospitalRI, United States
^bt Butler HospitalRI, United States
^bu Medical University South CarolinaCA, United States
^bv Nathan Kline InstituteNY, United States
^bw University of Iowa College of MedicineIA, United States
^bx USF Health Byrd Alzheimer’s Institute, University of South FloridaFL, United States

Abstract
Causal Structure Discovery (CSD) is the problem of identifying causal relationships from large quantities of data through computational methods. With the limited ability of traditional association-based computational methods to discover causal relationships, CSD methodologies are gaining popularity. The goal of the study was to systematically examine whether (i) CSD methods can discover the known causal relationships from observational clinical data and (ii) to offer guidance to accurately discover known causal relationships. We used Alzheimer’s disease (AD), a complex progressive disease, as a model because the well-established evidence provides a “gold-standard” causal graph for evaluation. We evaluated two CSD methods, Fast Causal Inference (FCI) and Fast Greedy Equivalence Search (FGES) in their ability to discover this structure from data collected by the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We used structural equation models (which is not designed for CSD) as control. We applied these methods under three scenarios defined by increasing amounts of background knowledge provided to the methods. The methods were evaluated by comparing the resulting causal relationships with the “gold standard” graph that was constructed from literature. Dedicated CSD methods managed to discover graphs that nearly coincided with the gold standard. For best results, CSD algorithms should be used with longitudinal data providing as much prior knowledge as possible. © 2020, The Author(s).

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

“The English lexicon mirrors functional brain activation for a sensory hierarchy dominated by vision and audition: Point-counterpoint” (2020) Journal of Neurolinguistics

The English lexicon mirrors functional brain activation for a sensory hierarchy dominated by vision and audition: Point-counterpoint
(2020) Journal of Neurolinguistics, 55, art. no. 100895, .

Reilly, J.^a ^b , Flurie, M.^a ^b , Peelle, J.E.^c

^a Eleanor M. Saffran Center for Cognitive Neuroscience, United States
^b Department of Communication Sciences and Disorders Temple University, Philadelphia, PA, United States
^c Department of Otolaryngology Washington University in St. Louis, St. Louis, MO, United States

Abstract
Word meanings are often suffused with sensory, motor, and affective features. For many of us, a word such as beach evokes a diverse range of pleasant associations including blue skies (visual), gritty sand (tactile), crashing waves (auditory), and the distinctive smell of sunscreen (olfactory). Aristotle argued for a hierarchy of the senses where vision and audition eclipse the lesser modalities of odor, taste, and touch. A direct test of Aristotle’s premise was recently made possible with the establishment of the Lancaster Sensorimotor Norms (2019), a crowdsourced database cataloging sensorimotor salience for nearly 40,000 English words. Neurosynth, a metanalytic database of functional magnetic resonance imaging studies, can potentially confirm if Aristotle’s sensory hierarchy is reflected in functional activation within the human brain. We correlated sensory salience of English words as assessed by subjective ratings of vision, audition, olfaction, touch, and gustation (Lancaster Ratings) with volumes of cortical activation for each of these respective sensory modalities (Neurosynth). English word ratings reflected the following sensory hierarchy: vision > audition > haptic > olfaction ≈ gustation. This linguistic hierarchy nearly perfectly correlated with voxel counts of functional activation maps by each sensory modality (Pearson r =. 99). These findings are grossly consistent with Aristotle’s hierarchy of the senses. We discuss implications and counterevidence from other natural languages. © 2020 Elsevier Ltd

Author Keywords
fMRI; Language evolution; Perception; Semantic memory; Sensation

Document Type: Article
Publication Stage: Final
Source: Scopus

“Is it time? Episodic imagining and the discounting of delayed and probabilistic rewards in young and older adults” (2020) Cognition

Is it time? Episodic imagining and the discounting of delayed and probabilistic rewards in young and older adults
(2020) Cognition, 199, art. no. 104222, .

Mok, J.N.Y.^a , Kwan, D.^a , Green, L.^b , Myerson, J.^b , Craver, C.F.^c , Rosenbaum, R.S.^a ^d

^a Department of Psychology, York University, Toronto, Ontario, Canada
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Philosophy, Philosophy-Neuroscience-Psychology Program, Washington University in St. Louis
^d Rotman Research Institute, Baycrest Health Sciences, Toronto, Ontario, Canada

Abstract
Remembering and imagining specific, personal experiences can help shape our decisions. For example, cues to imagine future events can reduce delay discounting (i.e., increase the subjective value of future rewards). It is not known, however, whether such cues can also modulate other forms of reward discounting, such as probability discounting (i.e., the decrease in the subjective value of a possible reward as the odds against its occurrence increase). In addition, it is unclear whether there are age-related differences in the effects of cueing on either delay or probability discounting. Accordingly, young and older adult participants were administered delay and probability discounting tasks both with and without cues to imagine specific, personally meaningful events. As expected, cued episodic imagining decreased the discounting of delayed rewards. Notably, however, this effect was significantly less pronounced in older adults. In contrast to the effects of cueing on delay discounting, personally relevant event cues had little or no effect on the discounting of probabilistic rewards in either young or older adults; Bayesian analysis revealed compelling support for the null hypothesis that event cues do not modulate the subjective value of probabilistic rewards. In sum, imagining future events appears only to affect decisions involving delayed rewards. Although the cueing effect is smaller in older adults, nevertheless, it likely contributes to how adults of all ages evaluate delayed rewards and thus, it is, in fact, about time. © 2020 Elsevier B.V.

Author Keywords
Aging; Delay discounting; Episodic cueing; Future imagining; Intertemporal choice; Probability discounting

Document Type: Review
Publication Stage: Final
Source: Scopus

“Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2” (2020) Neurobiology of Disease

Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2
(2020) Neurobiology of Disease, 139, art. no. 104817, .

Hsu, S.^a , Pimenova, A.A.^b , Hayes, K.^a , Villa, J.A.^a , Rosene, M.J.^a , Jere, M.^a , Goate, A.M.^b , Karch, C.M.^a

^a Department of Psychiatry, Washington University School of Medicine, 425 S Euclid Avenue, St Louis, MO 63110, United States
^b Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, United States

Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease that is clinically characterized by progressive cognitive decline. More than 200 pathogenic mutations have been identified in amyloid-β precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Additionally, common and rare variants occur within APP, PSEN1, and PSEN2 that may be risk factors, protective factors, or benign, non-pathogenic polymorphisms. Yet, to date, no single study has carefully examined the effect of all of the variants of unknown significance reported in APP, PSEN1 and PSEN2 on Aβ isoform levels in vitro. In this study, we analyzed Aβ isoform levels by ELISA in a cell-based system in which each reported pathogenic and risk variant in APP, PSEN1, and PSEN2 was expressed individually. In order to classify variants for which limited family history data is available, we have implemented an algorithm for determining pathogenicity using available information from multiple domains, including genetic, bioinformatic, and in vitro analyses. We identified 90 variants of unknown significance and classified 19 as likely pathogenic mutations. We also propose that five variants are possibly protective. In defining a subset of these variants as pathogenic, individuals from these families may eligible to enroll in observational studies and clinical trials. © 2020 The Authors

Author Keywords
Alzheimer’s disease; APP; Cell-based assays; Pathogenicity algorithm; PSEN1; PSEN2

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

“Socioeconomic status and race are correlated with affective symptoms in multiple sclerosis” (2020) Multiple Sclerosis and Related Disorders

Socioeconomic status and race are correlated with affective symptoms in multiple sclerosis
(2020) Multiple Sclerosis and Related Disorders, 41, art. no. 102010, .

Wang, Y.^a , Tian, F.^a , Fitzgerald, K.C.^a , Bhattarai, J.“.^b , Naismith, R.T.^c , Hyland, M.^d , Calabresi, P.A.^a , Mowry, E.M.^a

^a Department of Neurology, Johns Hopkins University School of Medicine, 600 N. Wolfe St.Pathology 627, Baltimore, MD 21287, United States
^b Department of Physical Medicine and Rehabilitation, Johns Hopkins University School of Medicine, United States
^c Department of Neurology, Washington University in St. Louis School of Medicine, United States
^d Department of Neurology, University of Rochester School of Medicine, United States

Abstract
Objective: Investigate the relationship between socioeconomic status (SES) and race with self-reported fatigue, depression, and anxiety levels in multiple sclerosis (MS). Methods: Cross-sectional review of the MS Partners Advancing Technology and Health Solutions (MS PATHS) database for adults with MS in the United States. We evaluated race and socioeconomic status (available markers: insurance, employment status, or level of education) as predictors of fatigue, depression, and anxiety sub-scores of the Neuro-QoL (Quality of life in neurological disorders), with particular interest between Caucasians/whites (CA) and African Americans/blacks (AA). Multivariate linear regression models included as covariates age, sex, disability status, smoking status, body mass index, and disease-modifying therapy. Results: 7,430 individuals were included; compared to CA, AA tended to be younger, more female-predominant, and had a higher level of disability. AA had completed slightly less education, had a higher level of Medicaid coverage or uninsured status, and had higher rates of unemployed or disabled status. In the univariate model, markers of lower SES, by whichever definition we used, correlated with worse affective symptoms. In the multivariate model stratified by race, CA showed similar trends. In contrast, in AA, only lower SES by employment status was correlated with worse affective symptoms. In both CA and AA, moderate and severe level of disability correlated with worse affective symptoms. Conclusion: SES and race may influence affective symptoms reported by individuals with MS. The reasons for the correlation are likely multifactorial. Longitudinal studies should strive to identify factors associated with risk of affective symptoms in MS that may be modifiable. © 2020 Elsevier B.V.

Author Keywords
Epidemiology; Health outcomes; Multiple sclerosis; Quality of life

Document Type: Article
Publication Stage: Final
Source: Scopus

“Does the child brain rest?: An examination and interpretation of resting cognition in developmental cognitive neuroscience” (2020) NeuroImage

Does the child brain rest?: An examination and interpretation of resting cognition in developmental cognitive neuroscience
(2020) NeuroImage, 212, art. no. 116688, .

