WashU weekly Neuroscience publications

Analysis of Modulation of the ρ1 GABAA Receptor by Combinations of Inhibitory and Potentiating Neurosteroids Reveals Shared and Distinct Binding Sites
(2020) Molecular Pharmacology, 98 (4), pp. 280-291. 

Germann, A.L., Reichert, D.E., Burbridge, A.B., Pierce, S.R., Evers, A.S., Steinbach, J.H., Akk, G.

Departments of Anesthesiology (A.L.G., A.B.B., S.R.P., G.A.) and Radiology (D.E.R.) and the Taylor Family Institute for Innovative Psychiatric Research (D.E.R., A.S.E., Washington University School of Medicine, St. Louis, MO, United States

Abstract
The ρ1 GABAA receptor is prominently expressed in the retina and is present at lower levels in several brain regions and other tissues. Although the ρ1 receptor is insensitive to many anesthetic drugs that modulate the heteromeric GABAA receptor, it maintains a rich and multifaceted steroid pharmacology. The receptor is negatively modulated by 5β-reduced steroids, sulfated or carboxylated steroids, and β-estradiol, whereas many 5α-reduced steroids potentiate the receptor. In this study, we analyzed modulation of the human ρ1 GABAA receptor by several neurosteroids, individually and in combination, in the framework of the coagonist concerted transition model. Experiments involving coapplication of two or more steroids revealed that the receptor contains at least three classes of distinct, nonoverlapping sites for steroids, one each for the inhibitory steroids pregnanolone (3α5βP), 3α5βP sulfate, and β-estradiol. The site for 3α5βP can accommodate the potentiating steroid 5αTHDOC. The findings are discussed with respect to receptor modulation by combinations of endogenous neurosteroids. SIGNIFICANCE STATEMENT: The study describes modulation of the ρ1 GABAA receptor by neurosteroids. The coagonist concerted transition model was used to determine overlap of binding sites for several inhibitory and potentiating steroids. Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

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

Enhancement of Muscimol Binding and Gating by Allosteric Modulators of the GABAA Receptor: Relating Occupancy to State Functions
(2020) Molecular Pharmacology, 98 (4), pp. 303-313. 

Akk, G., Germann, A.L., Sugasawa, Y., Pierce, S.R., Evers, A.S., Steinbach, J.H.

Department of Anesthesiology (G.A., A.L.G., S.R.P., J.H.S.) and the Taylor Family Institute for Innovative Psychiatric Research (G.A., A.S.E., Washington University School of Medicine, St. Louis, MO, United States

Abstract
Muscimol is a psychoactive isoxazole derived from the mushroom Amanita muscaria and a potent orthosteric agonist of the GABAA receptor. The binding of [3H]muscimol has been used to evaluate the distribution of GABAA receptors in the brain, and studies of modulation of [3H]muscimol binding by allosteric GABAergic modulators such as barbiturates and steroid anesthetics have provided insight into the modes of action of these drugs on the GABAA receptor. It has, however, not been feasible to directly apply interaction parameters derived from functional studies to describe the binding of muscimol to the receptor. Here, we employed the Monod-Wyman-Changeux concerted transition model to analyze muscimol binding isotherms. We show that the binding isotherms from recombinant α1β3 GABAA receptors can be qualitatively predicted using electrophysiological data pertaining to properties of receptor activation and desensitization in the presence of muscimol. The model predicts enhancement of [3H]muscimol binding in the presence of the steroids allopregnanolone and pregnenolone sulfate, although the steroids interact with distinct sites and either enhance (allopregnanolone) or reduce (pregnenolone sulfate) receptor function. We infer that the concerted transition model can be used to link radioligand binding and electrophysiological data. SIGNIFICANCE STATEMENT: The study employs a three-state resting-active-desensitized model to link radioligand binding and electrophysiological data. We show that the binding isotherms can be qualitatively predicted using parameters estimated in electrophysiological experiments and that the model accurately predicts the enhancement of [3H]muscimol binding in the presence of the potentiating steroid allopregnanolone and the inhibitory steroid pregnenolone sulfate. Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of C-reactive protein and metabolic risk with cognitive effects of lurasidone in patients with schizophrenia
(2020) Comprehensive Psychiatry, 102, art. no. 152195, . 

