WashU weekly Neuroscience publications

Human inference reflects a normative balance of complexity and accuracy
(2022) Nature Human Behaviour, . 

Tavoni, G.^a , Doi, T.^b , Pizzica, C.^c , Balasubramanian, V.^c d , Gold, J.I.^c

^a Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
^c Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Physics & Astronomy, University of Pennsylvania, Philadelphia, PA, United States

Abstract
We must often infer latent properties of the world from noisy and changing observations. Complex, probabilistic approaches to this challenge such as Bayesian inference are accurate but cognitively demanding, relying on extensive working memory and adaptive processing. Simple heuristics are easy to implement but may be less accurate. What is the appropriate balance between complexity and accuracy? Here we model a hierarchy of strategies of variable complexity and find a power law of diminishing returns: increasing complexity gives progressively smaller gains in accuracy. The rate of diminishing returns depends systematically on the statistical uncertainty in the world, such that complex strategies do not provide substantial benefits over simple ones when uncertainty is either too high or too low. In between, there is a complexity dividend. In two psychophysical experiments, we confirm specific model predictions about how working memory and adaptivity should be modulated by uncertainty. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
1533623
575556
National Institutes of HealthNIHR01 MH115557, R01EB026945
University of Pennsylvania
Washington University in St. LouisWUSTL

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

Multidimensional poverty and children’s behavioral trajectories in immigrant families: Beating the odds?
(2022) Children and Youth Services Review, 139, art. no. 106534, .

Zhang, L.^a , Han, W.-J.^b 

^a Brown School, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
^b Silver School of Social Work, New York University, 1 Washington Square North, New York, NY 10003, United States

Abstract
Despite a large body of scholarship examining the relation between poverty and child behavioral outcomes, little is known about how such a relation may differ when poverty is viewed through a multidimensional lens. In addition, the evidence is mixed on the behavioral well-being of children of immigrants relative to their counterparts with U.S.-born parents under various poverty conditions. Using data from the ECLS-K (N ≈ 16,660), this study examines the relation among three dimensions of poverty—depth, volatility, and duration—and internalizing and externalizing behavioral trajectories from kindergarten through eighth grade, paying particular attention to children of immigrants with diverse racial-ethnic backgrounds. Growth-curve analysis results indicate that under the same poverty conditions, children of immigrants received more favorable ratings by teachers on internalizing and externalizing behaviors, but self-reported worse internalizing scores than children with U.S.-born parents. Among children of immigrants, Black and Hispanic children had relatively worse teacher-reported externalizing behaviors, while Hispanic and Asian children reported unfavorable internalizing behaviors. The results shed light on the intersectional forces of poverty, immigration, and race-ethnicity in shaping children’s behavioral trajectories, confirming aspects of the immigrant risk and immigrant paradox stories. The discrepancy between teacher- and youth-reported outcomes highlights the importance of using multiple informants. © 2022 Elsevier Ltd

Author Keywords
ECLS-K;  Immigrant;  Internalizing and externalizing behaviors;  Multidimensional poverty;  Race-ethnicity

Document Type: Article
Publication Stage: Final
Source: Scopus

Use of laboratory data for illicit drug use surveillance and identification of socioeconomic risk factors
(2022) Drug and Alcohol Dependence, 236, art. no. 109499, . 

Azimi, V., Jackups, R., Jr., Farnsworth, C.W., Budelier, M.M.

Department of Pathology & Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Background: Drug overdose is the leading cause of death among people 25–44 years of age in the United States. Existing drug surveillance methods are important for prevention and directing treatment, but are limited by delayed reporting and lack of geographic granularity. Methods: Laboratory urine drug screen and complete metabolic panel data from patients presenting to the emergency department was used to observe long-term and short-term temporal and geospatial changes at the zip code-level in St. Louis. Multivariate linear regression was performed to investigate associations between zip code-level socioeconomic factors and drug screening positivity rates. Results: An increase in the fentanyl positive drug screens was seen during the initial COVID-19 shutdown period in the spring of 2020. A decrease in cocaine positivity was seen in the fall and winter of 2020, with a return to baseline coinciding with the second major COVID-19 shutdown in the summer of 2021. These changes appeared to be independent of changes in emergency department utilization as measured by complete metabolic panels ordered. Significant short-term changes in fentanyl and cocaine positivity rates between specific time periods were able to be localized to individual zip codes. Zip code-level multivariate analysis demonstrated independent associations between socioeconomic/demographic factors and fentanyl/cocaine positivity rates as determined by laboratory drug screening data. Conclusions: Analyzing clinical laboratory drug screening data can enable a more temporally and geographically granular view of population-level drug use surveillance. Additionally, laboratory data can be utilized to find population-level socioeconomic associations with illicit drug use, presenting a potential avenue for the use of this data to guide public health and healthcare policy decisions. © 2022

Author Keywords
Big Data;  Illicit drug use;  Laboratory surveillance

Document Type: Article
Publication Stage: Final
Source: Scopus

Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns
(2022) Stroke, 53 (6), pp. 1883-1891. 

Baker, A.D.^a , Schwamm, L.H.^w , Sanborn, D.Y.^b , Furie, K.^c , Stretz, C.^c , Mac Grory, B.^d , Yaghi, S.^c , Kleindorfer, D.^e f , Sucharew, H.^g , Mackey, J.^h , Walsh, K.ⁱ , Flaherty, M.^j , Kissela, B.^j , Alwell, K.^f , Khoury, J.^k , Khatri, P.^j , Adeoye, O.^l , Ferioli, S.^j , Woo, D.^j , Martini, S.^m , De Los Rios La Rosa, F.^f n , Demel, S.L.^j , Madsen, T.^o , Star, M.^p , Coleman, E.^q , Slavin, S.^r , Jasne, A.^a , Mistry, E.A.^s , Haverbusch, M.^f , Merkler, A.E.^t , Kamel, H.^t , Schindler, J.^a , Sansing, L.H.^a u , Faridi, K.F.^v , Sugeng, L.^v , Sheth, K.N.^a , Sharma, R.^a

^a Department of Neurology (A.D.B., L.H.S., Yale School of Medicine, CT, New Haven, United States
^b Division of Cardiology (D.Y.S.), Massachusetts General Hospital and Harvard Medical School Boston
^c Department of Neurology (K.F., C.S., S.Y.), Alpert Medical School of Brown University, Providence, RI
^d Department of Neurology, Duke University School of Medicine (B.M.G.)
^e Department of Neurology, University of Michigan School of Medicine
^f Department of Neurology, University of Cincinnati, K.A
^g Department of Pediatrics, Division of Biostatistics and Epidemiology (H.S.), Cincinnati Children’s Hospital Medical Center, OH, Switzerland
^h Department of Neurology, Indiana University School of Medicine
ⁱ Department of Emergency Medicine (K.W.), University of Cincinnati Gardner Neuroscience Institute, OH, Switzerland
^j Department of Neurology & Rehabilitation Medicine and Comprehensive Stroke Center (M.F., B.K., P.K., S.F., University of Cincinnati Gardner Neuroscience Institute, OH, Switzerland
^k Division of Biostatistics and Epidemiology, Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati Medical Center (J.K.), OH, Switzerland
^l Department of Emergency Medicine, Washington University School of Medicine, St. Louis, United States
^m Department of Neurology, Baylor College of Medicine and VA National TeleStroke Program, Houston
ⁿ Miami Neuroscience Institute, Baptist Health South Florida, FL (F.D.L.R.L.R.), Miami, United States
^o Department of Emergency Medicine, Division of Sex and Gender (T.M.), Alpert Medical School of Brown University, Providence, RI
^p Department of Neurology, Soroka Medical Center, Beersheva
^q Department of Neurology, Northwestern Memorial Hospital, Chicago, Mexico
^r Department of Neurology, University of Kansas Medical Center (S.S.)
^s Department of Neurology, Vanderbilt University Medical Center, Nashville, United States
^t Department of Neurology, Weill Cornell Medicine
^u Department of Neurology and Comprehensive Stroke Center (L.H.S.), Massachusetts General Hospital and Harvard Medical School Boston
^v Section of Cardiovascular Medicine, Department of Medicine (K.F.F., Yale School of Medicine, CT, New Haven, United States