Camacho, M.C.^a , Quiñones-Camacho, L.E.^b , Perlman, S.B.^a ^b

^a Division of Biology and Biomedical Sciences (Neurosciences), Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States

Abstract
In cognitive neuroscience, measurements of “resting baseline” are often considered stable across age and used as a reference point against which to judge cognitive state. The task-based approach—comparing resting baseline to task conditions—implies that resting baseline is an equalizer across participants and—in the case of studies of developmental changes in cognition—across age groups. In contrast, network neuroscience explicitly examines the development of “resting state” networks across age, at odds with the idea of a consistent resting baseline. Little attention has been paid to how cognition during rest may shift across development, particularly in children under the age of eight. Childhood is marked by striking maturation of neural systems, including a protracted developmental period for cognitive control systems. To grow and shape these cognitive systems, children have a developmental imperative to engage their neural circuitry at every possible opportunity. Thus, periods of “rest” without specific instructions may require additional control for children as they fight against developmental expectation to move, speak, or otherwise engage. We therefore theorize that the child brain does not rest in a manner consistent with the adult brain as longer rest periods may represent increased cognitive control. To shape this theory, we first review the extant literature on neurodevelopment across early childhood within the context of cognitive development. Next, we present nascent evidence for a destabilized baseline for comparisons across age. Finally, we present recommendations for designing, analyzing, and interpreting tasks conducted with young children as well as for resting state. Future work must aim to tease apart the cognitive context under which we examine functional brain development in young children and take considerations into account unique to each age. © 2020

Author Keywords
Baselines; Brain development; Cognitive development; Early childhood; Resting state

Document Type: Review
Publication Stage: Final
Source: Scopus

“Design-Based stereology and binary image histomorphometry in nerve assessment” (2020) Journal of Neuroscience Methods

Design-Based stereology and binary image histomorphometry in nerve assessment
(2020) Journal of Neuroscience Methods, 336, art. no. 108635, .

Hunter, D.A.^a , Pan, D.^a , Wood, M.D.^a , Snyder-Warwick, A.K.^a , Moore, A.M.^b , Feldman, E.L.^c , Mackinnon, S.E.^a , Brenner, M.J.^d

^a Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine in Saint Louis, St Louis, MO 63110, United States
^b Department of Plastic and Reconstructive Surgery, The Ohio State University, Wexner Medical Center, 915 Olentangy River Rd, Suite 2100, Columbus, OH 43212, United States
^c Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States
^d Department of Otolaryngology – Head and Neck Surgery, University of Michigan, Ann Arbor, MI 48109, United States

Abstract
Background: Stereology and histomorphometry are widely used by investigators to quantify nerve characteristics in normal and pathological states, including nerve injury and regeneration. While these methods of analysis are complementary, no study to date has systematically compared both approaches in peripheral nerve. This study investigated the reliability of design-based stereology versus semi-automated binary imaging histomorphometry for assessing healthy peripheral nerve characteristics. New Method: Stereological analysis was compared to histomorphometry with binary image analysis on uninjured sciatic nerves to determine nerve fiber number, nerve area, neural density, and fiber distribution. Results: Sciatic nerves were harvested from 6 male Lewis rats, aged 8–12 weeks for comprehensive analysis of 6 nerve specimens. From each animal, sciatic nerve specimens were fixed, stained, and sectioned for analysis by light and electron microscopy. Both histomorphometry and stereological peripheral nerve analyses were performed on all specimens by two blinded and independent investigators who quantified nerve fiber count, fiber width, density, and related distribution parameters. Comparison with existing methods: Histomorphometry and stereological analysis provided similar outcomes in nerve fiber number and total nerve area. However, the light microscopy, but not electron microscopy, stereological analysis yielded higher nerve fiber area compared to histomorphometry or manual measurement. Conclusion: Both methods measure similar fiber number and overall nerve fiber area; however, stereology with light microscopy quantified higher fiber area. Histomorphometry optimizes throughput and comprehensive analysis but requires user thresholding. © 2020 Elsevier B.V.

Author Keywords
Binary image analysis; Design-Based stereology; Electron microscopy; Nerve injury; Nerve regeneration; Quantitative histomorphometry

Document Type: Article
Publication Stage: Final
Source: Scopus

“Nerve Entrapments” (2020) Clinics in Plastic Surgery

Nerve Entrapments
(2020) Clinics in Plastic Surgery, 47 (2), pp. 267-278.

Jacobson, L.^a , Dengler, J.^b , Moore, A.M.^c

^a Division of Plastic and Reconstructive Surgery, Department of Surgery, Barnes-Jewish Hospital, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8238, St Louis, MO 63110, United States
^b Division of Plastic and Reconstructive Surgery, Department of Surgery, Sunnybrook Health Sciences Centre, M1-500, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada
^c Department of Plastic and Reconstructive Surgery, The Ohio State University Wexner Medical Center, 915 Olentangy River Road, Suite 2100, Columbus, OH 43212, United States

Abstract
There are more than 2 dozen nerve entrapment syndromes in the body. Generally, these occur at sites of fibroosseous or fibromuscular tunnels. Any insult that leads to an increase in the size of the nerve or a decrease in the volume of the tunnel will cause compression. Resultant nerve ischemia sets off a cascade of events that lead to predictable clinical signs and symptoms. Here, we review the most common nerve entrapment syndromes and highlight their assessment and management. Specific clinical scenarios that require a high suspicion for nerve entrapment are highlighted. © 2020 Elsevier Inc.

Author Keywords
Carpal tunnel syndrome; Cubital tunnel syndrome; Nerve compression; Nerve entrapment; Radial tunnel syndrome

Document Type: Review
Publication Stage: Final
Source: Scopus

“High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539” (2020) International Journal of Radiation Oncology Biology Physics

High-risk Meningioma: Initial Outcomes From NRG Oncology/RTOG 0539
(2020) International Journal of Radiation Oncology Biology Physics, 106 (4), pp. 790-799.

Rogers, C.L.^a , Won, M.^b , Vogelbaum, M.A.^c , Perry, A.^d , Ashby, L.S.^e , Modi, J.M.^f , Alleman, A.M.^g , Galvin, J.^h , Fogh, S.E.^d , Youssef, E.^a , Deb, N.ⁱ , Kwok, Y.^j , Robinson, C.G.^k , Shu, H.-K.^l , Fisher, B.J.^m , Panet-Raymond, V.ⁿ , McMillan, W.G.^o , de Groot, J.F.^p , Zhang, P.^b , Mehta, M.P.^q

^a Department of Radiation Oncology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
^b NRG Oncology Statistics and Data Management Center/American College of Radiology, Philadelphia, PA, United States
^c Moffitt Cancer Center, Tampa, FL, United States
^d University of California–San Francisco, San Francisco, CA, United States
^e Saint Joseph’s Hospital and Medical Center, Phoenix, AZ, United States
^f Yale New Haven Hospital, New Haven, CT, United States
^g The University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
^h IROC Philadelphia, Philadelphia, PA, United States
ⁱ Department of Radiation Oncology, St. Luke’s University Health Network, Bethlehem, PA, United States
^j University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, MD, United States
^k Washington University, St. Louis, MO, United States
^l Emory University, Atlanta, Georgia
^m London Regional Cancer Program, London, Ontario, Canada
ⁿ McGill University, Montréal, Québec, Canada
^o Juravinski Cancer Centre, Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
^p University of Texas MD Anderson Cancer Center, Houston, TX, United States
^q Miami Cancer Institute, Baptist Health, Miami, FL, United States

Abstract
Background: Phase 2 cooperative group meningioma trial assessing the safety and efficacy of risk-adaptive management strategies. This is the initial analysis of the high-risk cohort. Methods and Materials: High-risk patients were those with a new or recurrent World Health Organization (WHO) grade III meningioma of any resection extent, recurrent WHO grade II of any resection extent, or new WHO grade II after subtotal resection. Patients received intensity-modulated radiotherapy (IMRT) using a simultaneous integrated boost technique (60 Gy high dose and 54 Gy low dose in 30 fractions). Three-year progression-free survival (PFS) was the primary endpoint. Adverse events (AEs) were scored per NCI Common Terminology Criteria for Adverse Events version 3. Results: Of 57 enrolled patients, 53 received protocol treatment. Median follow-up was 4.0 years (4.8 years for living patients). Two patients withdrew without progression before year 3; for the remaining 51 patients, 3-year PFS was 58.8%. Among all 53 protocol-treated patients, 3-year PFS was 59.2%. Three-year local control was 68.9%, and overall survival was 78.6%. Of 51 patients, 1 patient (1.9%) experienced a late grade-5 necrosis-related AE. All other acute (23 of 53 patients) and late (21 of 51 patients) AEs were grades 1 to 3. Conclusions: Patients with high-risk meningioma treated with IMRT (60 Gy/30) experienced 3-year PFS of 58.8%. Combined acute and late AEs were limited to grades 1 to 3, except for a single necrosis-related grade 5 event. These results support postoperative IMRT for high-risk meningioma and invite ongoing investigations to improve outcomes further. © 2019 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Huntington’s Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy” (2020) Neuron

Huntington’s Disease Pathogenesis Is Modified In Vivo by Alfy/Wdfy3 and Selective Macroautophagy
(2020) Neuron, 105 (5), pp. 813-821.e6.

Fox, L.M.^a ^b , Kim, K.^b , Johnson, C.W.^b , Chen, S.^e , Croce, K.R.^c , Victor, M.B.^e , Eenjes, E.^b , Bosco, J.R.^b , Randolph, L.K.^a , Dragatsis, I.^f , Dragich, J.M.^b , Yoo, A.S.^e , Yamamoto, A.^a ^b ^d

^a Doctoral Program in Neurobiology and Behavior, Department of Neuroscience, Columbia University, New York, NY, United States
^b Department of Neurology, Columbia University, New York, NY, United States
^c Graduate Program in Pathobiology and Molecular Medicine, Columbia University, New York, NY, United States
^d Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
^e Department of Developmental Biology, Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Physiology, University of Tennessee, Memphis, TN, United States

Abstract
Fox et al. demonstrate in a Huntington’s disease (HD) mouse model and HD-patient-derived neurons that the autophagy adaptor protein Alfy/WDFY3 is required for removal of aggregated protein and that depletion of Alfy hastens the pathogenic onset of HD. © 2019 Elsevier Inc.