Miller, B.J.^a , Pikalov, A.^b , Siu, C.O.^c , Tocco, M.^b , Tsai, J.^b , Harvey, P.D.^d , Newcomer, J.W.^{e f} , Loebel, A.^b

^a Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA, United States
^b Sunovion Pharmaceuticals Inc., Marlborough, MA and Fort Lee, NJ, United States
^c COS and Associates Ltd., Central, Hong Kong
^d University of Miami Miller School of Medicine, Miami, FL, United States
^e Thriving Mind South Florida, Miami, FL, United States
^f Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. Methods: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. Results: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p <.05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. Conclusions: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia. © 2020 The Authors

Author Keywords
C-reactive protein;  Cognitive performance;  lurasidone;  Metabolic risk;  Schizophrenia

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

The Opioid Epidemic: Associated Infections and Diagnostic Methods
(2020) Clinical Microbiology Newsletter, 42 (18), pp. 145-155. 

Lloyd, M., Farnsworth, C.W.

Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University, St. Louis, MO, United States

Abstract
The opioid epidemic and the associated increases in intravenous drug use are significant causes of morbidity and mortality in the United States. Infections have long been associated with illicit drug use and contribute considerably to the high morbidity and mortality. Risky behaviors associated with drug use, including needle sharing and poor injection hygiene, have added to the increasing burden of infections related to drug use. This review addresses the associations between opioid use disorder and infectious organisms, highlighting the important role of laboratory testing for diagnosis and managing these patients. © 2020 Elsevier Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Deep anaesthesia
(2020) The Lancet, 396 (10252), p. 666. 

Vlisides, P.E.^{a b} , Avidan, M.S.^c

^a Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^b Center for Consciousness Science, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^c Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

A Comparison of Medication for Opioid Use Disorder Treatment Strategies for Persons Who Inject Drugs With Invasive Bacterial and Fungal Infections
(2020) The Journal of Infectious Diseases, 222 (5), pp. S513-S520. 

Marks, L.R.^a , Munigala, S.^a , Warren, D.K.^a , Liss, D.B.^{b c} , Liang, S.Y.^{a b} , Schwarz, E.S.^{b c} , Durkin, M.J.^a

^a Division of Infectious Diseases, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Division of Emergency Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^c Section of Medical Toxicology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Patients with opioid use disorder (OUD) are frequently admitted for invasive infections. Medications for OUD (MOUD) may improve outcomes in hospitalized patients. METHODS: In this retrospective cohort of 220 admissions to a tertiary care center for invasive infections due to OUD, we compared 4 MOUD treatment strategies: methadone, buprenorphine, methadone taper for detoxification, and no medication to determine whether there were differences in parenteral antibiotic completion and readmission rates. RESULTS: The MOUDs were associated with increased completion of parenteral antimicrobial therapy (64.08% vs 46.15%; odds ratio [OR] = 2.08; 95% CI, 1.23-3.61). On multivariate analysis, use of MOUD maintenance with either buprenorphine (OR = 0.38; 95% CI, .17-.85) or methadone maintenance (OR = 0.43; 95% CI, .20-.94) and continuation of MOUD on discharge (OR = 0.35; 95% CI, .18-.67) was associated with lower 90-day readmissions. In contrast, use of methadone for detoxification followed by tapering of the medication without continuation on discharge was not associated with decreased readmissions (OR = 1.87; 95% CI, .62-5.10). CONCLUSIONS: Long-term MOUDs, regardless of selection, are an integral component of care in patients hospitalized with OUD-related infections. Patients with OUD should have arrangements made for MOUDs to be continued after discharge, and MOUDs should not be discontinued before discharge. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Author Keywords
injection drug use;  medications for opioid use disorder;  opioid use disorder;  opioids;  people who inject drugs (PWID)

Document Type: Article
Publication Stage: Final
Source: Scopus

Anesthetic Management of Reversible Cerebral Vasoconstriction Syndrome During Vaginal Delivery: A Case Report
(2020) A&A Practice, 14 (11), p. e01298. 

Peace, J.M.^a , Bhat, A.D.^b , Peralta, F.M.^a

^a From the Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, IL, Mexico
^b Department of Anesthesiology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Reversible cerebral vasoconstriction syndrome (RCVS) is a rare group of vascular disorders characterized by severe headache with or without other neurologic symptoms. Pregnancy is known to precipitate RCVS, typically in the postpartum period. With improved recognition of this condition, RCVS is now increasingly identified in the antepartum period. Labor and vaginal delivery are characterized by fluctuations in hemodynamic and intracerebral pressures and present challenges for intrapartum anesthetic management. We report our experience with a patient with RCVS admitted for external cephalic version and subsequent vaginal delivery.