Abstract
BACKGROUND: There are limited data about the epidemiology and secondary stroke prevention strategies used for patients with depressed left ventricular ejection fraction (LVEF) and sinus rhythm following an acute ischemic stroke (AIS). We sought to describe the prevalence of LVEF ≤40% and sinus rhythm among patients with AIS and antithrombotic treatment practice in a multi-center cohort from 2002 to 2018. METHODS: This was a multi-center, retrospective cohort study comprised of patients with AIS hospitalized in the Greater Cincinnati Northern Kentucky Stroke Study and 4 academic, hospital-based cohorts in the United States. A 1-stage meta-analysis of proportions was undertaken to calculate a pooled prevalence. Univariate analyses and an adjusted multivariable logistic regression model were performed to identify demographic, clinical, and echocardiographic characteristics associated with being prescribed an anticoagulant upon AIS hospitalization discharge. RESULTS: Among 14 338 patients with AIS with documented LVEF during the stroke hospitalization, the weighted pooled prevalence of LVEF ≤40% and sinus rhythm was 5.0% (95% CI, 4.1-6.0%; I2, 84.4%). Of 524 patients with no cardiac thrombus and no prior indication for anticoagulant who survived postdischarge, 200 (38%) were discharged on anticoagulant, 289 (55%) were discharged on antiplatelet therapy only, and 35 (7%) on neither. There was heterogeneity by site in the proportion discharged with an anticoagulant (22% to 45%, P<0.0001). Cohort site and National Institutes of Health Stroke Severity scale >8 (odds ratio, 2.0 [95% CI, 1.1-3.8]) were significant, independent predictors of being discharged with an anticoagulant in an adjusted analysis. CONCLUSIONS: Nearly 5% of patients with AIS have a depressed LVEF and are in sinus rhythm. There is significant variation in the clinical practice of antithrombotic therapy prescription by site and stroke severity. Given this clinical equipoise, further study is needed to define optimal antithrombotic treatment regimens for secondary stroke prevention in this patient population.

Author Keywords
atrial fibrillation;  echocardiograph;  ischemic stroke;  prevalence

Document Type: Article
Publication Stage: Final
Source: Scopus

Measures of Intracranial Injury Size Do Not Improve Clinical Decision Making for Children With Mild Traumatic Brain Injuries and Intracranial Injuries
(2022) Neurosurgery, 90 (6), pp. 691-699. 

Greenberg, J.K.^a , Olsen, M.A.^b , Johnson, G.W.^a , Ahluwalia, R.^c , Hill, M.^d , Hale, A.T.^c , Belal, A.^e , Baygani, S.^e , Foraker, R.E.^b , Carpenter, C.R.^f , Ackerman, L.L.^e , Noje, C.^g , Jackson, E.M.^h , Burns, E.ⁱ , Sayama, C.M.^i j , Selden, N.R.^i j , Vachhrajani, S.^d k , Shannon, C.N.^d , Kuppermann, N.^l m , Limbrick, D.D., Jr^a

^a Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
^d Division of Neurosurgery, Dayton Children’s Hospital, Dayton, OH, United States
^e Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
^f Department of Emergency Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Critical Care Medicine, Charlotte R. Bloomberg Children’s Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^h Neurological Surgery, Johns Hopkins School of Medicine, Baltimore, MD, United States
ⁱ Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA
^j Department of Neurological Surgery, Oregon Health and Science University, Portland, Oregon, USA
^k Department of Pediatrics, Wright State University, Dayton, OH, United States
^l Department of Emergency Medicine, University of California Davis, School of Medicine, Sacramento, CA, United States
^m Department of Pediatrics, University of California Davis, School of Medicine, Sacramento, CA, United States

Abstract
BACKGROUND: When evaluating children with mild traumatic brain injuries (mTBIs) and intracranial injuries (ICIs), neurosurgeons intuitively consider injury size. However, the extent to which such measures (eg, hematoma size) improve risk prediction compared with the kids intracranial injury decision support tool for traumatic brain injury (KIIDS-TBI) model, which only includes the presence/absence of imaging findings, remains unknown. OBJECTIVE: To determine the extent to which measures of injury size improve risk prediction for children with mild traumatic brain injuries and ICIs. METHODS: We included children ≤18 years who presented to 1 of the 5 centers within 24 hours of TBI, had Glasgow Coma Scale scores of 13 to 15, and had ICI on neuroimaging. The data set was split into training (n = 1126) and testing (n = 374) cohorts. We used generalized linear modeling (GLM) and recursive partitioning (RP) to predict the composite of neurosurgery, intubation >24 hours, or death because of TBI. Each model’s sensitivity/specificity was compared with the validated KIIDS-TBI model across 3 decision-making risk cutoffs (<1%, <3%, and <5% predicted risk). RESULTS: The GLM and RP models included similar imaging variables (eg, epidural hematoma size) while the GLM model incorporated additional clinical predictors (eg, Glasgow Coma Scale score). The GLM (76%-90%) and RP (79%-87%) models showed similar specificity across all risk cutoffs, but the GLM model had higher sensitivity (89%-96% for GLM; 89% for RP). By comparison, the KIIDS-TBI model had slightly higher sensitivity (93%-100%) but lower specificity (27%-82%). CONCLUSION: Although measures of ICI size have clear intuitive value, the tradeoff between higher specificity and lower sensitivity does not support the addition of such information to the KIIDS-TBI model. Copyright © Congress of Neurological Surgeons 2022. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Estrogen metabolites increase nociceptor hyperactivity in a mouse model of uterine pain
(2022) JCI Insight, 7 (10), art. no. e149107, . 

Xie, Z.^a b , Feng, J.^a b c , Cai, T.^a b d , McCarthy, R.^e , Eschbach II, M.D.^f , Wang, Y.^a b g , Zhao, Y.^a b , Yi, Z.^a b h , Zang, K.^a b , Yuan, Y.^a b , Hu, X.^a b , Li, F.^a b , Liu, Q.^a b , Das, A.^f , England, S.K.^e , Hu, H.^a b

^a Center for the Study of Itch and Sensory Disorders, Washington University, School of Medicine, St. Louis, MO, United States
^b Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
^c Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai, China
^d The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
^e Center for Reproductive Health Sciences, Department of Obstetrics & Gynecology, Washington University, School of Medicine, St. Louis, MO, United States
^f Department of Bioengineering, Neuroscience Program, University of Illinois Urbana-Champaign, Urbana, IL, United States
^g Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
^h Department of Nursing, Medical College of Nanchang University, Nanchang, China

Abstract
Pain emanating from the female reproductive tract is notoriously difficult to treat, and the prevalence of transient pelvic pain has been placed as high as 70%-80% in women surveyed. Although sex hormones, especially estrogen, are thought to underlie enhanced pain perception in females, the underlying molecular and cellular mechanisms are not completely understood. Here, we showed that the pain-initiating TRPA1 channel was required for pain-related behaviors in a mouse model of estrogen-induced uterine pain in ovariectomized female mice. Surprisingly, 2- and 4-hydroxylated estrogen metabolites (2- and 4-HEMs) in the estrogen hydroxylation pathway, but not estrone, estradiol, or 16-HEMs, directly increased nociceptor hyperactivity through TRPA1 and TRPV1 channels, and picomolar concentrations of 2- and 4-hydroxylation estrone (2- or 4-OHE1) could sensitize TRPA1 channel function. Moreover, both TRPA1 and TRPV1 were expressed in uterine-innervating primary nociceptors, and their expression was increased in the estrogeninduced uterine pain model. Importantly, pretreatment with 2- or 4-OHE1 recapitulated estrogeninduced uterine pain-like behaviors, and intraplantar injections of 2- and 4-OHE1 directly produced a TRPA1-dependent mechanical hypersensitivity. Our findings demonstrated that TRPA1 is critically involved in estrogen-induced uterine pain-like behaviors, which may provide a potential drug target for treating female reproductive tract pain. © 2022, Xie et al.