Despite being an autosomal dominant disorder caused by a known coding mutation in the gene HTT, Huntington’s disease (HD) patients with similar trinucleotide repeat mutations can have an age of onset that varies by decades. One likely contributing factor is the genetic heterogeneity of patients that might modify their vulnerability to disease. We report that although the heterozygous depletion of the autophagy adaptor protein Alfy/Wdfy3 has no consequence in control mice, it significantly accelerates age of onset and progression of HD pathogenesis. Alfy is required in the adult brain for the autophagy-dependent clearance of proteinaceous deposits, and its depletion in mice and neurons derived from patient fibroblasts accelerates the aberrant accumulation of this pathological hallmark shared across adult-onset neurodegenerative diseases. These findings indicate that selectively compromising the ability to eliminate aggregated proteins is a pathogenic driver, and the selective elimination of aggregates may confer disease resistance. © 2019 Elsevier Inc.

Author Keywords
Alfy; autophagy; direct conversion; Huntington’s disease; mice; neurodegeneration; patient fibroblasts; proteinopathy; selective autophagy; Wdfy3

Document Type: Article
Publication Stage: Final
Source: Scopus

“Assessing consonant production in children with cochlear implants” (2020) Journal of Communication Disorders

Assessing consonant production in children with cochlear implants
(2020) Journal of Communication Disorders, 84, art. no. 105966, .

Sundarrajan, M.^a , Tobey, E.A.^b , Nicholas, J.^c , Geers, A.E.^b

^a Department of Speech-Language Pathology, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, United States
^b Dallas Cochlear Implant Program, Callier Advanced Hearing Research Center, University of Texas at Dallas, Dallas, TX, United States
^c Department of Otolaryngology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: The objective of this study was to investigate the development of consonant inventory and accuracy in pediatric cochlear implant (CI) recipients and compare their performance to typical hearing (TH) children. Methods: One hundred and twenty nine children with CIs, implanted between 6–38 months of age, and 30 age-matched children with TH participated in this study. Spontaneous speech samples were collected at 3.5 and 4.5 years chronological age and the first 100 different words spoken by each participant were transcribed. Two consonant production measures were subsequently calculated to assess consonant acquisition and mastery. The percentage of Consonants Correct (CC) was used for measuring accuracy and Consonant Diversity (CD), an inventory measure, was used to identify the number of different consonants spoken by each participant. Repeated measures analyses of variance were conducted to examine the differences in consonant production scores based on presence of CI (participants with CI versus typical hearing (TH) participants), and chronological age at data collection (3.5 years versus 4.5 years). Results: CI recipients displayed lower consonant production scores compared to TH children. Children with the most device experience (32–38 months at 3.5 years) performed on par with their TH peers. Conclusions: The two measures used in this study together appear capable of comprehensively describing the changes in consonant production skills of children. Results from this study indicate that while most CI participants display lower scores compared to TH children, many of the CI users are able to produce speech sounds on par with TH children. © 2019

Author Keywords
Accuracy; Consonant; Consonant inventory; Consonant production; Pediatric cochlear implants

Document Type: Article
Publication Stage: Final
Source: Scopus

“Letter to the Editor Regarding ‘Tumoral Mimics of Subdural Hematomas: 29 Case report and Review of Diagnostic and Management Strategies in Primary B-Cell 30 Lymphoma of the Subdural Space'” (2020) World Neurosurgery

Letter to the Editor Regarding “Tumoral Mimics of Subdural Hematomas: 29 Case report and Review of Diagnostic and Management Strategies in Primary B-Cell 30 Lymphoma of the Subdural Space”
(2020) World Neurosurgery, 135, p. 396.

Shenoy, S.

Brown School, Washington University, St. Louis, MO, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

“Delivering information about medication assisted treatment to individuals who misuse opioids through a mobile app: a pilot study” (2020) Journal of Public Health (Oxford, England)

Delivering information about medication assisted treatment to individuals who misuse opioids through a mobile app: a pilot study
(2020) Journal of Public Health (Oxford, England), 42 (1), pp. 149-154.

Cavazos-Rehg, P.A.^a , Krauss, M.J.^a , Costello, S.J.^a , Ramsey, A.T.^a , Petkas, D.^b , Gunderson, S.^b , Bierut, L.J.^a , Marsch, L.A.^c

^a Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO, USA
^b iTether Technologies, AZ, 1300 East Missouri Avenue ,Suite 100, Phoenix, United States
^c Department of Psychiatry, Dartmouth College, NHHanover, United States

Abstract
BACKGROUND: Digital therapeutic tools (e.g. mobile applications) can be accessible, low-cost interventions that counter misconceptions about medication assisted treatment (MAT) and/or improve deficits in MAT knowledge that are common barriers to treatment entry among individuals with opioid dependence. The purpose of this pilot study was to examine the preliminary effectiveness of a mobile application, ‘uMAT-R’, that includes health information about OUD recovery supported by science and MAT benefits. METHODS: Twenty-six adult participants with OUD recruited via social media completed all modules and pre/post-assessments within uMAT-R. McNemar’s test was used to compare interest in treatment before and after completing the app, and paired t tests were used to compare MAT attitude scores before and after completing the modules within uMAT-R. RESULTS: Before viewing uMAT-R, 32% agreed/strongly agreed that they were interested in starting treatment to recover from opioid misuse, compared to 48% after completing uMAT-R. The average scores on the MAT attitudes scale and its Aid to Behavior Change subscale improved from before to after viewing uMAT-R. Among the participants, 88% felt that uMAT-R would be useful to consult when making decisions about recovery. CONCLUSIONS: Our encouraging pilot findings support the use of uMAT-R to help address the current opioid epidemic. © The Author(s) 2018. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
buprenorphine; methadone; opiate substitution treatment; opioid dependence; telemedicine

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

“Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells” (2020) eLife

Agonist-selective recruitment of engineered protein probes and of GRK2 by opioid receptors in living cells
(2020) eLife, 9, .

Stoeber, M.^a ^b , Jullié, D.^a ^c , Li, J.^a ^c , Chakraborty, S.^d ^e , Majumdar, S.^d ^e , Lambert, N.A.^f , Manglik, A.^g ^h , von Zastrow, M.^a ^c

^a Department of Psychiatry, University of California, San Francisco, United States
^b Department of Cell Physiology and Metabolism, University of GenevaGeneva, Switzerland
^c Department of Cellular and Molecular Pharmacology, University of California, San Francisco, United States
^d Center for Clinical Pharmacology, Washington University School of Medicine, St. Louis, United States
^e St Louis College of Pharmacy, St. Louis, United States
^f Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, United States
^g Department of Pharmaceutical Chemistry, University of California, San Francisco, United States
^h Department of Anesthesia, University of California, San Francisco, United States

Abstract
G protein-coupled receptors (GPCRs) signal through allostery, and it is increasingly clear that chemically distinct agonists can produce different receptor-based effects. It has been proposed that agonists selectively promote receptors to recruit one cellular interacting partner over another, introducing allosteric ‘bias’ into the signaling system. However, the underlying hypothesis – that different agonists drive GPCRs to engage different cytoplasmic proteins in living cells – remains untested due to the complexity of readouts through which receptor-proximal interactions are typically inferred. We describe a cell-based assay to overcome this challenge, based on GPCR-interacting biosensors that are disconnected from endogenous transduction mechanisms. Focusing on opioid receptors, we directly demonstrate differences between biosensor recruitment produced by chemically distinct opioid ligands in living cells. We then show that selective recruitment applies to GRK2, a biologically relevant GPCR regulator, through discrete interactions of GRK2 with receptors or with G protein beta-gamma subunits which are differentially promoted by agonists. © 2020, Stoeber et al.

About a third of all drugs work by targeting a group of proteins known as G-protein coupled receptors, or GPCRs for short. These receptors are found on the surface of cells and transmit messages across the cell’s outer barrier. When a signaling molecule, like a hormone, is released in the body, it binds to a GPCR and changes the receptor’s shape. The change in structure affects how the GPCR interacts and binds to other proteins on the inside of the cell, triggering a series of reactions that alter the cell’s activity. Scientists have previously seen that a GPCR can trigger different responses depending on which signaling molecule is binding on the surface of the cell. However, the mechanism for this is unknown. One hypothesis is that different signaling molecules change the GPCR’s preference for binding to different proteins on the inside of the cell. The challenge has been to observe this happening without interfering with the process. Stoeber et al. have now tested this idea by attaching fluorescent tags to proteins that bind to activated GPCRs directly and without binding other signaling proteins. This meant these proteins could be tracked under a microscope as they made their way to bind to the GPCRs. Stoeber et al. focused on one particular GPCR, known as the opioid receptor, and tested the binding of two different opioid signaling molecules, etorphine and Dynorphin A. The experiments revealed that the different opioids did affect which of the engineered proteins would preferentially bind to the opioid receptor. This was followed by a similar experiment, where the engineered proteins were replaced with another protein called GRK2, which binds to the opioid receptor under normal conditions in the cell. This showed that GRK2 binds much more strongly to the opioid receptor when Dynorphin A is added compared to adding etorphine. These findings show that GPCRs can not only communicate that a signaling molecule is binding but can respond differently to convey what molecule it is more specifically. This could be important in developing drugs, particularly to specifically trigger the desired response and reduce side effects. Stoeber et al. suggest that an important next step for research is to understand how the GPCRs preferentially bind to different proteins.

Author Keywords
agonist bias; biochemistry; biosensor; cell biology; chemical biology; GPCR; none; opioid; receptor kinase; TIRF

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

“Taste and smell function in Wolfram syndrome” (2020) Orphanet Journal of Rare Diseases

Taste and smell function in Wolfram syndrome
(2020) Orphanet Journal of Rare Diseases, 15 (1), art. no. 57, .