Document Type: Article
Publication Stage: Final
Source: Scopus

Special Issue: “Genomics and Models of Nerve Sheath Tumors”
(2020) Genes, 11 (9), . 

Hirbe, A.C.^a , Dodd, R.D.^b , Pratilas, C.A.^c

^a Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8076, St. Louis, MO 63110, USA
^b Holden Comprehensive Cancer Center, Carver College of Medicine, University of Iowa, 285 Newton Road, Iowa City, IA 52242, United States
^c Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, United States

Abstract
Nerve sheath tumors arising in the context of neurofibromatosis type 1 (NF1) include benign tumors such as cutaneous, diffuse and plexiform neurofibromas; atypical neurofibromas or atypical neurofibromatosis neoplasms of uncertain biological potential (ANNUBP); and the aggressive soft tissue sarcoma, the malignant peripheral nerve sheath tumor (MPNST) […].

Author Keywords
genomics;  mouse models;  nerve sheath tumors;  NF1

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

Effort in daily life: Relationships between experimental tasks and daily experience
(2020) Motivation Science, 6 (3), pp. 303-308. 

Culbreth, A.J.^a , Westbrook, A.^b , Braver, T.S.^c , Barch, D.M.^d

^a Washington University, St. Louis, United States
^b Brown University, Radboud University, Netherlands
^c Washington University, St. Louis, United States
^d Washington University, Washington University School of Medicine, St. Louis, United States

Abstract
Recently, experimental tasks have been developed that index individual differences in willingness to expend effort for reward. However, little is known regarding whether such measures are associated with daily experience of effort. To test this, 31 participants completed an ecological momentary assessment (EMA) protocol, answering surveys regarding the mental and physical demand of their daily activities, and also completed 2 effort-based decision-making tasks: the Effort Expenditure for Rewards Task (EEfRT) and the Cognitive Effort Discounting (COGED) Task. Individuals who reported engaging in more mentally and physically demanding activities via EMA were also more willing to expend effort in the COGED task. However, EMA variables were not significantly associated with EEfRT decisionmaking. The results demonstrate the ecological, discriminant, and incremental validity of the COGED task, and provide preliminary evidence that individual differences in daily experience of effort may arise, in part, from differences in trait-level tendencies to weigh the costs versus benefits of actions. © 2019 American Psychological Association.

Author Keywords
Ecological monetary assessment;  Effort-based decision-making;  Motivation

Document Type: Article
Publication Stage: Final
Source: Scopus

Krabbe disease successfully treated via monotherapy of intrathecal gene therapy
(2020) The Journal of Clinical Investigation, 130 (9), pp. 4906-4920. 

Bradbury, A.M.^a , Bagel, J.H.^a , Nguyen, D.^b , Lykken, E.A.^c , Pesayco Salvador, J.^d , Jiang, X.^e , Swain, G.P.^a , Assenmacher, C.A.^f , Hendricks, I.J.^a , Miyadera, K.^a , Hess, R.S.^a , Ostrager, A.^a , ODonnell, P.^a , Sands, M.S.^e , Ory, D.S.^e , Shelton, G.D.^d , Bongarzone, E.R.^b , Gray, S.J.^c , Vite, C.H.^a

^a Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
^b Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
^c Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
^d Department of Pathology, School of Medicine, University of California San Diego, La JollaCA, United States
^e Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States

Abstract
Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased GALC enzyme activity, normalized psychosine concentration, improved myelination, and attenuated inflammation in both the CNS and PNS. Moreover, AAV-mediated therapy successfully prevented clinical neurological dysfunction, allowing treated dogs to live beyond 2.5 years of age, more than 7 times longer than untreated dogs. Furthermore, we found that a 5-fold lower dose resulted in an attenuated form of disease, indicating that sufficient dosing is critical. Finally, postsymptomatic therapy with high-dose AAV9 also significantly extended lifespan, signifying a treatment option for patients for whom HSCT is not applicable. If translatable to patients, these findings would improve the outcomes of patients treated either pre- or postsymptomatically.

Author Keywords
Demyelinating disorders;  Gene therapy;  Neurological disorders;  Neuroscience;  Therapeutics

Document Type: Article
Publication Stage: Final
Source: Scopus

Timing of the Diagnosis of Autism in African American Children
(2020) Pediatrics, 146 (3), . 