Funding details
National Institutes of HealthNIHR01AA027065, R01AR077183, R01DK103901
Department of Anesthesiology, Medical College of Wisconsin

Document Type: Article
Publication Stage: Final
Source: Scopus

Surprise and recency in novelty detection in the primate brain
(2022) Current Biology, 32 (10), pp. 2160-2173.e6. 

Zhang, K.^a , Bromberg-Martin, E.S.^b , Sogukpinar, F.^c , Kocher, K.^b , Monosov, I.E.^{a b c d e}

^a Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
^b Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Electrical Engineering, Washington University, St. Louis, MO 63130, United States
^d Department of Neurosurgery School of Medicine, Washington University, St. Louis, MO 63110, United States
^e Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Primates and other animals must detect novel objects. However, the neuronal mechanisms of novelty detection remain unclear. Prominent theories propose that visual object novelty is either derived from the computation of recency (how long ago a stimulus was experienced) or is a form of sensory surprise (stimulus unpredictability). Here, we use high-channel electrophysiology in primates to show that in many primate prefrontal, temporal, and subcortical brain areas, object novelty detection is intertwined with the computations of recency and sensory surprise. Also, distinct circuits could be engaged by expected versus unexpected sensory surprise. Finally, we studied neuronal novelty-to-familiarity transformations during learning across many days. We found a diversity of timescales in neurons’ learning rates and between-session forgetting rates, both within and across brain areas, that are well suited to support flexible behavior and learning in response to novelty. Our findings show that novelty sensitivity arises on multiple timescales across single neurons due to diverse but related computations of sensory surprise and recency and shed light on the computational underpinnings of novelty detection in the primate brain. © 2022 The Author(s)

Author Keywords
electrophysiology;  learning;  memory;  novelty;  recency;  surprise;  timescales

Funding details
HR0011-16-2-0022
National Institute of Mental HealthNIMHR01MH110594, R01MH116937
Army Research OfficeARO78259-NS-MUR
Defense Advanced Research Projects AgencyDARPA
McKnight Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Loss of H3K27 Trimethylation Promotes Radiotherapy Resistance in Medulloblastoma and Induces an Actionable Vulnerability to BET Inhibition
(2022) Cancer Research, 82 (10), pp. 2019-2030. 

Gabriel, N.^a , Balaji, K.^a , Jayachandran, K.^a , Inkman, M.^a , Zhang, J.^a , Dahiya, S.^b , Goldstein, M.^a c

^a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
Medulloblastoma has been categorized into four subgroups based on genetic, epigenetic, and transcriptional profiling. Radiation is used for treating medulloblastoma regardless of the subgroup. A better understanding of the molecular pathways determining radiotherapy response could help improve medulloblastoma treatment. Here, we investigated the role of the EZH2 (enhancer of zeste 2 polycomb repressive complex 2 subunit)-dependent histone H3K27 trimethylation in radiotherapy response in medulloblastoma. The tumors in 47.2% of patients with group 3 and 4 medulloblastoma displayed H3K27me3 deficiency. Loss of H3K27me3 was associated with a radioresistant phenotype, high relapse rates, and poor overall survival. In H3K27me3-deficient medulloblastoma cells, an epigenetic switch from H3K27me3 to H3K27ac occurred at specific genomic loci, altering the transcriptional profile. The resulting upregulation of EPHA2 stimulated excessive activation of the prosurvival AKT signaling pathway, leading to radiotherapy resistance. Bromodomain and extraterminal motif (BET) inhibition overcame radiation resistance in H3K27me3-deficient medulloblastoma cells by suppressing H3K27ac levels, blunting EPHA2 overexpression, and mitigating excessive AKT signaling. In addition, BET inhibition sensitized medulloblastoma cells to radiation by enhancing the apoptotic response through suppression of Bcl-xL and upregulation of Bim. This work demonstrates a novel mechanism of radiation resistance in medulloblastoma and identifies an epigenetic marker predictive of radiotherapy response. On the basis of these findings, we propose an epigenetically guided treatment approach targeting radiotherapy resistance in patients with medulloblastoma. Significance: This study demonstrates a novel epigenetic mechanism of radiation resistance in medulloblastoma and identifies a therapeutic approach to improve outcomes in these patients. ©2022 American Association for Cancer Research

Funding details
National Institutes of HealthNIH1K08CA256170-01A1
Andrew McDonough B+ FoundationAMBF

Document Type: Article
Publication Stage: Final
Source: Scopus

Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors
(2022) Journal of Pediatric Gastroenterology and Nutrition, 74 (5), pp. 636-642. 

Tham, S.W.^a , Wang, F.^b , Gariepy, C.E.^c , Cress, G.A.^d , Abu-El-Haija, M.A.^e , Bellin, M.D.^f , Ellery, K.M.^g , Fishman, D.S.^h , Gonska, T.ⁱ , Heyman, M.B.^j , Lin, T.K.^e , Maqbool, A.^k , McFerron, B.A.^l , Morinville, V.D.^m , Nathan, J.D.^c , Ooi, C.Y.ⁿ , Perito, E.R.^j , Schwarzenberg, S.J.^f , Sellers, Z.M.^o , Shah, U.^p , Troendle, D.M.^q , Wilschanski, M.^r , Zheng, Y.^s , Yuan, Y.^b , Lowe, M.E.^t , Uc, A.^d , Palermo, T.M.^a , INternational Study Group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) and Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC)^u

^a Department of Anesthesiology & Pain Medicine, University of Washington School of Medicine, Seattle, WA
^b University of Texas, MD Anderson Cancer Center, TX, Houston
^c Nationwide Children’s Hospital, Columbus, OH
^d University of Iowa, Stead Family Children’s Hospital, IA, Iowa City, United States
^e Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, Cincinnati, OH
^f University of Minnesota Masonic Children’s Hospital, MN, Minneapolis, United States
^g UPMC Children’s Hospital of Pittsburgh, PA, Pittsburgh, United States
^h Division of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine and Texas Children’s Hospital, TX, Houston
ⁱ Hospital for Sick Children, ON, Toronto, Canada
^j University of California San Francisco, San Francisco, CA
^k Children’s Hospital of Philadelphia, PA, Philadelphia, United States
^l Riley Hospital for Children, Indiana University School of Medicine, IN, Indianapolis, United States
^m Montreal Children’s Hospital, McGill University, QC, Montreal, France
ⁿ School of Women’s and Children’s Health, Faculty of Medicine, Sydney Children’s Hospital Randwick, NSW, University of New South Wales and Department of Gastroenterology, Sydney, Australia
^o Stanford University, Stanford Children’s Health, Palo Alto, CA
^p Massachusetts General Hospital for Children, Harvard Medical School, MA, Boston
^q University of Texas Southwestern Medical School, TX, Dallas, United States
^r Hadassah Hebrew University HospitalJerusalem, Israel
^s Children’s Hospital Los Angeles, Los Angeles, CA
^t Washington University School of Medicine, St. Louis, MO

Abstract
OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% girls, mean age = 12.7years, standard deviation [SD] = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B = -10.28, P  < 0.001), episodic and constant abdominal pain (B = 04.66, P = 0.03; B = -13.25, P < 0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271] = 8.34, P < 0.001). Borderline and clinical levels of emotional and behavioral problems (B = -10.18, P < 0.001; B = -15.98, P < 0.001), and constant pain (B = -4.46, P < 0.001) were associated with low psychosocial HRQOL (F [9, 271] = 17.18, P < 0.001). CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children. Copyright © 2022 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Document Type: Article
Publication Stage: Final
Source: Scopus

Disrupted and Disconnected: Child Activities, Social Skills, and Race/Ethnicity During the Pandemic
(2022) Frontiers in Education, 7, art. no. 869183, . 