Alfaro, R.^a , Doty, T.^b , Narayanan, A.^b , Lugar, H.^b , Hershey, T.^b ^c , Pepino, M.Y.^a ^d

^a Department of Food Science and Human Nutrition, University of Illinois at Urbana Champaign, Urbana, IL, United States
^b Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, United States
^c Department of Radiology, School of Medicine, Washington University, St. Louis, MO, United States
^d Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, IL, United States

Abstract
Background: Wolfram syndrome is a rare genetic disease characterized by insulin-dependent diabetes, optic nerve atrophy, sensorineural hearing loss and neurodegeneration. Although olfactory dysfunction, a classical clinical marker of neurodegenerative processes, has been reported in Wolfram syndrome, its use as a clinical marker in Wolfram is limited due to data scarcity. In addition, it is unknown whether Wolfram syndrome affects the sense of taste. Methods: Smell and taste perception were assessed in participants with Wolfram syndrome (n = 40) who were 15.1 ± 6.0 years of age (range: 5.1-28.7 years) and two sex-and age-matched control groups: one group with type 1 diabetes mellitus (T1D; n = 25) and a healthy control group (HC; n = 29). Smell sensitivity was assessed by measuring n-butanol detection thresholds and smell identification by using the University of Pennsylvania Smell Identification Test (UPSIT). Taste function was assessed using NIH Toolbox, which includes the assessment of sucrose (sweet) taste preference, and perceived intensity of sucrose, sodium chloride (salty), and quinine hydrochloride (bitter) both in the tip of the tongue (regional test) and the whole mouth. Results: Smell sensitivity was not significantly different among groups; however, smell identification was impaired in Wolfram syndrome, as reflected by significantly lower UPSIT scores in Wolfram syndrome compared to HC and T1D (P < 0.001). Compared to participants in the control groups, participants with Wolfram syndrome had a blunted perception of sweetness and saltiness when taste stimuli were applied regionally (P < 0.05), but differences in perceived intensity were no longer significant among groups when taste stimuli were tasted with the whole mouth. Groups preferred similar sucrose concentrations. Conclusion: Wolfram syndrome was associated with olfactory dysfunction. However, the olfactory dysfunction was qualitative (related to smell identification) and not secondary to olfactory insensitivity or diabetes, suggesting is arising from dysfunction in central olfactory brain regions. In contrast to olfaction, and despite decreased perception of taste intensity in the anterior tongue, the sense of taste was overall well-conserved in individuals with Wolfram syndrome. Future longitudinal studies of taste and smell perception in Wolfram syndrome will be important to determine the use of the chemical senses as clinical markers of disease progression. © 2020 The Author(s).

Author Keywords
DIDMOAD; Neurodegeneration; Olfaction; Sniffin’ sticks; Taste; UPSIT; Wolfram syndrome

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

“An inducible Cre mouse line to sparsely target nervous system cells, including Remak Schwann cells” (2020) Neural Development

An inducible Cre mouse line to sparsely target nervous system cells, including Remak Schwann cells
(2020) Neural Development, 15 (1), art. no. 2, .

Sapkota, D.^a , Dougherty, J.D.^a ^b

^a Department of Genetics, Washington University School of Medicine, Campus Box 8232, 4566 Scott Ave, St. Louis, MO 63110-1093, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Nerves of the peripheral nervous system contain two classes of Schwann cells: myelinating Schwann cells that ensheath large caliber axons and generate the myelin sheath, and Remak Schwann cells that surround smaller axons and do not myelinate. While tools exist for genetic targeting of Schwann cell precursors and myelinating Schwann cells, such reagents have been challenging to generate specifically for the Remak population, in part because many of the genes that mark this population in maturity are also robustly expressed in Schwann cell precursors. To circumvent this challenge, we utilized BAC transgenesis to generate a mouse line expressing a tamoxifen-inducible Cre under the control of a Remak-expressed gene promoter (Egr1). However, as Egr1 is also an activity dependent gene expressed by some neurons, we flanked this Cre by flippase (Flpe) recognition sites, and coinjected a BAC expressing Flpe under control of a pan-neuronal Snap25 promoter to excise the Cre transgene from these neuronal cells. Genotyping and inheritance demonstrate that the two BACs co-integrated into a single locus, facilitating maintenance of the line. Anatomical studies following a cross to a reporter line show sparse tamoxifen-dependent recombination in Remak Schwann cells within the mature sciatic nerve. However, depletion of neuronal Cre activity by Flpe is partial, with some neurons and astrocytes also showing evidence of Cre reporter activity in the central nervous system. Thus, this mouse line will be useful in mosaic loss-of-function studies, lineage tracing studies following injury, live cell imaging studies, or other experiments benefiting from sparse labeling. © 2020 The Author(s).

Author Keywords
Cre; Nervous system; Remak; Schwann; Sparse; Tamoxifen

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

“Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1” (2020) Genes

Integrative analysis identifies candidate tumor microenvironment and intracellular signaling pathways that define tumor heterogeneity in NF1
(2020) Genes, 11 (2), art. no. 226, .

Banerjee, J.^a , Allaway, R.J.^a , Taroni, J.N.^b , Baker, A.^a ^c ^d , Zhang, X.^e , Moon, C.I.^e , Pratilas, C.A.^f , Blakeley, J.O.^f ^g , Guinney, J.^a , Hirbe, A.^e , Greene, C.S.^b ^h , Gosline, S.J.C.^a

^a Computational Oncology, Sage Bionetworks, Seattle, WA 98121, United States
^b Childhood Cancer Data Lab, Alex’s Lemonade Stand Foundation, Philadelphia, PA 19102, United States
^c Department of Computer Sciences, University of Wisconsin-Madison, Madison, WI 53715, United States
^d Morgridge Institute for Research, Madison, WI 53715, United States
^e Division of Oncology, Washington University Medical School, St. Louis, MO 63110, United States
^f Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, United States
^g Neurology, Neurosurgery and Oncology, Johns Hopkins University, Baltimore, MD 21287, United States
^h Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
Neurofibromatosis type 1 (NF1) is a monogenic syndrome that gives rise to numerous symptoms including cognitive impairment, skeletal abnormalities, and growth of benign nerve sheath tumors. Nearly all NF1 patients develop cutaneous neurofibromas (cNFs), which occur on the skin surface, whereas 40–60% of patients develop plexiform neurofibromas (pNFs), which are deeply embedded in the peripheral nerves. Patients with pNFs have a ~10% lifetime chance of these tumors becoming malignant peripheral nerve sheath tumors (MPNSTs). These tumors have a severe prognosis and few treatment options other than surgery. Given the lack of therapeutic options available to patients with these tumors, identification of druggable pathways or other key molecular features could aid ongoing therapeutic discovery studies. In this work, we used statistical and machine learning methods to analyze 77 NF1 tumors with genomic data to characterize key signaling pathways that distinguish these tumors and identify candidates for drug development. We identified subsets of latent gene expression variables that may be important in the identification and etiology of cNFs, pNFs, other neurofibromas, and MPNSTs. Furthermore, we characterized the association between these latent variables and genetic variants, immune deconvolution predictions, and protein activity predictions. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Cancer; Latent variables; Machine learning; MetaVIPER; Nerve sheath tumor; Neurofibromatosis type 1; Random forest; Supervised learning; Transfer learning; Tumor deconvolution

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

“The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABRs/GABAA receptors in rat glaucoma models” (2020) Autophagy

The neurosteroid allopregnanolone protects retinal neurons by effects on autophagy and GABRs/GABAA receptors in rat glaucoma models
(2020) Autophagy, .

Ishikawa, M.^a , Takaseki, S.^a , Yoshitomi, T.^a , Covey, D.F.^b ^c ^d , Zorumski, C.F.^c ^d ^e , Izumi, Y.^c ^d ^e

^a Department of Ophthalmology, Akita University Graduate School of Medicine, Akita, Japan
^b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
^c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, MO, United States

Abstract
In an ex vivo rat glaucoma model using dissected retinas, the neurosteroid allopregnanolone (AlloP) protects retinal ganglion cells (RGCs) via GABR/GABAA receptors. To determine the involvement of macroautophagy/autophagy in neuroprotection by AlloP, we examined the effects of autophagy activators, rapamycin and torin 2, and autophagy inhibitors, bafilomycin A1 and SAR405, on retinal retinal morphology and expression of MAP1 LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) and SQSTM1 (sequestosome 1). Administration of rapamycin or torin 2 exerted partial histological neuroprotection, while combined administration of AlloP with bafilomycin A1 or SAR405 induced severe degeneration in a hyperbaric condition. Electron microscopic analyses showed that the addition of AlloP significantly increased autophagosomes and degenerative autophagic vacuoles in the retinal nerve fiber layer. Immunoblotting showed that the addition of AlloP or autophagic activators increased the lipidated form of LC3B (LC3B-II) and suppressed SQSTM1. Moreover, bafilomycin A1 increased LC3B-II and SQSTM1 protein levels in the presence of AlloP without changes in corresponding mRNAs compared to AlloP-treated retinas in a hyperbaric condition. These data indicate that AlloP likely induces a protective form of autophagy in this model. In an in vivo rat model of glaucoma, we also observed neuroprotective effects of AlloP. Injection of polystyrene microbeads into the anterior chamber increased intraocular pressure about 3-fold and induced RGC apoptosis. A single intravitreal injection of AlloP or autophagy activators prevented apoptosis and protected RGCs with autophagy activation. We conclude that AlloP may serve as a potential therapeutic agent for the treatment of glaucoma via diverse mechanisms. Abbreviations: 2HBCD: 2-Hydroxypropyl)-β-cyclodextrin; 3-MA: 3-methyladenine; AlloP: allopregnanolone; AP: autophagosome; AVd: degradative autophagic vacuoles; GCL: ganglion cell layer; INL: inner nuclear layer; IOP: intraocular pressure; IPL: inner plexiform layer; LC3B-I: cytosolic form of LC3B; LCB-II: lipidated form of LC3B; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; mPTP: mitochondrial permeability transition pore; NDS: neuronal damage score; NFL: nerve fiber layer; OH: ocular hypertension; ON: optic nerve; ONL: outer nuclear layer; OPL: outer plexiform layer; p-STR: scotopic threshold response; RGC: retinal ganglion cells; RT-PCR: real-time reverse transcription polymerase chain reaction; SQSTM1: sequestosome 1; TUNEL: TdT-mediated dUTP Nick End Labeling. © 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
Allopregnanolone; autophagy; glaucoma; intraocular pressure; neurosteroid

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

“Frontotemporal Dementia Knowledge Scale: Development and Preliminary Psychometric Properties” (2020) Alzheimer Disease and Associated Disorders

Frontotemporal Dementia Knowledge Scale: Development and Preliminary Psychometric Properties
(2020) Alzheimer Disease and Associated Disorders, 34 (1), pp. 59-65.