Constantino, J.N.^{a b} , Abbacchi, A.M.^{b c} , Saulnier, C.^{d e} , Klaiman, C.^d , Mandell, D.S.^f , Zhang, Y.^c , Hawks, Z.^c , Bates, J.^g , Klin, A.^d , Shattuck, P.^h , Molholm, S.^g , Fitzgerald, R.^c , Roux, A.^h , Lowe, J.K.ⁱ , Geschwind, D.H.ⁱ

^a Department of Psychiatry, School of Medicine, Washington University, St Louis, Missouri;
^b Contributed equally as co-first authors
^c Department of Psychiatry, School of Medicine, Washington University, St Louis, MO, United States
^d Marcus Autism Center, School of Medicine, Emory University, Atlanta, Georgia
^e Neurodevelopmental Assessment and Consulting Services, Atlanta, Georgia
^f Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^g Departments of Pediatrics, Neuroscience, Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, United States
^h Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania; and
ⁱ Departments of Neurology, Psychiatry, Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, Mexico

Abstract
OBJECTIVES: African American (AA) children affected by autism spectrum disorder (ASD) experience delays in diagnosis and obstacles to service access, as well as a disproportionate burden of intellectual disability (ID) as documented in surveillance data recently published by the US Centers for Disease Control and Prevention. Our objective in this study was to analyze data from the largest-available repository of diagnostic and phenotypic information on AA children with ASD, and to explore the wide variation in outcome within the cohort as a function of sociodemographic risk and specific obstacles to service access for the purpose of informing a national approach to resolution of these disparities. METHODS: Parents of 584 AA children with autism consecutively enrolled in the Autism Genetic Resource Exchange across 4 US data collection sites completed event history calendar interviews of the diagnostic odysseys for their children with ASD. These data were examined in relation to developmental outcomes of the children with autism and their unaffected siblings. RESULTS: The average age of ASD diagnosis was 64.9 months (±49.6), on average 42.3 months (±45.1) after parents’ first concerns about their children’s development. The relationship between timing of diagnosis and ASD severity was complex, and ID comorbidity was not predicted in a straightforward manner by familial factors associated with cognitive variation in the general population. CONCLUSIONS: These findings document significant opportunity to expedite diagnosis, the need to further understand causes of ID comorbidity, and the necessity to identify effective approaches to the resolution of disparities in severity-of-outcome for AA children with autism. Copyright © 2020 by the American Academy of Pediatrics.

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

Testing Effect on High-Level Cognitive Skills
(2020) CBE Life Sciences Education, 19 (3), p. ar39. 

Jensen, J.L.^a , McDaniel, M.A.^b , Kummer, T.A.^a , Godoy, P.D.D.M.^c , St Clair, B.^c

^a Department of Biology, Brigham Young University, Provo, UT 84602, United States
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO 63130-4899
^c Department of Biology, Saint Joseph Catholic Schools, Ogden, United States

Abstract
The testing effect is one of the strongest learning techniques documented to date. Although the effects of testing on high-level learning are promising, fewer studies on this have been done. In this classroom application of the testing effect, we aimed to 1) determine whether a testing effect exists on high-level testing; 2) determine whether higher-level testing has an effect on low-level content retention; and 3) determine whether content knowledge, cognitive skill, or additional components are responsible for this effect. Through a series of two experiments, we confirmed a testing effect on high-level items. However, improved content retention due to testing was not observed. We suggest that this high-level testing effect is due to a better ability to apply specific skills to specific content when this application process has appeared on a previous exam.

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

Preliminary data on help-seeking intentions and behaviors of individuals completing a widely available online screen for eating disorders in the United States
(2020) International Journal of Eating Disorders, 53 (9), pp. 1556-1562. 

Fitzsimmons-Craft, E.E.^a , Balantekin, K.N.^b , Graham, A.K.^c , DePietro, B.^a , Laing, O.^a , Firebaugh, M.-L.^a , Smolar, L.^d , Park, D.^d , Mysko, C.^d , Funk, B.^e , Taylor, C.B.^{f g} , Wilfley, D.E.^a

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, United States
^c Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^d National Eating Disorders Association, New York, NY, United States
^e Institute of Information Systems, Leuphana University, Lüneburg, Germany
^f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^g Center for m2Health, Palo Alto University, Palo Alto, CA, United States