Hernández, R., Jabbari, J.

Social Policy Institute, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Early in the COVID-19 pandemic, parents reported that their children spent the majority of their time at home, which can dramatically change their activities and negatively impact their social skills. However, research has yet to uncover the relationships between changes in activities during the pandemic and children’s social skills, nor the degree to which these relationships might differ across race and ethnicity. To fill this gap in knowledge, we leverage a nationally representative survey with 948 parents conducted in May 2021 and use Likert scaled questions to explore the relationships between increases or decreases across a range of child activities (e.g., outdoor activities, schoolwork activities, friend activities, extracurricular activities, and screen activities) and better or worse child social skills during COVID-19. By exploring the relationship between changes in children’s activities and changes in children’s social skills during the first 15 months of the pandemic, we provide new evidence for the long-term effects of COVID-19’s disruptions on children’s social development, while highlighting opportunities to improve children’s social skills through targeted activities. First, we used a multivariate linear regression strategy to capture associations between changes in child activities and changes in child social skills, while accounting for a robust set of student, school, and parent covariates. Then, we used interaction terms to examine the moderating role of race and ethnicity on the associations between changes in child activities and changes in child social skills. We found that an increase in outdoor activities, schoolwork activities, friend activities, and extracurricular activities were significantly associated with an increase in social skills. We also found evidence that for Hispanic households an increase in schoolwork activities was especially important for the development of social skills, and that for Black and Hispanic households, an increase in screen time was associated with an increase in social skills. Copyright © 2022 Hernández and Jabbari.

Author Keywords
child activities;  COVID-19;  education;  race/ethnicity;  social skills

Funding details
Annie E. Casey FoundationAECF

Document Type: Article
Publication Stage: Final
Source: Scopus

Cardiorespiratory Fitness Is Associated with Better White Matter Integrity in Persons Living with HIV
(2022) Journal of Acquired Immune Deficiency Syndromes, 89 (5), pp. 558-565. 

Kilgore, C.B.^a , Strain, J.F.^a , Nelson, B.^a , Cooley, S.A.^a , Rosenow, A.^a , Glans, M.^a , Cade, W.T.^b , Reeds, D.N.^c , Paul, R.H.^d , Ances, B.M.^a e f

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Doctor of Physical Therapy Division, Duke University, Durham, NC, United States
^c Department of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychology, University of Missouri – St. Louis, St. Louis, MO, United States
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
^f Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background:Despite improved survival rates, neurocognitive impairment persists in persons living with HIV (PLWH). An active lifestyle is linked to improved cognition among PLWH, yet the neural substrates remain unclear. Diffusion tensor imaging and diffusion basis spectrum imaging measure HIV-related changes in brain white matter integrity. We used these measures of structural brain integrity to assess white matter changes, physical fitness, and cognition in a cross-sectional study of PLWH.Methods:Forty-four virologically well-controlled PLWH were recruited (average age of 56 years, a median recent CD4+count of 682 cells/mm3). Diffusion tensor imaging -derived fractional anisotropy (FA) and diffusion basis spectrum imaging-derived axonal density were calculated. Cardiorespiratory fitness [maximal volume of oxygen consumption (VO2max)] was measured by performing indirect calorimetry during exercise to volitional exhaustion. Cardiovascular risk was assessed by the Framingham risk score. Neuropsychological performance (NP) testing evaluated learning, memory, psychomotor/processing speed, and executive function. Partial correlations assessed the relationships among cardiorespiratory fitness, neuroimaging, NP, and HIV clinical metrics (CD4+count and time since diagnosis).Results:Higher VO2max was associated with higher FA and higher axonal density in multiple white matter tracts, including the corticospinal tract and superior longitudinal fasciculus. Better NP in the motor/psychomotor domain was positively associated with FA and axonal density in diverse tracts including those associated with motor and visuospatial processing. However, higher VO2max was not associated with NP or HIV clinical metrics.Conclusions:An active lifestyle promoting cardiorespiratory fitness may lead to better white matter integrity and decreased susceptibility to cognitive decline in virologically well-controlled PLWH. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
cognition;  exercise;  HIV;  neuroimaging;  VO2max

Funding details
National Institute of Mental HealthNIMHR01MH118031
National Institute of Nursing ResearchNINRR01NR015738
National Center for Advancing Translational SciencesNCATS
Institute of Clinical and Translational SciencesICTSUL1TR000448

Document Type: Article
Publication Stage: Final
Source: Scopus

Covariance and Correlation Analysis of Resting State Functional Magnetic Resonance Imaging Data Acquired in a Clinical Trial of Mindfulness-Based Stress Reduction and Exercise in Older Individuals
(2022) Frontiers in Neuroscience, 16, art. no. 825547, . 

Snyder, A.Z.^a b , Nishino, T.^c , Shimony, J.S.^a , Lenze, E.J.^c , Wetherell, J.L.^d e , Voegtle, M.^c , Miller, J.P.^f , Yingling, M.D.^f , Marcus, D.^a , Gurney, J.^a , Rutlin, J.^c , Scott, D.^g , Eyler, L.^e , Barch, D.^a b h , the MEDEX Research Groupⁱ

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d VA San Diego Healthcare System, San Diego, CA, United States
^e Department of Psychiatry, University of California, San Diego, CA, United States
^f Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^g Master of Social Welfare Program, University of California, Berkeley, , CA, United States
^h Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
We describe and apply novel methodology for whole-brain analysis of resting state fMRI functional connectivity data, combining conventional multi-channel Pearson correlation with covariance analysis. Unlike correlation, covariance analysis preserves signal amplitude information, which feature of fMRI time series may carry physiological significance. Additionally, we demonstrate that dimensionality reduction of the fMRI data offers several computational advantages including projection onto a space of manageable dimension, enabling linear operations on functional connectivity measures and exclusion of variance unrelated to resting state network structure. We show that group-averaged, dimensionality reduced, covariance and correlation matrices are related, to reasonable approximation, by a single scalar factor. We apply this methodology to the analysis of a large, resting state fMRI data set acquired in a prospective, controlled study of mindfulness training and exercise in older, sedentary participants at risk for developing cognitive decline. Results show marginally significant effects of both mindfulness training and exercise in both covariance and correlation measures of functional connectivity. Copyright © 2022 Snyder, Nishino, Shimony, Lenze, Wetherell, Voegtle, Miller, Yingling, Marcus, Gurney, Rutlin, Scott, Eyler and Barch.

Author Keywords
correlation;  covariance;  exercise;  functional connectivity;  mindfulness;  resting state—fMRI

Funding details
National Institutes of HealthNIHP50 HD103525, R01AG049689
National Institute on AgingNIA
Office of Behavioral and Social Sciences ResearchOBSSR1P30NS098577, R01 AG072694-01A1, R01 MH090786, U19 AG032438, UL1TR002345
National Center for Advancing Translational SciencesNCATS
University of WashingtonUW
National Center for Complementary and Integrative HealthNCCIH

Document Type: Article
Publication Stage: Final
Source: Scopus

Speech and non-speech measures of audiovisual integration are not correlated
(2022) Attention, Perception, and Psychophysics, . 