Wynn, M.J., Carpenter, B.D.

Department of Psychological and Brain Sciences, Washington University in St. Louis, #1 Brookings Drive, Campus Box 1125, St. Louis, MO 63130-4899, United States

Abstract
Objective:Frontotemporal dementia (FTD) accounts for ∼10% of dementia cases and is the most common cause of early-onset dementia. However, no well-validated instrument currently exists to measure knowledge about FTD. In this study, we used systematic scale development procedures to create a scale to measure knowledge of FTD based on a contemporary understanding of the disease.Methods:Standard scale development methods were used to create items and evaluate their psychometric properties. A total of 72 health care professionals and 102 caregivers of people with FTD responded to items measuring FTD knowledge, general dementia knowledge, crystallized intelligence, experience with FTD, and demographic information.Results:The Frontotemporal Dementia Knowledge Scale (FTDKS) contains 18 items that cover key, basic knowledge about FTD in the domains of risk factors, symptoms, course, caregiving, and treatment. The scale uses a 4-point True/False format with a Don’t Know option and takes ∼5 minutes to complete. In the current sample the FTDKS had good psychometric properties in terms of reliability and validity.Implications:The FTDKS can be used with health care professionals and caregivers of people with FTD to assess their knowledge about the disease. The scale may be useful to evaluate knowledge in clinical care and educational program contexts. © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
frontotemporal dementia; health education; knowledge; psychometrics; scale

Document Type: Article
Publication Stage: Final
Source: Scopus

“δ subunit-containing GABAA IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons” (2020) Journal of Physiology

δ subunit-containing GABAA IPSCs are driven by both synaptic and diffusional GABA in mouse dentate granule neurons
(2020) Journal of Physiology, .

Sun, M.-Y.^a , Ziolkowski, L.^a , Mennerick, S.^a ^b ^c

^a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, Box 8134, St Louis, MO 63110, United States
^b Department of Neuroscience, Washington University School of Medicine, 660 S. Euclid Ave, Box 8134, St Louis, MO 63110, United States
^c Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, 660 S. Euclid Ave, Box 8134, St Louis, MO 63110, United States

Abstract
Key points: Current views suggest γ2 subunit-containing GABAA receptors mediate phasic IPSCs while extrasynaptic δ subunits mediate diffusional IPSCs and tonic current. We have re-examined the roles of the two receptor populations using mice with picrotoxin resistance engineered into receptors containing the δ subunit. Using pharmacological separation, we find that in general δ and γ IPSCs are modulated in parallel by manipulations of transmitter output and diffusion, with evidence favouring modestly more diffusional contribution to δ IPSCs. Our findings also reveal that spontaneous δ IPSCs are mainly driven by channel deactivation, rather than by diffusion of GABA. Understanding the functional contributions of the two receptor classes may help us understand the actions of drug therapies with selective effects on one population over the other. Abstract: GABAA receptors mediate transmission throughout the central nervous system and typically contain a δ subunit (δ receptors) or a γ2 subunit (γ2 receptors). δ IPSCs decay slower than γ2 IPSCs, but the reasons are unclear. Transmitter diffusion, rebinding, or slow deactivation kinetics of channels are candidates. We used gene editing to confer picrotoxin resistance on δ receptors in mice, then pharmacologically isolated δ receptors in mouse dentate granule cells to explore IPSCs. γ2 and δ components of IPSCs were modulated similarly by presynaptic manipulations and manipulations of transmitter lifetime, suggesting that GABA release recruits δ receptors proportionally to γ2 receptors. δ IPSCs showed more sensitivity to altered transmitter release and to a rapidly dissociating antagonist, suggesting an additional spillover contribution. Reducing GABA diffusion with 5% dextran increased the peak amplitude and decreased the decay of evoked δ IPSCs but had no effect on δ or dual-component (mainly γ2-driven) spontaneous IPSCs, suggesting that GABA actions can be local for both receptor types. Rapid application of varied [GABA] onto nucleated patches from dentate granule cells demonstrated a deactivation rate of δ receptors similar to that of δ spontaneous IPSCs, consistent with the idea that deactivation and local GABA actions drive δ spontaneous IPSCs. Overall, our results indicate that δ IPSCs are activated by both synaptic and diffusional GABA. Our results are consistent with a functional relationship between δ and γ2 GABAA receptors akin to that of slow NMDA and fast AMPA EPSCs at glutamate synapses. © 2020 The Authors. The Journal of Physiology © 2020 The Physiological Society

Author Keywords
dentate granule neurons; GABAA receptors; phasic inhibition

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

“Impact of parameter selection on estimates of motoneuron excitability using paired motor unit analysis” (2020) Journal of Neural Engineering

Impact of parameter selection on estimates of motoneuron excitability using paired motor unit analysis
(2020) Journal of Neural Engineering, 17 (1), art. no. 016063, .

Hassan, A.^a ^b , Thompson, C.K.^c , Negro, F.^d , Cummings, M.^a , Powers, R.K.^e , Heckman, C.J.^a ^f , Dewald, J.P.A.^a ^b ⁱ , McPherson, L.M.^g ^h

^a Department of Physical Therapy and Human Movement Sciences, Northwestern University, Chicago, IL, United States
^b Department of Biomedical Engineering, Northwestern University, Chicago, IL, United States
^c Department of Health and Rehabilitation Sciences, Temple University, Philadelphia, PA, United States
^d Department of Clinical and Experimental Sciences, Research Centre for Neuromuscular Function and Adapted Physical Activity Teresa Camplani, Universita Degli Studi di Brescia, Brescia, Italy
^e Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States
^f Department of Physiology, Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL, United States
^g Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Physical Med. and Rehab., Northwestern University, Chicago, IL, United States

Abstract
Objective. Noninvasive estimation of motoneuron excitability in human motoneurons is achieved through a paired motor unit analysis (ΔF) that quantifies hysteresis in the instantaneous firing rates at motor unit recruitment and de-recruitment. The ΔF technique provides insight into the magnitude of neuromodulatory synaptic input and persistent inward currents (PICs). While the ΔF technique is commonly used for estimating motoneuron excitability during voluntary contractions, computational parameters used for the technique vary across studies. A systematic investigation into the relationship between these parameters and ΔF values is necessary. Approach. We assessed the sensitivity of the ΔF technique with several criteria commonly used in selecting motor unit pairs for analysis and methods used for smoothing the instantaneous motor unit firing rates. Using high-density surface EMG and convolutive blind source separation, we obtained a large number of motor unit pairs (5409) from the triceps brachii of ten healthy individuals during triangular isometric contractions. Main results. We found an exponential plateau relationship between ΔF and the recruitment time difference between the motor unit pairs and an exponential decay relationship between ΔF and the de-recruitment time difference between the motor unit pairs, with the plateaus occurring at approximately 1 s and 1.5 s, respectively. Reduction or removal of the minimum threshold for rate-rate correlation of the two units did not affect ΔF values or variance. Removing motor unit pairs in which the firing rate of the control unit was saturated had no significant effect on ΔF. Smoothing the filter selection had no substantial effect on ΔF values and ΔF variance; however, filter selection affected the minimum recruitment and de-recruitment time differences. Significance. Our results offer recommendations for standardized parameters for the ΔF approach and facilitate the interpretation of findings from studies that implement the ΔF analysis but use different computational parameters. © 2020 IOP Publishing Ltd.

Author Keywords
decomposition; delta-F; high-density EMG; motoneuron; motor unit; paired motor unit analysis; persistent inward currents

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

“’I Feel Like I Know Them’: the Positive Effect of Celebrity Self-disclosure of Mental Illness” (2020) Academic Psychiatry

“I Feel Like I Know Them”: the Positive Effect of Celebrity Self-disclosure of Mental Illness
(2020) Academic Psychiatry, .

Calhoun, A.J.^a , Gold, J.A.^b

^a Yale University, New Haven, CT, United States
^b Washington University, St. Louis, MO, United States

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

“Pharmacogenetic Implications for Antidepressant Pharmacotherapy in Late-Life Depression: A Systematic Review of the Literature for Response, Pharmacokinetics and Adverse Drug Reactions” (2020) American Journal of Geriatric Psychiatry

Pharmacogenetic Implications for Antidepressant Pharmacotherapy in Late-Life Depression: A Systematic Review of the Literature for Response, Pharmacokinetics and Adverse Drug Reactions
(2020) American Journal of Geriatric Psychiatry, .

Marshe, V.S.^a ^b , Islam, F.^b ^c , Maciukiewicz, M.^b , Bousman, C.^d ^e , Eyre, H.A.^f ^g ^h ⁱ , Lavretsky, H.^j , Mulsant, B.H.^a ^b ^k , Reynolds, C.F., III^l , Lenze, E.J.^m , Müller, D.J.^a ^b ^c ^k

^a Institute of Medical Science, University of Toronto, Toronto, ON, Canada
^b Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
^c Department of Pharmacology, University of Toronto, Toronto, ON, Canada
^d Departments of Medical Genetics, Psychiatry, and Physiology & Pharmacology, University of Calgary, Calgary, AB, Canada
^e Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia
^f Innovation Institute, Texas Medical Center, Houston, TX, United States
^g School of Medicine, IMPACT SRC, Deakin University, Geelong, Victoria, Australia
^h Brainstorm Lab, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, United States
ⁱ Discipline of Psychiatry, The University of Adelaide, Adelaide, South Australia, Australia
^j Department of Psychiatry, University of California, Los Angeles, CA, United States
^k Department of Psychiatry, University of Toronto, Toronto, ON, Canada
^l Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^m Healthy Mind Lab, Department of Psychiatry, Washington University, St. Louis, MO, United States

Abstract
Affecting up to 15% of older adults, late-life depression (LLD) is characterized by the occurrence of depressive symptoms after the age of 50–65 years and maybe pathophysiologically distinct from depression in younger adults. Therefore, LLD is challenging to treat, and predictive genetic testing might be essential to improve treatment in this vulnerable population. The current review aims to provide a summary of the literature exploring genetic associations with antidepressant treatment outcomes in late-life. We conducted a systematic search of three integrated electronic databases. We identified 29 articles investigating genetic associations with antidepressant treatment outcomes, pharmacokinetic parameters, and adverse drug reactions in older adults. Given the small number of investigations conducted in older adults, it is difficult to conclude the presence or absence of genetic associations with the outcomes of interest. In sum, the most substantial amount of evidence exists for the CYP2D6 metabolizer status, SLC6A4 5-HTTLPR, and BDNF rs6265. These findings are consistent in the literature when not restricting to older adults, suggesting that similar treatment recommendations may be provided for older adults regarding genetic variation, such as those outlined for CYP2D6 by the Clinical Pharmacogenetics Implementation Consortium. Nonetheless, further studies are required in well-characterized samples, including genome-wide data, to validate if similar treatment adjustments are appropriate in older adults, given that there appear to be significant effects of genetic variation on antidepressant treatment factors. © 2020 American Association for Geriatric Psychiatry

Author Keywords
antidepressant; Late-life depression; pharmacogenetics; response; treatment outcomes

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

“Cerebrovascular Complications of Pediatric Blunt Trauma” (2020) Pediatric Neurology

Cerebrovascular Complications of Pediatric Blunt Trauma
(2020) Pediatric Neurology, .