Abstract
Objective: Scaling an online screen that provides referrals may be key in closing the treatment gap for eating disorders (EDs), but we need to understand respondents’ help-seeking intentions and behaviors after receiving screen results. This study reported on these constructs among respondents to the National Eating Disorders Association online screen who screened positive or at high risk for an ED. Method: Respondents completed the screen over 18 months (February 9, 2018–August 28, 2019). Those screening positive or at high risk for an ED (n = 343,072) had the option to provide data on help-seeking intentions (after screen completion) and behaviors (2-month follow-up). Results: Of eligible respondents, 4.8% (n = 16,396) provided data on help-seeking intentions, with only 33.7% of those reporting they would seek help. Only 7.6% of eligible respondents opted in to the 2-month follow-up, with 10.6% of those completing it (n = 2,765). Overall, 8.9% of respondents to the follow-up reported being in treatment when they took the screen, 15.5% subsequently initiated treatment, and 75.5% did not initiate/were not already in treatment. Discussion: Preliminary results suggest that among the small minority who provided data, only one-third expressed help-seeking intentions and 16% initiated treatment. Online screening should consider ways to increase respondents’ motivation for and follow-through with care. © 2020 Wiley Periodicals, Inc.

Author Keywords
eating disorders;  health care utilization;  help-seeking;  referral;  screening

Document Type: Article
Publication Stage: Final
Source: Scopus

Early Childhood Nurturance and the Sculpting of Neurodevelopment
(2020) The American Journal of Psychiatry, 177 (9), pp. 795-796. 

Luby, J.L.

Department of Psychiatry, Washington University, St. Louis, United States

Author Keywords
Imaging;  Neurodevelopment;  Pediatric

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

Identifying Common Peroneal Neuropathy before Foot Drop
(2020) Plastic and Reconstructive Surgery, 146 (3), pp. 664-675. 

Lu, J.C.-Y., Dengler, J., Poppler, L.H., Van Handel, A., Linkugel, A., Jacobson, L., Mackinnon, S.E.

St. Louis, Mo.; Taoyuan, Taiwan; and Toronto, Ontario, Canada From the Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University School of Medicine; the Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University; and the Division of Plastic and Reconstructive Surgery, Department of Surgery, University of Toronto

Abstract
BACKGROUND: Common peroneal neuropathy shares the same pathophysiology as carpal tunnel syndrome. However, management is often delayed because of the traditional misconception of recognizing foot drop as the defining symptom for diagnosis. The authors believe recognizing common peroneal neuropathy before foot drop can relieve pain and help improve quality of life. METHODS: One hundred eighty-five patients who underwent surgical common peroneal neuropathy decompression between 2011 and 2017 were included. The mean follow-up time was 249 ± 28 days. Patients were classified into two stages of severity based on clinical presentation: pre-foot drop and overt foot drop. Demographics, presenting symptoms, clinical signs, electrodiagnostic studies and response to surgery were compared between these two groups. Multivariate regression analysis was used to identify variables that predicted outcome following surgery. RESULTS: Overt foot drop patients presented with significantly lower preoperative motor function (percentage of patients with Medical Research Council grade ≤ 1: overt foot drop, 90 percent; pre-foot drop, 0 percent; p < 0.001). Pre-foot drop patients presented with a significantly higher preoperative pain visual analogue scale score (pre-foot drop, 6.2 ± 0.2; overt foot drop, 4.6 ± 0.3; p < 0.001) and normal electrodiagnostic studies (pre-foot drop, 31.4 percent; overt foot drop, 0.1 percent). Postoperatively, both groups of patients showed significant improvement in quality-of-life score (pre-foot drop, 2.6 ± 0.3; overt foot drop, 2.7 ± 0.3). Patients with obesity or a traumatic cause for common peroneal neuropathy were less likely to have improvements in quality of life after surgical decompression. CONCLUSION: Increased recognition of common peroneal neuropathy can aid early management, relieve pain, and improve quality of life.Risk, II.

Document Type: Article
Publication Stage: Final
Source: Scopus

Retrospective Analysis of the Test of Memory Malingering in a Low Intellectual Quotient Intractable Epilepsy Sample
(2020) Archives of Clinical Neuropsychology: the Official Journal of the National Academy of Neuropsychologists, 35 (6), pp. 726-734. 