Wilbiks, J.M.P.^a , Brown, V.A.^b , Strand, J.F.^c

^a Department of Psychology, University of New Brunswick, Saint John, NB, Canada
^b Department of Psychological & Brain Sciences, Washington University in St. Louis, Saint Louis, MO, United States
^c Department of Psychology, Carleton College, Northfield, MN, United States

Abstract
Many natural events generate both visual and auditory signals, and humans are remarkably adept at integrating information from those sources. However, individuals appear to differ markedly in their ability or propensity to combine what they hear with what they see. Individual differences in audiovisual integration have been established using a range of materials, including speech stimuli (seeing and hearing a talker) and simpler audiovisual stimuli (seeing flashes of light combined with tones). Although there are multiple tasks in the literature that are referred to as “measures of audiovisual integration,” the tasks themselves differ widely with respect to both the type of stimuli used (speech versus non-speech) and the nature of the tasks themselves (e.g., some tasks use conflicting auditory and visual stimuli whereas others use congruent stimuli). It is not clear whether these varied tasks are actually measuring the same underlying construct: audiovisual integration. This study tested the relationships among four commonly-used measures of audiovisual integration, two of which use speech stimuli (susceptibility to the McGurk effect and a measure of audiovisual benefit), and two of which use non-speech stimuli (the sound-induced flash illusion and audiovisual integration capacity). We replicated previous work showing large individual differences in each measure but found no significant correlations among any of the measures. These results suggest that tasks that are commonly referred to as measures of audiovisual integration may be tapping into different parts of the same process or different constructs entirely. © 2022, The Psychonomic Society, Inc.

Author Keywords
Audiovisual integration;  Convergent validity;  Individual differences

Funding details
PP-146-2018-1, RYC-2019-027216I
ES1304, SVP-2014-068732
Ministerio de Ciencia e InnovaciónMICINN

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

Memory and the value of social information in foraging bumble bees
(2022) Learning and Behavior, . 

Abts, B.J.^a b , Dunlap, A.S.^a

^a Department of Biology, University of Missouri, R223 Research Building, Saint Louis, MO 63121, United States
^b Department of Biology, Washington University, Saint Louis, MO, United States

Abstract
Not all information should be learned and remembered. The value of information is tied to the reliability and certainty of that information, which itself is determined by rates of environmental change, both within and across lifetimes. Theory of adaptive forgetting and remembering posits that memory should reflect the environment, with more valuable information remembered for longer amounts of time. Theory on biological preparedness predicts that rates of reliability through evolutionary time should influence what is learned and remembered. We use these ideas to predict that differential memory use will reflect the underlying value of the information being learned. We test this by comparing the learning and memory of social information versus floral information in foraging bumble bees. Bumble bees are extremely flexible in their use of both types of information and evidence suggests that social information is “special,” reflecting biological preparedness. Our experiment tests how bumble bees learn and remember social and floral information when their reliabilities, and thus value, differ. We find that bees learn both types of information at a similar speed. Bees show a decrement of memory of the trained associations in both treatments, but retain trained socially reliable information for longer, at both 4-hour and 8-hour retention intervals. Both training treatments influence whether bees match or avoid the locations of demonstrators, and this interacts with retention interval. Bees trained under reliable floral cues and unreliable social cues avoid conspecifics after 8-hr and 24-hr retention intervals. Bees thus learn about the reliability or unreliability of social cues and use this to modify their choices across time. © 2022, The Psychonomic Society, Inc.

Author Keywords
Bombus;  Foraging;  Memory;  Optimal memory;  Social information;  Social learning

Funding details
University of MissouriMU
Whitney R. Harris World Ecology CenterHWEC

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

Retaining Participants in Longitudinal Studies of Alzheimer’s Disease
(2022) Journal of Alzheimer’s Disease, 87 (2), pp. 945-955. 

Gabel, M.^a b , Bollinger, R.M.^c , Coble, D.W.^c , Grill, J.D.^d , Edwards, D.F.^e f , Lingler, J.H.^g h , Chin, E.^e , Stark, S.L.^b c

^a Department of Political Science, Washington University in St. Louis, St. Louis, MO, United States
^b Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^c School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Institute for Memory Impairments and Neurological Disorders, Departments of Psychiatry Human Behavior and Neurobiology Behavior, University of California Irvine, Irvine, CA, United States
^e School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^f Wisconsin Alzheimer’s Disease Research Center, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^g School of Nursing, University of Pittsburgh, Pittsburgh, PA, United States
^h Alzheimer’s Disease Research Center, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Background: Retention of study participants is essential to advancing Alzheimer’s disease (AD) research and developing therapeutic interventions. However, recent multi-year AD studies have lost 10% to 54% of participants. Objective: We surveyed a random sample of 443 participants (Clinical Dementia Rating [CDR]≤1) at four Alzheimer Disease Research Centers to elucidate perceived facilitators and barriers to continued participation in longitudinal AD research. Methods: Reasons for participation were characterized with factor analysis. Effects of perceived fulfillment of one’s own goals and complaints on attendance and likelihood of dropout were estimated with logistic regression models. Open-ended responses suggesting study improvements were analyzed with a Latent Dirichlet Allocation topic model. Results: Factor analyses revealed two categories, personal benefit and altruism, as drivers of continued participation. Participants with cognitive impairment (CDR > 0) emphasized personal benefits more than societal benefits. Participants with higher trust in medical researchers were more likely to emphasize broader social benefits. A minority endorsed any complaints. Higher perceived fulfillment of one’s own goals and fewer complaints were related to higher attendance and lower likelihood of dropout. Facilitators included access to medical center support and/or future treatment, learning about AD and memory concerns, and enjoying time with staff. Participants’ suggestions emphasized more feedback about individual test results and AD research. Conclusion: The results confirmed previously identified facilitators and barriers. Two new areas, improved communication about individual test results and greater feedback about AD research, emerged as the primary factors to improve participation. © 2022 – IOS Press. All rights reserved.

Author Keywords
Alzheimer’s disease;  barriers;  facilitators;  retention

Funding details
National Institutes of HealthNIHU01 AG016976
National Institute on AgingNIA
University of Wisconsin-MadisonUW
Washington University in St. LouisWUSTL
University of Pittsburgh
National Alzheimer’s Coordinating CenterNACC2017-01

Document Type: Article
Publication Stage: Final
Source: Scopus

Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia
(2022) Annals of Neurology, . 

Calame, D.G.^a b c , Herman, I.^a b c av , Maroofian, R.^d , Marshall, A.E.^e , Donis, K.C.^f g , Fatih, J.M.^b , Mitani, T.^b , Du, H.^b , Grochowski, C.M.^b , Sousa, S.B.^h i , Gijavanekar, C.^b , Bakhtiari, S.^j k , Ito, Y.A.^e , Rocca, C.^d , Hunter, J.V.^c l , Sutton, V.R.^b c , Emrick, L.T.^a b c , Boycott, K.M.^e , Lossos, A.^m , Fellig, Y.ⁿ , Prus, E.^o , Kalish, Y.^o , Meiner, V.^p , Suerink, M.^q , Ruivenkamp, C.^q , Muirhead, K.^r , Saadi, N.W.^s , Zaki, M.S.^t , Bouman, A.^u , Barakat, T.S.^u , Skidmore, D.L.^v , Osmond, M.^e , Silva, T.O.^g w , Murphy, D.^x , Karimiani, E.G.^y , Jamshidi, Y.^y , Jaddoa, A.G.^z , Tajsharghi, H.^aa , Jin, S.C.^ab , Abbaszadegan, M.R.^ac ad , Ebrahimzadeh-Vesal, R.^ad , Hosseini, S.^ad , Alavi, S.^ae , Bahreini, A.^af , Zarean, E.^ag , Salehi, M.M.^ah , Al-Sannaa, N.A.^ai , Zifarelli, G.^aj , Bauer, P.^aj , Robson, S.C.^ak , Coban-Akdemir, Z.^b al , Travaglini, L.^am an , Nicita, F.^am an , Jhangiani, S.N.^ao , Gibbs, R.A.^ao , Posey, J.E.^b , Kruer, M.C.^j k , Kernohan, K.D.^e ap , Morales Saute, J.A.^g aq ar , Houlden, H.^d , Vanderver, A.^r as , Elsea, S.H.^b , Pehlivan, D.^a b c , Marafi, D.^b at , Lupski, J.R.^b c ao au