Galardi, M.M.^a , Strahle, J.M.^b , Skidmore, A.^b , Kansagra, A.P.^a ^b ^c , Guilliams, K.P.^a ^d

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Ischemic and hemorrhagic stroke can occur in the setting of pediatric trauma, particularly those with head or neck injuries. The risk of stroke appears highest within the first two weeks after trauma. Stroke diagnosis may be challenging due to lack of awareness or concurrent injuries limiting detailed neurological assessment. Other injuries may also complicate stroke management, with competing priorities for blood pressure, ventilator management, or antithrombotic timing. Here we review epidemiology, clinical presentation, and diagnostic approach to blunt arterial injuries including dissection, cerebral sinovenous thrombosis, mineralizing angiopathy, stroke from abusive head trauma, and traumatic hemorrhagic stroke. Owing to the complexities and heterogeneity of concomitant injuries in stroke related to trauma, a single pathway for stroke management is impractical. Therefore providers must understand the goals and possible costs or consequences of stroke management decisions to individualize patient care. We discuss the physiological principles of cerebral perfusion and oxygen delivery, considerations for ventilator strategy when stroke and lung injury are present, and current available evidence of the risks and benefits of anticoagulation to provide a framework for multidisciplinary discussions of cerebrovascular injury management in pediatric patients with trauma. © 2020 Elsevier Inc.

Author Keywords
Arterial dissection; Cerebrovascular trauma; Child; Craniocerebral trauma; Hemorrhage; Humans; Stroke; Thrombosis

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

“Prevalence and Impact of Underlying Diagnosis and Comorbidities on Chiari 1 Malformation” (2020) Pediatric Neurology

Prevalence and Impact of Underlying Diagnosis and Comorbidities on Chiari 1 Malformation
(2020) Pediatric Neurology, .

Sadler, B.^a , Kuensting, T.^a , Strahle, J.^b , Park, T.S.^b , Smyth, M.^b , Limbrick, D.D.^b , Dobbs, M.B.^c , Haller, G.^b , Gurnett, C.A.^a

^a Department of Neurology, Washington University in St. Louis, St Louis, MO, United States
^b Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Orthopedic Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Chiari malformation type 1 affects approximately one in 1,000 people symptomatically, although one in 100 meet radiological criteria, making it a common neurological disorder. The diagnosis of underlying conditions has become more sophisticated, and new radiological markers of disease have been described. We sought to determine the prevalence and impact of additional comorbidities and underlying diagnoses in patients with Chiari malformation type 1 on symptomatology and surgical treatment. Methods: A retrospective review of 612 pediatric patients with a Chiari malformation type 1 diagnosis and imaging data evaluated between 2008 and 2018 was performed. Because of extensive clinical heterogeneity, patients were separated into four categories based on their primary comorbidities (nonsyndromic, central nervous system, skeletal, and multiple congenital anomalies) to identify associations with age of onset, radiographic measurements, syringomyelia, and surgical treatment. Results: The largest group had nonsyndromic Chiari malformation type 1 (70%) and the latest age at diagnosis of any group. In the syndromic group, 6% were diagnosed with a known genetic abnormality, with overgrowth syndromes being the most common. Patients with multiple congenital anomalies had the earliest Chiari malformation type 1 onset, the most severe tonsillar ectopia and obex position, and were overrepresented among surgical cases. Although there were no statistically significant differences between groups and rates of syrinx, we observed differences in individual diagnoses. Conclusion: The underlying diagnoses and presence of comorbidities in patients with Chiari malformation type 1 impacts rates of syringomyelia and surgery. Although most Chiari malformation type 1 cases are nonsyndromic, clinical evaluation of growth parameters, scoliosis, and joint hypermobility should be routine for all patients as they are useful to determine syringomyelia risk and may impact treatment. © 2019 Elsevier Inc.

Author Keywords
Chiari 1 malformation; Comorbidities; Epidemiology; Obex; Syringomyelia

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

“Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease” (2020) British Journal of Haematology

Association between hydroxycarbamide exposure and neurocognitive function in adolescents with sickle cell disease
(2020) British Journal of Haematology, .

Partanen, M.^a , Kang, G.^b , Wang, W.C.^c , Krull, K.^d , King, A.A.^e , Schreiber, J.E.^f , Porter, J.S.^a , Hodges, J.^c , Hankins, J.S.^c , Jacola, L.M.^a

^a Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^c Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, TN, United States
^e Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, PA, United States

Abstract
Patients with sickle cell disease (SCD) are at increased risk for neurocognitive impairments. While disease-modifying treatment, such as hydroxycarbamide (hydroxyurea), may decrease this risk, it has not been systematically investigated in children with SCD. We screened neurocognitive functioning in 103 adolescents with SCD (16–17 years, 50% female) and compared outcomes between patients with a history of exposure to hydroxycarbamide (n = 12 HbSC/HbSβ+ thalassaemia; n = 52 HbSS/HbSβ0 thalassaemia) and those never treated with hydroxycarbamide (n = 31 HbSC/HbSβ+ thalassaemia; n = 8 HbSS/HbSβ0 thalassaemia). Demographic distributions were similar between the groups. After adjusting for socioeconomic status, the hydroxycarbamide group had significantly higher scores on nonverbal IQ (HbSC/HbSβ thalassaemia: P = 0·036, effect size [d] = 0·65), reaction speed (HbSS/HbSβ0 thalassaemia: P = 0·002, d = 1·70), sustained attention (HbSS/HbSβ0 thalassaemia: P = 0·014, d = 1·30), working memory (HbSC/HbSβ+ thalassaemia: P = 0·034, d = 0·71) and verbal memory (HbSC/HbSβ+ thalassaemia: P = 0·038, d = 0·84) when compared to those who did not receive hydroxycarbamide. In patients with HbSS/HbSβ0 thalassaemia, longer treatment duration with hydroxycarbamide was associated with better verbal memory (P = 0·009) and reading (P = 0·002). Markers of hydroxycarbamide effect, including higher fetal haemoglobin (HbF), higher mean corpuscular volume (MCV) and lower white blood cell count (WBC), were associated with better verbal fluency (HbF: P = 0·014, MCV: P = 0·006, WBC: P = 0·047) and reading (MCV: P = 0·021, WBC: P = 0·037). Cognitive impairment may be mitigated by exposure to hydroxycarbamide in adolescents with SCD. © 2020 British Society for Haematology and John Wiley & Sons Ltd

Author Keywords
neurocognitive; paediatric haematology; sickle cell anaemia; sickle cell disease

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

“PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes” (2020) Journal of Investigative Dermatology

PAR2 Mediates Itch via TRPV3 Signaling in Keratinocytes
(2020) Journal of Investigative Dermatology, .

Zhao, J.^a ^b , Munanairi, A.^b ^c ^d , Liu, X.-Y.^b ^c , Zhang, J.^a , Hu, L.^a ^e ^f , Hu, M.^g , Bu, D.^a , Liu, L.^a , Xie, Z.^h , Kim, B.S.^b ⁱ , Yang, Y.^a ^e ^j , Chen, Z.-F.^b ^c ^k ^l

^a Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Disease, Beijing, China
^b Center for the Study of Itch and Sensory Disorders, Washington University School of Medicine, St. Louis, United States
^c Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^d Current Address: Department of Pediatrics, Washington University School of Medicine, St. Louis, United States
^e Peking-Tsinghua Center for Life Sciences, Beijing, China
^f Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
^g State Key Laboratory of Membrane Biology and Beijing Key Laboratory of Cardio-metabolic Molecular Medicine, Peking University, Beijing, China
^h Department of Dermatology, Peking University Third Hospital, Beijing, China
ⁱ Department of Dermatology<sup>,</sup> Washington University School of Medicine, St. Louis, United States
^j Current Address: Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
^k Department of Psychiatry, Washington University School of Medicine, St. Louis, United States
^l Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States

Abstract
Animal studies have suggested that transient receptor potential ion channels and G-protein coupled receptors play important roles in itch transmission. TRPV3 gain-of-function mutations have been identified in patients with Olmsted syndrome, which is associated with severe pruritus. However, the mechanisms causing itch remain poorly understood. Here, we show that keratinocytes lacking TRPV3 impair the function of protease-activated receptor 2 (PAR2), resulting in reduced neuronal activation and scratching behavior in response to PAR2 agonists. Moreover, we show that TRPV3 and PAR2 were upregulated in skin biopsies from patients and mice with atopic dermatitis, whereas their inhibition attenuated scratching and inflammatory responses in mouse atopic dermatitis models. These results reveal a previously unrecognized link between TRPV3 and PAR2 in keratinocytes to convey itch information and suggest that a blockade of PAR2 or TRPV3 individually or both may serve as a potential approach for antipruritic therapy in atopic dermatitis. © 2020 The Authors

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

“Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium” (2020) Molecular Psychiatry

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium
(2020) Molecular Psychiatry, .