Grant, A.F.^a , Werner, N.J.^b

^a Department of Psychology, Saint Louis University, St. Louis, MO, USA
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA

Abstract
OBJECTIVE: The Test of Memory Malingering (TOMM) is commonly used by neuropsychologists (Sharland, M. J., & Gfeller, J. D. (2007). A survey of neuropsychologists’ beliefs and practices with respect to the assessment of effort. Archives of Clinical Neuropsychology, 22 (2), 213-223); however there is variable research regarding its use in low intelligence and epileptic populations (Hill, S. K., Ryan, L. M., Kennedy, C. H., & Malamut, B. L. (2003). The relationship between measures of declarative memory and the Test of Memory Malingering in patients with and without temporal lobe dysfunction. Journal of Forensic Neuropsychology, 3 (3), 1-18; Hurley, K. E., & Deal, W. P. (2006). Assessment instruments measuring malingering used with individuals who have mental retardation: Potential problems and issues. Mental Retardation, 44 (2), 112-119; Simon, M. J. (2007). Performance of mentally retarded forensic patients on the Test of Memory Malingering. Journal of Clinical Psychology, 63 (4), 339-344). The present study evaluates whether the standard TOMM cutoffs are resistant to low estimated IQ (≤80) in a clinical sample of patients with intractable epilepsy. A second aim is to decipher possible relationships between the TOMM and memory performance. METHODS: Retrospective data analysis was conducted between 2010 and 2019 on 42 adults with intractable epilepsy who completed a comprehensive neuropsychological evaluation as part of screening procedures for epilepsy surgery. IQ estimates and TOMM were administered to all participants. Some were also administered memory- and mood-related measures. RESULTS: Traditional TOMM cutoffs demonstrated excellent specificity with only one participant scoring below the cutoff score on the Retention Trial, but not on Trial 2. The TOMM significantly correlated with several scores on various memory tests. CONCLUSIONS: The TOMM may be appropriate for use in low intellectually functioning populations with intractable epilepsy given the excellent specificity seen in this study. Future studies may seek to better understand the relationship between TOMM and memory performance in other low-functioning populations. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Effort;  Epilepsy;  Low intelligence;  Performance validity tests

Document Type: Article
Publication Stage: Final
Source: Scopus

Hierarchical dynamics as a macroscopic organizing principle of the human brain
(2020) Proceedings of the National Academy of Sciences of the United States of America, 117 (34), pp. 20890-20897. 

Raut, R.V.^a , Snyder, A.Z.^{b c} , Raichle, M.E.^{b c}

^a Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110;
^b Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110

Abstract
Multimodal evidence suggests that brain regions accumulate information over timescales that vary according to anatomical hierarchy. Thus, these experimentally defined “temporal receptive windows” are longest in cortical regions that are distant from sensory input. Interestingly, spontaneous activity in these regions also plays out over relatively slow timescales (i.e., exhibits slower temporal autocorrelation decay). These findings raise the possibility that hierarchical timescales represent an intrinsic organizing principle of brain function. Here, using resting-state functional MRI, we show that the timescale of ongoing dynamics follows hierarchical spatial gradients throughout human cerebral cortex. These intrinsic timescale gradients give rise to systematic frequency differences among large-scale cortical networks and predict individual-specific features of functional connectivity. Whole-brain coverage permitted us to further investigate the large-scale organization of subcortical dynamics. We show that cortical timescale gradients are topographically mirrored in striatum, thalamus, and cerebellum. Finally, timescales in the hippocampus followed a posterior-to-anterior gradient, corresponding to the longitudinal axis of increasing representational scale. Thus, hierarchical dynamics emerge as a global organizing principle of mammalian brains.

Author Keywords
fMRI;  frequency;  functional connectivity;  intrinsic;  subcortex

Document Type: Article
Publication Stage: Final
Source: Scopus

Effectiveness of a Digital Cognitive Behavior Therapy-Guided Self-Help Intervention for Eating Disorders in College Women: A Cluster Randomized Clinical Trial
(2020) JAMA Network Open, 3 (8), p. e2015633. 

Fitzsimmons-Craft, E.E.^a , Taylor, C.B.^{b c} , Graham, A.K.^d , Sadeh-Sharvit, S.^{b c e} , Balantekin, K.N.^f , Eichen, D.M.^g , Monterubio, G.E.^a , Goel, N.J.^{h i} , Flatt, R.E.^j , Karam, A.M.^a , Firebaugh, M.-L.^a , Jacobi, C.^k , Jo, B.^b , Trockel, M.T.^b , Wilfley, D.E.^a

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^c Center for m Health, Palo Alto University, Palo Alto, CA, Mexico
^d Department of Medical Social Sciences, Northwestern University, Chicago, IL, Mexico
^e Interdisciplinary Center, Baruch Ivcher School of Psychology, Herzliya, Israel
^f Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, United States
^g Department of Pediatrics, University of California, San Diego, Mexico
^h Department of Psychology, Virginia Commonwealth University, Richmond
ⁱ Innovation (iCubed), Virginia Commonwealth University, Richmond
^j Department of Psychology and Neurosciences, University of North Carolina at Chapel Hill, Chapel Hill
^k Institute of Clinical Psychology and Psychotherapy, Technische Universität, Dresden, Germany