^a Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
^b Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
^c Texas Children’s Hospital, Houston, TX, United States
^d Department of Neuromuscular Disorders, Queen Square Institute of Neurology, University College London, London, United Kingdom
^e Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada
^f Graduate Program in Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
^g Medical Genetics Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil
^h University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal
ⁱ Medical Genetics Unit, Hospital Pediatrico, Centro Hospitalar e Universitario de Coimbra, Coimbra, Portugal
^j Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United States
^k Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine–Phoenix, Phoenix, AZ, United States
^l Division of Neuroradiology, Edward B. Singleton Department of Radiology, Texas Children’s Hospital, Houston, TX, United States
^m Department of Neurology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel
ⁿ Department of Pathology, Hadassah Medical Organization and Faculty of Medicine, Hebrew University, Jerusalem, Israel
^o Hematology and Bone Marrow Transplantation Division, Hadassah Medical Center and Hebrew University, Jerusalem, Israel
^p Department of Genetics, Hadassah Medical Center and Hebrew University, Jerusalem, Israel
^q Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
^r Division of Neurology, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States
^s College of Medicine/University of Baghdad, Unit of Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq
^t Clinical Genetics Department, Human Genetics and Genome Research Institute, Center of Excellence of Human Genetics, National Research Centre, Dokki, Cairo, Egypt
^u Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
^v Department of Pediatrics, Dalhousie University, Halifax, NS, Canada
^w Postgraduate Program in Medicine: Medical Sciences, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
^x Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
^y Genetics Section, Molecular and Clinical Sciences Institute, St George’s University of London, London, United Kingdom
^z Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq
^aa School of Health Sciences, Division Biomedicine, University of Skövde, Skövde, Sweden
^ab Department of Genetics, Washington University School of Medicine, St Louis, MO, United States
^ac Medical Genetics Research Center, Medical School, Mashhad University of Medical Sciences, Mashhad, Iran
^ad Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran
^ae Department of Cell and Molecular Biology & Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
^af Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
^ag Department of Perinatology, Isfahan University of Medical Sciences, Isfahan, Iran
^ah Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
^ai Pediatric Services, John Hopkins Aramco Health Care, Dhahran, Saudi Arabia
^aj Centogene GmbH, Rostock, Germany
^ak Center for Inflammation Research, Transplantation, Departments of Medicine and Anesthesia, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
^al Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, United States
^am Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital, Scientific Institute for Research and Health Care, Rome, Italy
^an Laboratory of Molecular Medicine, Department of Neuroscience, Bambino Gesù Children’s Hospital, Scientific Institute for Research and Health Care, Rome, Italy
^ao Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
^ap Newborn Screening Ontario, Ottawa, ON, Canada
^aq Department of Internal Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
^ar Neurology Service, Porto Alegre Clinical Hospital, Porto Alegre, Brazil
^as Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^at Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
^au Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
^av Current address for Dr Herman: Boys Town Hospital Rd, Omaha, NE 69116, United States

Abstract
Objective: Human genomics established that pathogenic variation in diverse genes can underlie a single disorder. For example, hereditary spastic paraplegia is associated with >80 genes, with frequently only few affected individuals described for each gene. Herein, we characterize a large cohort of individuals with biallelic variation in ENTPD1, a gene previously linked to spastic paraplegia 64 (Mendelian Inheritance in Man # 615683). Methods: Individuals with biallelic ENTPD1 variants were recruited worldwide. Deep phenotyping and molecular characterization were performed. Results: A total of 27 individuals from 17 unrelated families were studied; additional phenotypic information was collected from published cases. Twelve novel pathogenic ENTPD1 variants are described (NM 001776.6): c.398_399delinsAA; p.(Gly133Glu), c.540del; p.(Thr181Leufs*18), c.640del; p.(Gly216Glufs*75), c.185 T > G; p.(Leu62*), c.1531 T > C; p.(*511Glnext*100), c.967C > T; p.(Gln323*), c.414-2_414-1del, and c.146 A > G; p.(Tyr49Cys) including 4 recurrent variants c.1109 T > A; p.(Leu370*), c.574-6_574-3del, c.770_771del; p.(Gly257Glufs*18), and c.1041del; p.(Ile348Phefs*19). Shared disease traits include childhood onset, progressive spastic paraplegia, intellectual disability (ID), dysarthria, and white matter abnormalities. In vitro assays demonstrate that ENTPD1 expression and function are impaired and that c.574-6_574-3del causes exon skipping. Global metabolomics demonstrate ENTPD1 deficiency leads to impaired nucleotide, lipid, and energy metabolism. Interpretation: The ENTPD1 locus trait consists of childhood disease onset, ID, progressive spastic paraparesis, dysarthria, dysmorphisms, and white matter abnormalities, with some individuals showing neurocognitive regression. Investigation of an allelic series of ENTPD1 (1) expands previously described features of ENTPD1-related neurological disease, (2) highlights the importance of genotype-driven deep phenotyping, (3) documents the need for global collaborative efforts to characterize rare autosomal recessive disease traits, and (4) provides insights into disease trait neurobiology. ANN NEUROL 2022. © 2022 American Neurological Association.

Funding details
U54HG003273
R01 DK108894, R21 CA164970, R21 CA221702
91617021
National Institutes of HealthNIHT32 GM007526‐42
U.S. Department of DefenseDODW81XWH‐16‐0464
National Heart, Lung, and Blood InstituteNHLBIUM1 HG006542
National Human Genome Research InstituteNHGRI
National Institute of Neurological Disorders and StrokeNINDSR01NS106298, R35NS105078
Brain and Behavior Research FoundationBBRF
International Rett Syndrome FoundationIRSF3701‐1, 873841, K08 HG008986, MFE‐176616, T32 NS043124‐19
Muscular Dystrophy AssociationMDA512848
American Brain FoundationABF
Uehara Memorial Foundation
Genome CanadaGC
National Alliance for Research on Schizophrenia and DepressionNARSAD
Ontario Research FoundationORF
Cerebral Palsy Alliance Research FoundationCPARF
Children’s Hospital of Eastern Ontario Foundation
Spastic Paraplegia FoundationSPF
Canadian Institutes of Health ResearchIRSC
Ontario Genomics InstituteOGIOGI‐147
Genome British Columbia
Ministry of Health -SingaporeMOH5914
Erasmus Medisch CentrumErasmus MC
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
Conselho Nacional de Desenvolvimento Científico e TecnológicoCNPq
Seventh Framework ProgrammeFP7608473
Ministry of Health, State of Israel
Genome Alberta

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

Fluid and Crystallized Cognitive Resources Differentially Linked to Emotion Regulation Success in Adulthood
(2022) Emotion, . 

Growney, C.M., English, T.