Polimanti, R.^a , Walters, R.K.^b , Johnson, E.C.^c , McClintick, J.N.^d , Adkins, A.E.^e , Adkins, D.E.^f , Bacanu, S.-A.^g , Bierut, L.J.^c , Bigdeli, T.B.^h , Brown, S.ⁱ , Bucholz, K.K.^c , Copeland, W.E.^j , Costello, E.J.^k , Degenhardt, L.^l , Farrer, L.A.^m , Foroud, T.M.ⁿ , Fox, L.^c , Goate, A.M.^o , Grucza, R.^c , Hack, L.M.^p , Hancock, D.B.^q , Hartz, S.M.^c , Heath, A.C.^c , Hewitt, J.K.^r , Hopfer, C.J.^s , Johnson, E.O.^q , Kendler, K.S.^t , Kranzler, H.R.^u , Krauter, K.^v , Lai, D.ⁿ , Madden, P.A.F.^c , Martin, N.G.^w , Maes, H.H.^t , Nelson, E.C.^c , Peterson, R.E.^x , Porjesz, B.^h , Riley, B.P.^g , Saccone, N.^y , Stallings, M.^r , Wall, T.L.ⁱ , Webb, B.T.^g , Wetherill, L.ⁿ , Edenberg, H.J.^d , Agrawal, A.^c , Gelernter, J.^a , on behalf of the Psychiatric Genomics Consortium Substance Use Disorders Workgroup^z

^a Department of Psychiatry, Yale University School of Medicine, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, United States
^b Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^c Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^e Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^f Department of Psychiatry, University of Utah, Salt Lake City, UT, United States
^g Virginia Commonwealth University Alcohol Research Center, Virginia Institute for Psychiatric and Behavioral Genetics, Richmond, VA, United States
^h Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, United States
ⁱ Department of Psychiatry, University of California San Diego, San Diego, CA, United States
^j Department of Psychiatry, University of Vermont Medical Center, Burlington, VT, United States
^k Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, United States
^l National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW, Australia
^m Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, MA, United States
ⁿ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^o Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^p Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, United States
^q Center for Omics Discovery and Epidemiology, RTI International, Research Triangle Park, NC, United States
^r Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, United States
^s Department of Psychiatry, University of Colorado Denver, Aurora, CO, United States
^t Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
^u Center for Studies of Addiction, University of Pennsylvania Perelman School of Medicine, VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, United States
^v Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO, United States
^w QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
^x Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^y Department of Genetics, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = −5.39, p = 7.2 × 10–8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10–8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10–6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10–8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10–7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10–5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10–5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10–5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction. © 2020, Springer Nature Limited.

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

“Pre-Synaptic Pool Modification (PSPM): A supervised learning procedure for recurrent spiking neural networks” (2020) PLoS ONE

Pre-Synaptic Pool Modification (PSPM): A supervised learning procedure for recurrent spiking neural networks
(2020) PLoS ONE, 15 (2), art. no. e0229083, .

Bagley, B.A.^a ^b ^c ^d , Bordelon, B.^a ^b , Moseley, B.^c ^e , Wessel, R.^b

^a Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Physics, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Computer Science, Washington University in St. Louis, St. Louis, MO, United States
^d Stanford Institute for Theoretical Physics, Stanford University, Stanford, CA, United States
^e Department of Operations Research, Carnegie Mellon University, Pittsburgh, PA, United States

Abstract
Learning synaptic weights of spiking neural network (SNN) models that can reproduce target spike trains from provided neural firing data is a central problem in computational neuroscience and spike-based computing. The discovery of the optimal weight values can be posed as a supervised learning task wherein the weights of the model network are chosen to maximize the similarity between the target spike trains and the model outputs. It is still largely unknown whether optimizing spike train similarity of highly recurrent SNNs produces weight matrices similar to those of the ground truth model. To this end, we propose flexible heuristic supervised learning rules, termed Pre-Synaptic Pool Modification (PSPM), that rely on stochastic weight updates in order to produce spikes within a short window of the desired times and eliminate spikes outside of this window. PSPM improves spike train similarity for all-to-all SNNs and makes no assumption about the post-synaptic potential of the neurons or the structure of the network since no gradients are required. We test whether optimizing for spike train similarity entails the discovery of accurate weights and explore the relative contributions of local and homeostatic weight updates. Although PSPM improves similarity between spike trains, the learned weights often differ from the weights of the ground truth model, implying that connectome inference from spike data may require additional constraints on connectivity statistics. We also find that spike train similarity is sensitive to local updates, but other measures of network activity such as avalanche distributions, can be learned through synaptic homeostasis. © 2020 Bagley 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

“Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams–Beuren syndrome” (2020) American Journal of Medical Genetics, Part A

Social, neurodevelopmental, endocrine, and head size differences associated with atypical deletions in Williams–Beuren syndrome
(2020) American Journal of Medical Genetics, Part A, .

Lugo, M.^a ^b , Wong, Z.C.^b , Billington, C.J., Jr.^c , Parrish, P.C.R.^b ^d , Muldoon, G.^e , Liu, D.^b , Pober, B.R.^f , Kozel, B.A.^b ^g

^a Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
^b Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
^c Medical Genetics and Genomic Medicine Training Program, National Human Genetics Research Institute, National Institutes of Health, Bethesda, MD, United States
^d Department of Genome Sciences, University of Washington, Seattle, WA, United States
^e Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States
^f Department of Pediatrics, Massachusetts General Hospital, Boston, MA, United States
^g Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Williams–Beuren syndrome (WBS) is a multisystem disorder caused by a hemizygous deletion on 7q11.23 encompassing 26–28 genes. An estimated 2–5% of patients have “atypical” deletions, which extend in the centromeric and/or telomeric direction from the WBS critical region. To elucidate clinical differentiators among these deletion types, we evaluated 10 individuals with atypical deletions in our cohort and 17 individuals with similarly classified deletions previously described in the literature. Larger deletions in either direction often led to more severe developmental delays, while deletions containing MAGI2 were associated with infantile spasms and seizures in patients. In addition, head size was notably smaller in those with centromeric deletions including AUTS2. Because children with atypical deletions were noted to be less socially engaged, we additionally sought to determine how atypical deletions relate to social phenotypes. Using the Social Responsiveness Scale-2, raters scored individuals with atypical deletions as having different social characteristics to those with typical WBS deletions (p =.001), with higher (more impaired) scores for social motivation (p =.005) in the atypical deletion group. In recognizing these distinctions, physicians can better identify patients, including those who may already carry a clinical or FISH WBS diagnosis, who may benefit from additional molecular evaluation, screening, and therapy. In addition to the clinical findings, we note mild endocrine findings distinct from those typically seen in WBS in several patients with telomeric deletions that included POR. Further study in additional telomeric deletion cases will be needed to confirm this observation. Published 2020. This article is a U.S. Government work and is in the public domain in the USA.

Author Keywords
atypical deletion; autism spectrum; microcephaly; phenotype; social behavior; Williams–Beuren syndrome

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

“The Congenital Heart Disease Brain: Prenatal Considerations for Perioperative Neurocritical Care” (2020) Pediatric Neurology

The Congenital Heart Disease Brain: Prenatal Considerations for Perioperative Neurocritical Care
(2020) Pediatric Neurology, .

Ortinau, C.M.^a , Shimony, J.S.^b

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b Mallinkrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Altered brain development has been highlighted as an important contributor to adverse neurodevelopmental outcomes in children with congenital heart disease. Abnormalities begin prenatally and include micro- and macrostructural disturbances that lead to an altered trajectory of brain growth throughout gestation. Recent progress in fetal imaging has improved understanding of the neurobiological mechanisms and risk factors for impaired fetal brain development. The impact of the prenatal environment on postnatal neurological care has also gained increased focus. This review summarizes current data on the timing and pattern of altered prenatal brain development in congenital heart disease, the potential mechanisms of these abnormalities, and the association with perioperative neurological complications. © 2020 Elsevier Inc.

Author Keywords
Brain; Brain development; Brain injury; Congenital heart disease; Fetal; Prenatal

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

“Approaches to Defining Common and Dissociable Neurobiological Deficits Associated With Psychopathology in Youth” (2020) Biological Psychiatry

Approaches to Defining Common and Dissociable Neurobiological Deficits Associated With Psychopathology in Youth
(2020) Biological Psychiatry, .

Kaczkurkin, A.N.^a , Moore, T.M.^b , Sotiras, A.^d ^e , Xia, C.H.^b , Shinohara, R.T.^c , Satterthwaite, T.D.^b

^a Department of Psychology, Vanderbilt University, Nashville, TN, United States
^b Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e Institute for Informatics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Psychiatric disorders show high rates of comorbidity and nonspecificity of presenting clinical symptoms, while demonstrating substantial heterogeneity within diagnostic categories. Notably, many of these psychiatric disorders first manifest in youth. We review progress and next steps in efforts to parse heterogeneity in psychiatric symptoms in youths by identifying abnormalities within neural circuits. To address this fundamental challenge in psychiatry, a number of methods have been proposed. We provide an overview of these methods, broadly organized into dimensional versus categorical approaches and single-view versus multiview approaches. Dimensional approaches including factor analysis and canonical correlation analysis aim to capture dimensional associations between psychopathology and brain measures across a continuous spectrum from health to disease. In contrast, categorical approaches, such as clustering and community detection, aim to identify subtypes of individuals within a class of symptoms or brain features. We highlight several studies that apply these methods to samples of youths and discuss issues to consider when using these approaches. Finally, we end by highlighting avenues for future research. © 2019 Society of Biological Psychiatry

Author Keywords
Adolescents; Heterogeneity; Imaging; Neurobiology; Psychopathology; Youth

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

“The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease” (2020) Genetics in Medicine

The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease
(2020) Genetics in Medicine, .