Abstract
Importance: Eating disorders (EDs) are common, serious psychiatric disorders on college campuses, yet most affected individuals do not receive treatment. Digital interventions have the potential to bridge this gap. Objective: To determine whether a coached, digital, cognitive behavior therapy (CBT) intervention improves outcomes for college women with EDs compared with referral to usual care. Design, Setting, and Participants: This cluster randomized trial was conducted from 2014 to 2018 at 27 US universities. Women with binge-purge EDs (with both threshold and subthreshold presentations) were recruited from enrolled universities. The 690 participants were followed up for up to 2 years after the intervention. Data analysis was performed from February to September 2019. Interventions: Universities were randomized to the intervention, Student Bodies-Eating Disorders, a digital CBT-guided self-help program, or to referral to usual care. Main Outcomes and Measures: The main outcome was change in overall ED psychopathology. Secondary outcomes were abstinence from binge eating and compensatory behaviors, as well as ED behavior frequencies, depression, anxiety, clinical impairment, academic impairment, and realized treatment access. Results: A total of 690 women with EDs (mean [SD] age, 22.12 [4.85] years; 414 [60.0%] White; 120 [17.4%] Hispanic; 512 [74.2%] undergraduates) were included in the analyses. For ED psychopathology, there was a significantly greater reduction in the intervention group compared with the control group at the postintervention assessment (β [SE], -0.44 [0.10]; d = -0.40; t1387 = -4.23; P < .001), as well as over the follow-up period (β [SE], -0.39 [0.12]; d = -0.35; t1387 = -3.30; P < .001). There was not a significant difference in abstinence from any ED behaviors at the postintervention assessment (odds ratio, 1.48; 95% CI, 0.48-4.62; P = .50) or at follow-up (odds ratio, 1.51; 95% CI, 0.63-3.58; P = .36). Compared with the control group, the intervention group had significantly greater reductions in binge eating (rate ratio, 0.82; 95% CI, 0.70-0.96; P = .02), compensatory behaviors (rate ratio, 0.68; 95% CI, 0.54-0.86; P < .001), depression (β [SE], -1.34 [0.53]; d = -0.22; t1387 = -2.52; P = .01), and clinical impairment (β [SE], -2.33 [0.94]; d = -0.21; t1387 = -2.49; P = .01) at the postintervention assessment, with these gains sustained through follow-up for all outcomes except binge eating. Groups did not differ in terms of academic impairment. The majority of intervention participants (318 of 385 participants [83%]) began the intervention, whereas only 28% of control participants (76 of 271 participants with follow-up data available) sought treatment for their ED (odds ratio, 12.36; 95% CI, 8.73-17.51; P < .001). Conclusions and Relevance: In this cluster randomized clinical trial comparing a coached, digital CBT intervention with referral to usual care, the intervention was effective in reducing ED psychopathology, compensatory behaviors, depression, and clinical impairment through long-term follow-up, as well as realizing treatment access. No difference was found between the intervention and control groups for abstinence for all ED behaviors or academic impairment. Given its scalability, a coached, digital, CBT intervention for college women with EDs has the potential to address the wide treatment gap for these disorders. Trial Registration: ClinicalTrials.gov Identifier: NCT02076464.

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

Hearing loss in mucopolysaccharidoses: Current knowledge and future directions
(2020) Diagnostics, 10 (8), art. no. 554, . 

Wolfberg, J.^{a b} , Chintalapati, K.^{a c} , Tomatsu, S.^{a d e f} , Nagao, K.^{a g}

^a Nemours Biomedical Research, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE 19803, United States
^b Department of Communication Sciences and Disorders, West Chester University, West Chester, PA 19383, United States
^c Department of Biology, Washington University in Saint Louis, Saint Louis, MO 63130, United States
^d Department of Pediatrics, Thomas Jefferson University, Philadelphia, PA 19107, United States
^e Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, 501-1194, Japan
^f Department of Pediatrics, Shimane University, Shimane, 690-8504, Japan
^g College of Health Sciences, University of Delaware, Newark, DE 19716, United States