Department of Psychological and Brain Sciences, Washington University in St. Louis, United States

Abstract
Effective emotion regulation (ER) is theorized to require cognitive resources. Past work has identified inconsistent relationships between cognitive ability and ER success and has focused on implementation of instructed ER strategies. In the present study, we examine a wide range of cognitive abilities as predictors of ER success in the absence of constraints on strategy selection. An age-diverse sample of participants (N = 129, age 25–83) completed an ER task in which they viewed film clips eliciting disgust, sadness, and amusement under instructions to regulate in a prohedonic fashion. ER success was measured through self-reports of positive emotion (PA) and negative emotion (NA) following each clip. Fluid and crystallized cognitive ability were assessed with tasks from the NIH Toolbox Cognitive Battery. Effects of fluid cognition varied by film type, such that fluid cognition was generally less associated with ER success for the disgust clip. Effects of fluid cognition also varied by facet (e.g., processing speed and inhibitory control related to lower NA with the sadness clip, while working memory and episodic memory related to higher PA with the amusement and disgust clips). Crystallized cognition was positively associated with ER success (lower NA) across film types. Findings suggest that both fluid and crystallized cognition are important resources for effective emotion regulation. We propose that crystallized cognition may be particularly important when regulators can rely on life experience to select ER strategies. © 2022 American Psychological Association

Author Keywords
Adult lifespan;  Crystallized cognition;  Emotion regulation;  Fluid cognition;  Well-being

Funding details
National Institute on AgingNIA

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

A Multimodal Analysis of Sustained Attention in Younger and Older Adults
(2022) Psychology and Aging, . 

Robison, M.K.^a , Diede, N.T.^b , Nicosia, J.^c , Ball, B.H.^a , Bugg, J.M.^b

^a Department of Psychology, University of Texas, Arlington, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^c Department of Neurology, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, United States

Abstract
Age-related cognitive decline has been attributed to processing speed differences, as well as differences in executive control and response inhibition. However, recent research has shown that healthy older adults have intact, if not superior, sustained attention abilities compared to younger adults. The present study used a combination of reaction time (RT), thought probes, and pupillometry to measure sustained attention in samples of younger and older adults. The RT data revealed that, while slightly slower overall, older adults sustained their attention to the task better than younger adults, and did not show a vigilance decrement. Older adults also reported fewer instances of task-unrelated thoughts and reported feeling more motivated and alert than younger adults, despite finding the task more demanding. Additionally, older adults showed larger, albeit laterpeaking, task-evoked pupillary responses (TEPRs), corroborating the behavioral and self-report data. Finally, older adults did not show a shallowing of TEPRs across time, corroborating the finding that their RTs also did not change across time. The present findings are interpreted in light of processing speed theory, resourcedepletion theories of vigilance, and recent neurological theories of cognitive aging. © 2022 American Psychological Association

Author Keywords
Aging;  Mind wandering;  Pupillometry;  Sustained attention;  Vigilance

Funding details
National Institute on AgingNIAT32AG000030-40
Washington University in St. LouisWUSTL
McDonnell Center for Systems Neuroscience

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

Lidocaine Nerve Block Diminishes the Effects of Therapeutic Electrical Stimulation to Enhance Nerve Regeneration in Rats
(2022) Hand, . 

Keane, G.C.^a , Marsh, E.B.^a , Hunter, D.A.^a , Schellhardt, L.^a , Walker, E.R.^b , Wood, M.D.^a

^a Washington University School of Medicine in St. LouisMO, United States
^b Checkpoint Surgical, Inc, Cleveland, OH, United States

Abstract
Background: Although electrical stimulation (ES) can improve nerve regeneration, the impact of nerve block, such as lidocaine (Lido), on the therapeutic benefits of ES remains unclear. We used a rat tibial nerve transection-and-repair model to explore how either preoperative (PreOp) or postoperative (PostOp) nerve block affects ES-related improvement in regeneration. Methods: Lewis rats were used in 1 of 2 studies. The first evaluated the effects of extraneural Lido on both healthy and injured nerves. In the second study, rats were randomized to 5 experimental groups: No ES (negative control), PreOp Lido, ES + PreOp Lido, PostOp + ES, and ES (positive control). All groups underwent tibial nerve transection and repair. In both studies, nerves were harvested for histological analysis of regeneration distal to the injury site. Results: Application of extraneural Lido did not damage healthy or injured nerve based on qualitative histological observations. In the context of nerve transection and repair, the ES group exhibited improved axon regeneration at 21 days measured by the total number of myelinated fibers compared with No ES. Fiber density and percentage of neural tissue in the ES group were greater than those in both No ES and PreOp Lido + ES groups. ES + PostOp Lido was not different from No ES or ES group. Conclusions: Extraneural application of Lido did not damage nerves. Electrical stimulation augmented nerve regeneration, but Lido diminished the ES-related improvement in nerve regeneration. Clinical studies on the effects of ES to nerve regeneration may need to consider nerve block as a variable affecting ES outcome. © The Author(s) 2022.

Author Keywords
diagnosis;  electrical stimulation;  lidocaine;  nerve;  nerve regeneration;  peripheral nerve;  rat

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

The Physical Home Environment and Sleep: What Matters Most for Sleep in Early Childhood
(2022) Journal of Family Psychology, . 

Hoyniak, C.P.^a , Bates, J.E.^b , Camacho, M.C.^a , McQuillan, M.E.^c , Whalen, D.J.^a , Staples, A.D.^d , Rudasill, K.M.^e , Deater-Deckard, K.^f

^a Department of Psychiatry, Washington University in St. Louis School of Medicine, United States
^b Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States
^c Department of Pediatrics, Indiana University School of Medicine, United States
^d Psychology Department, Eastern Michigan University, United States
^e School of Education, Virginia Commonwealth University, United States
^f Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, United States

Abstract
The physical home environment is thought to play a crucial role in facilitating healthy sleep in young children. However, relatively little is known about how various features of the physical home environment are associated with sleep in early childhood, and some of the recommendations clinicians make for improving child sleep environments are based on limited research evidence. The present study examined how observer and parent descriptions of the child’s physical home environment were associated with child sleep, measured using actigraphy and parent’s reports, across a year in early childhood. The study used a machine learning approach (elastic net regression) to specify which aspects of the physical home environment were most important for predicting five aspects of child sleep, sleep duration, sleep variability, sleep timing, sleep activity, and latency to fall asleep. The study included 546 toddlers (265 females) recruited at 30 months of age and reassessed at 36 and 42 months of age. Poorer quality physical home environments were associated with later sleep schedules, more variable sleep schedules, shorter sleep durations, and more parent-reported sleep problems in young children. The most important environmental predictors of sleep were room sharing with an adult, bed sharing, and quality of both the child’s sleep space and the wider home environment. © 2022 American Psychological Association

Author Keywords
Early childhood;  Home environment;  Machine learning;  Physical environment;  Sleep

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

The Quest for Objectivity and Measurements in Phrenology’s “Bumpy” History
(2022) History of Psychology, . 

Finger, S.^a , Eling, P.^b

^a Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
^b Department of Psychology, Radboud University, Donders Institute for Brain, Cognition and Behaviour, Netherlands

Abstract
Phrenology is based on correlating character traits with visible or palpable cranial bumps (or depressions) thought to reflect underlying brain areas differing in size and levels of activity. Franz Joseph Gall, who introduced the doctrine during the 1790s, relied heavily on seeing and feeling skulls when he formulated his theory, as did Johann Spurzheim, who served as his assistant until 1813 and then set forth on his own. But Peter Mark Roget, a British critic of the doctrine, first assailed these methods as too subjective in 1818, and never changed his mind. George Combe, a Scotsman who admired Spurzheim, introduced calipers and other measuring instruments during the 1820s, hoping to make phrenology more like the admired physical sciences. In the United States, the Fowlers also called for more numbers, including measuring distances between the cortical sites above the organs of mind. Nonetheless, phrenologists realized they faced formidable barriers when it came to measuring the physical organs of mind, as opposed to basic skull dimensions. This essay examines the subjectivity that left phrenology open to criticism and shows how some phrenologists tried to overcome it. It also shows how vision and touch remained features of phrenological examinations throughout the numbers-obsessed 19th century. © 2022 American Psychological Association

Author Keywords
Craniometry;  Franz joseph gall;  Phrenological examination;  Phrenology;  Pseudoscience

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

Smartphone assessment uncovers real-time relationships between depressed mood and daily functional behaviors after stroke
(2022) Journal of Telemedicine and Telecare, . 