Guenzel, A.J.^a , Turgeon, C.T.^a , Nickander, K.K.^a , White, A.L.^a , Peck, D.S.^a , Pino, G.B.^a , Studinski, A.L.^a , Prasad, V.K.^b , Kurtzberg, J.^b , Escolar, M.L.^c , Lasio, M.L.D.^d , Pellegrino, J.E.^e , Sakonju, A.^e , Hickey, R.E.^f , Shallow, N.M.^g , Ream, M.A.^h , Orsini, J.J.ⁱ , Gelb, M.H.^j , Raymond, K.^a , Gavrilov, D.K.^a , Oglesbee, D.^a , Rinaldo, P.^a , Tortorelli, S.^a , Matern, D.^a

^a Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^b Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
^c Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^d Department of Pediatrics, Washington University, St. Louis, MO, United States
^e Department of Pediatrics, Upstate Medical University, Syracuse, NY, United States
^f Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^g Vanderbilt University Medical Center, Nashville, TN, United States
^h Nationwide Children’s Hospital, Columbus, OH, United States
ⁱ Newborn Screening Program, Wadsworth Center, New York State Department of Health, Albany, NY, United States
^j Departments of Chemistry and Biochemistry, University of Washington, Seattle, WA, United States

Abstract
Purpose: Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations. Methods: PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography–tandem mass spectrometry. Results: Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT). Conclusion: This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment. © 2020, American College of Medical Genetics and Genomics.

Author Keywords
biomarker; dried blood spot; Krabbe disease; newborn screening; psychosine

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

“Neural Activity During Self-referential Processing in Children at Risk for Depression” (2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging

Neural Activity During Self-referential Processing in Children at Risk for Depression
(2020) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, .

Liu, P.^a ^b , Vandermeer, M.R.J.^a ^b , Joanisse, M.F.^a ^b , Barch, D.M.^c , Dozois, D.J.A.^a , Hayden, E.P.^a ^b

^a Department of Psychology, University of Western Ontario, London, Ontario, Canada
^b The Brain and Mind Institute, University of Western Ontario, London, Ontario, Canada
^c Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
Background: According to cognitive theories of depression, more negative and less positive self-schemas are thought to play a causal role in the disorder. Existing evidence speaks to the neural substrates of self-referential processes in both healthy and depressed individuals, but little is known about how the brain relates to self-referential processing in the context of depression risk in children. We therefore studied the neural substrates of self-referential processing in never-depressed preadolescent children at high and low risk for depression based on maternal depression history. Methods: A total of 87 never-depressed 10–12-year-old children (29 with maternal depression) completed a self-referential encoding task during a functional magnetic resonance imaging session, in which they were presented a series of positive and negative trait adjectives and endorsed whether each word was self-descriptive. Small volume correction analyses were conducted within 7 regions of interest that are important for self-referential and emotion-related processes. Results: Analyses of small volume correction indicated that high-risk children showed greater activation in the ventrolateral prefrontal cortex and ventromedial prefrontal cortex during the positive-word self-referential encoding task condition than low-risk children. Ventrolateral prefrontal cortex activation mediated the association between maternal depression and child depressive symptoms only when children had lower positive self-schemas, indicating that more positive self-schemas may protect at-risk children from developing depressive symptoms. Conclusions: Cortical midline and prefrontal regions are important to self-, emotion-, and regulation-related processes. Heightened activation within these regions in never-depressed high-risk children indicates that these neurobiological substrates may mediate early vulnerability to depression in the context of cognitive processes relevant to self-concepts. © 2019 Society of Biological Psychiatry

Author Keywords
Depression; fMRI; Maternal history; Preadolescence; Self-referential encoding task; vlPFC

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

“Making Functional Cognition a Professional Priority” (2020) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association

Making Functional Cognition a Professional Priority
(2020) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association, 74 (1), pp. 7401090010p1-7401090010p6.

Giles, G.M.^a , Edwards, D.F.^a , Baum, C.^b , Furniss, J.^c , Skidmore, E.^d , Wolf, T.^e , Leland, N.E.^f

^a Department of Kinesiology, University of Wisconsin-Madison, is Professor of Kinesiology and Medicine
^b Carolyn Baum, PhD, OTR, FAOTA, is Professor of Occupational Therapy, Neurology and Social Work, Department of Occupational Therapy, Washington University in St. Louis, St. Louis, MO
^c OTR/L, BCG, Knowledge and Data Science, American Occupational Therapy Association, MD, is Vice President, North Bethesda, United States
^d OTR/L, Department of Occupational Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh, is Professor, Pittsburgh, United States
^e OTR/L, Department of Occupational Therapy, School of Health Professions, University of Missouri, is Associate Professor, Columbia, United States
^f Natalie E. Leland, OTR/L, BCG, Department of Occupational Therapy, School of Health and Rehabilitation Sciences, University of Pittsburgh, is Associate Professor and Vice Chair for Research, Pittsburgh, United States

Abstract
Functional cognition is a critical domain of concern for occupational therapy practice. As the health care system moves to assessing value through achievement of quality outcomes, the field of occupational therapy must address the inclusion of functional cognition in evaluation and treatment. Evidence indicates that impaired cognition contributes to risk of hospital readmission and poor overall health outcomes across diagnostic groups. Moreover, expenditure on occupational therapy services that address functional cognition has been shown to lower hospital readmission rates. To improve client outcomes, occupational therapists must consistently screen for and, when appropriate, evaluate and treat functional cognition impairments and consider functional cognition in the discharge planning process. Occupational therapy professionals must make a proactive, coordinated effort to establish the profession’s role in evaluating and treating clients’ limitations in functional cognition as a means to achieving improved quality care and client outcomes. Copyright © 2019 by the American Occupational Therapy Association, Inc.

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

“An early description of Crouzon syndrome in a manuscript written in 1828 by Franz Joseph Gall” (2020) Journal of the History of the Neurosciences

An early description of Crouzon syndrome in a manuscript written in 1828 by Franz Joseph Gall
(2020) Journal of the History of the Neurosciences, .

Nolte, S.H.^a , Hansen, W.^b , Eling, P.^c , Finger, S.^d

^a Medical Faculty, Philipps University Marburg, Marburg, Germany
^b 2nd Medical Department, Technical University of Munich, Munich, Germany
^c Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen, Nijmegen, Netherlands
^d Department of Psychological and Brain Sciences and Program in History of Medicine, Washington University, St. Louis, MO, United States

Abstract
Just a few weeks before his death in 1828, Franz Joseph Gall, the father of what others would later call phrenology, wrote a letter to an unknown person, presumably a fellow physician. The manuscript describes the case of girl, 19 months of age. The girl’s skull showed marked deformations consistent with what would be called craniosynostosis or Crouzon(’s) syndrome by physicians today. Gall related some clinical features of her case and suggested some treatment options. This case report is particularly interesting because it is almost 200 years old, predates Crouzon’s description of the syndrome by 84 years, and shows that Gall was still involved with treating patients, even in his final year. © 2020, © 2020 Taylor & Francis.

Author Keywords
craniology; craniosynostosis; Crouzon’s syndrome; Gall (Franz Joseph); organology; phrenology

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

“Cortical Plasticity in Rehabilitation for Upper Extremity Peripheral Nerve Injury: A Scoping Review” (2020) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association

Cortical Plasticity in Rehabilitation for Upper Extremity Peripheral Nerve Injury: A Scoping Review
(2020) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association, 74 (1), pp. 7401205030p1-7401205030p15.

Zink, P.J.^a , Philip, B.A.^b

^a Patrick J. Zink, MSOT, is Occupational Therapist, Select Physical Therapy, Kansas City, MO. At the time of the study, he was Student, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO
^b Benjamin A. Philip, PhD, is Assistant Professor, Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO;

Abstract
IMPORTANCE: Poor outcomes after upper extremity peripheral nerve injury (PNI) may arise, in part, from the challenges and complexities of cortical plasticity. Occupational therapy practitioners need to understand how the brain changes after peripheral injury and how principles of cortical plasticity can be applied to improve rehabilitation for clients with PNI. OBJECTIVE: To identify the mechanisms of cortical plasticity after PNI and describe how cortical plasticity can contribute to rehabilitation. DATA SOURCES: PubMed and Embase (1900-2017) were searched for articles that addressed either (1) the relationship between PNI and cortical plasticity or (2) rehabilitative interventions based on cortical plastic changes after PNI. Study Selection and Data Collectio: : PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Articles were selected if they addressed all of the following concepts: human PNI, cortical plasticity, and rehabilitation. Phantom limb pain and sensation were excluded. FINDINGS: Sixty-three articles met the study criteria. The most common evidence level was Level V (46%). We identified four commonly studied mechanisms of cortical plasticity after PNI and the functional implications for each. We found seven rehabilitative interventions based on cortical plasticity: traditional sensory reeducation, activity-based sensory reeducation, selective deafferentation, cross-modal sensory substitution, mirror therapy, mental motor imagery, and action observation with simultaneous peripheral nerve stimulation. CONCLUSION AND RELEVANCE: The seven interventions ranged from theoretically well justified (traditional and activity-based sensory reeducation) to unjustified (selective deafferentation). Overall, articles were heterogeneous and of low quality, and future research should prioritize randomized controlled trials for specific neuropathies, interventions, or cortical plasticity mechanisms. WHAT THIS ARTICLE ADDS: This article reviews current knowledge about how the brain changes after PNI and how occupational therapy practitioners can take advantage of those changes for rehabilitation. Copyright © 2020 by the American Occupational Therapy Association, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

“Trial of SAGE-217 in Patients with Major Depressive Disorder” (2019) Obstetrical and Gynecological Survey

Trial of SAGE-217 in Patients with Major Depressive Disorder
(2019) Obstetrical and Gynecological Survey, 74 (12), pp. 723-724.

Gunduz-Bruce, H.^a , Silber, C.^a , Kaul, I.^a , Rothschild, A.J.^a , Riesenberg, R.^a , Sankoh, A.J.^a , Li, H.^b , Lasser, R.^c , Zorumski, C.F.^d , Rubinow, D.R.^e , Paul, S.M.^a , Jonas, J.^a , Doherty, J.J.^f , Kanes, S.J.^a

^a Sage Therapeutics, Cambridge, United States
^b Kaul Consulting, Concord, United States
^c University of Massachusetts Medical School, UMass Memorial Healthcare, Worcester, MA, United States
^d Atlanta Center for Medical Research, Atlanta, GA, United States
^e Washington University School of Medicine, St. Louis, MO, United States
^f University of North Carolina School of Medicine, Chapel Hill, NC, United States

Document Type: Note
Publication Stage: Final
Source: Scopus