Abstract
Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders caused by a deficiency of one of the enzymes involved in the degradation of glycosaminoglycans. Hearing loss is a common clinical presentation in MPS. This paper reviews the literature on hearing loss for each of the seven recognized subtypes of MPS. Hearing loss was found to be common in MPS I, II, III, IVA, VI, and VII, and absent from MPS IVB and MPS IX. MPS VI presents primarily with conductive hearing loss, while the other subtypes (MPS I, MPS II, MPS III, MPS IVA, and MPS VII) can present with any type of hearing loss (conductive, sensorineural, or mixed hearing loss). The sensorineural component develops as the disease progresses, but there is no consensus on the etiology of the sensorineural component. Enzyme replacement therapy (ERT) is the most common therapy utilized for MPS, but the effects of ERT on hearing function have been inconclusive. This review highlights a need for more comprehensive and multidisciplinary research on hearing function that includes behavioral testing, objective testing, and temporal bone imaging. This information would allow for better understanding of the progression and etiology of hearing loss. Owing to the prevalence of hearing loss in MPS, early diagnosis of hearing loss and annual comprehensive audiological evaluations are recommended. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Author Keywords
Hearing loss;  Inner ear;  Middle ear;  Otitis media

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

Endoscopic treatment of combined metopic-sagittal craniosynostosis
(2020) Journal of Neurosurgery: Pediatrics, 26 (2), pp. 113-121. 

Zubovic, E.^a , Skolnick, G.B.^a , Naidoo, S.D.^a , Bellanger, M.^c , Smyth, M.D.^b , Patel, K.B.^a

^a Division of Plastic & Reconstructive Surgery, Department of Surgery, St. Louis, MO, United States
^b Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Orthotic and Prosthetic Lab, St. Louis, MO, United States

Abstract
OBJECTIVE Combined metopic-sagittal craniosynostosis is traditionally treated with open cranial vault remodeling and fronto-orbital advancement, sometimes in multiple operations. Endoscopic treatment of this multisuture synostosis presents a complex challenge for the surgeon and orthotist. METHODS The authors retrospectively analyzed the preoperative and 1-year postoperative CT scans of 3 patients with combined metopic-sagittal synostosis, all of whom were treated with simultaneous endoscope-assisted craniectomy of the metopic and sagittal sutures followed by helmet therapy. Established anthropometric measurements were applied to assess pre- and postoperative morphology, including cranial index and interfrontal divergence angle (IFDA). Patients’ measurements were compared to those obtained in 18 normal controls. RESULTS Two boys and one girl underwent endoscope-assisted craniectomy at a mean age of 81 days. The mean preoperative cranial index was 0.70 (vs control mean of 0.82, p = 0.009), corrected postoperatively to a mean of 0.82 (vs control mean of 0.80, p = 0.606). The mean preoperative IFDA was 110.4° (vs control mean of 152.6°, p = 0.017), corrected postoperatively to a mean of 139.1° (vs control mean of 140.3°, p = 0.348). The mean blood loss was 100 mL and the mean length of stay was 1.7 days. No patient underwent reoperation. The mean clinical follow-up was 3.4 years. CONCLUSIONS Endoscope-assisted craniectomy with helmet therapy is a viable single-stage treatment option for combined metopic-sagittal synostosis, providing correction of the stigmata of trigonoscaphocephaly, with normalization of the cranial index and IFDA. © 2020 American Association of Neurological Surgeons. All rights reserved.

Author Keywords
Craniofacial;  Craniosynostosis;  Endoscopic;  Metopic-sagittal synostosis;  Multisuture

Document Type: Article
Publication Stage: Final
Source: Scopus

Deconvolving the contributions of cell-type heterogeneity on cortical gene expression
(2020) PLoS Computational Biology, 16 (8), p. e1008120. 

Patrick, E.^{a b} , Taga, M.^c , Ergun, A.^d , Ng, B.^{e f} , Casazza, W.^{e f g} , Cimpean, M.^h , Yung, C.^c , Schneider, J.A.ⁱ , Bennett, D.A.ⁱ , Gaiteri, C.ⁱ , De Jager, P.L.^c , Bradshaw, E.M.^j , Mostafavi, S.^{e f}

^a School of Mathematics and Statistics, University of Sydney, Sydney, NSW, Australia
^b Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, Australia
^c Center for Translational & Computational Neuroimmunology, Department of Neurology, Columbia University Medical Center, New York City, NY, United States
^d Research and Development, Biogen, Cambridge, MA, United States
^e Departments of Statistics and Medical Genetics, University of British Columbia, Vancouver, BC, Canada
^f Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada
^g Bioinformatics Training Program, University of British Columbia, Vancouver, Canada
^h Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^j Department of Neurology, Columbia University Medical Center, New York City, NY, United States

Abstract
Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer’s disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).

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