Bui, Q.^a , Kaufman, K.J.^b , Munsell, E.G.S.^b c , Lenze, E.J.^d , Lee, J.-M.^e , Mohr, D.C.^f , Fong, M.W.M.^e g h , Metts, C.L.ⁱ , Tomazin, S.E.^b , Pham, V.^d , Wong, A.W.K.^b j

^a Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
^b Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL, United States
^c Center for Education in Health Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^d Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Center for Behavioral Intervention Technologies and Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^g Psychology and Patient Family Counseling, Shirley Ryan AbilityLab, Chicago, IL, United States
^h Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
ⁱ Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
^j Department of Physical Medicine and Rehabilitation and Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States

Abstract
Introduction: The impact of depressed mood in daily life is difficult to investigate using traditional retrospective assessments, given daily or even within-day mood fluctuations in various contexts. This study aimed to use a smartphone-based ambulatory assessment to examine real-time relationships between depressed mood and functional behaviors among individuals with stroke. Methods: A total of 202 participants with mild-to-moderate stroke (90% ischemic, 45% female, 44% Black) completed an ecological momentary assessment five times per day for 2 weeks by reporting their depressed mood and functional behaviors regarding where, with whom, and what activity was spent. Results: Participants spent 28% of their wake-up time participating in passive leisure activities but spent the least time in physical (4%) and vocational (9%) activities. Depressed mood was concurrently lower when participants engaged in social activities (β = −0.023 ± 0.011) and instrumental activities of daily living (β = −0.061 ± 0.013); spent time with family members (β = −0.061 ± 0.014), spouses (β = −0.043, ± 0.016), friends (β = −0.094, ± 0.021), and coworkers (β = −0.050 ± 0.021); and were located in restaurants (β = −0.068 ± 0.029), and homes of family members (β = −0.039 ± 0.020) or friends (β = −0.069 ± 0.031). Greater depressed mood was associated with worse ratings in satisfaction, performance, and engagement of activities in concurrent (βs = −0.036 ± 0.003, −0.053 ± 0.003, −0.044 ± 0.003) and time-lagged models (βs = −0.011 ± 0.004, −0.012 ± 0.004, −0.013 ± 0.004). Discussion: Smartphone-based ambulatory assessment can elucidate functional behaviors and associated mood after stroke. Findings support behavioral activation treatments to schedule social and instrumental activities for stroke survivors to reduce their depressed mood. © The Author(s) 2022.

Author Keywords
ambulatory assessment;  daily functional behaviors;  depression;  ecological momentary assessment;  mobile health;  smartphone;  stroke;  Telemedicine

Funding details
National Institutes of HealthNIH
American Occupational Therapy FoundationAOTF
Craig H. Neilsen FoundationCHNF
Biogen
National Center for Medical Rehabilitation ResearchNCMRRAOTFIRG20Wong, K01HD095388, P2CHD101899

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

Preschool Depression and Hippocampal Volume: The Moderating Role of Family Income
(2022) Journal of the American Academy of Child and Adolescent Psychiatry, . 

Herzberg, M.P., Tillman, R., Kandala, S., Barch, D.M., Luby, J.

Washington University in St. Louis, St. Louis, Missouri

Abstract
Objective: Depression and low socioeconomic status have both been associated with hippocampal volume alterations. Whether these factors interact to predict neurobehavioral outcomes has not been adequately studied. The authors investigated family income as a moderator of the relationship between depression and hippocampal volume in a longitudinal sample. Method: Longitudinal behavioral data, beginning at preschool age, and behavioral and neuroimaging data from school age to adolescence were used to assess the impact of preschool only and total preschool to adolescent depression symptoms on hippocampal volumes using family income as a moderator (N = 176). Results: Depression severity during the preschool period interacted with family income to predict hippocampal volumes at the intercept (ie, age 13 years; B = −0.078, p = .003). Interaction decomposition revealed that only individuals with relatively high family income exhibited smaller hippocampal volume with increasing depression severity (B = −0.146, p = .005). Family income was associated with hippocampus volumes only in individuals with low to moderate preschool depression severity (B = 0.289, p = .007 and B = 0.169, p = .030, respectively). Conclusion: Preschool depression severity interacts with family income to predict hippocampal volume across development, such that the effects of early depression are evident only in those with higher income. These findings suggest that hippocampal volume may not be an effective marker of risk for depression at different levels of socioeconomic status, and emphasizes the importance of the environmental context when assessing risk markers for depression. Future research should explore how socioeconomic stress may eclipse the effects of depression on hippocampal development, setting alternative neurodevelopmental risk trajectories. © 2022 American Academy of Child and Adolescent Psychiatry

Author Keywords
hippocampus;  poverty;  preschool depression;  structural MRI

Funding details
National Institute of Mental HealthNIMHMH090876, R01 MH064769, T32 MH100019

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

Neonatal Intensive Care Unit Network Neurobehavioral Scale Profiles in Full-Term Infants: Associations with Maternal Adversity, Medical Risk, and Neonatal Outcomes
(2022) Journal of Pediatrics, . 

Parikh, A.N.^a , Triplett, R.L.^b , Wu, T.J.^a , Arora, J.^c , Lukas, K.^b , Smyser, T.A.^d , Miller, J.P.^c , Luby, J.L.^d , Rogers, C.E.^d e , Barch, D.M.^d f g , Warner, B.B.^e , Smyser, C.D.^b e g

^a School of Medicine, Washington University in St. Louis, MO, St. Louis
^b Department of Neurology, Washington University in St. Louis, MO, St. Louis
^c Division of Biostatistics, Washington University in St. Louis, MO, St. Louis
^d Department of Psychiatry, Washington University in St. Louis, MO, St. Louis
^e Department of Pediatrics, Washington University in St. Louis, MO, St. Louis
^f Department of Psychological and Brain Sciences, Washington University in St. Louis, MO, St. Louis
^g Department of Radiology, Washington University in St. Louis, MO, St. Louis

Abstract
Objectives: To examine healthy, full-term neonatal behavior using the Neonatal Intensive Care Unit Network Neurobehavioral Scale (NNNS) in relation to measures of maternal adversity, maternal medical risk, and infant brain volumes. Study design: This was a prospective, longitudinal, observational cohort study of pregnant mothers followed from the first trimester and their healthy, full-term infants. Infants underwent an NNNS assessment and high-quality magnetic resonance imaging 2-5 weeks after birth. A latent profile analysis of NNNS scores categorized infants into neurobehavioral profiles. Univariate and multivariate analyses compared differences in maternal factors (social advantage, psychosocial stress, and medical risk) and neonatal characteristics between profiles. Results: The latent profile analysis of NNNS summary scales of 296 infants generated 3 profiles: regulated (46.6%), hypotonic (16.6%), and fussy (36.8%). Infants with a hypotonic profile were more likely to be male (χ2 = 8.601; P = .014). Fussy infants had smaller head circumferences (F = 3.871; P = .022) and smaller total brain (F = 3.522; P = .031) and cerebral white matter (F = 3.986; P = .020) volumes compared with infants with a hypotonic profile. There were no differences between profiles in prenatal maternal health, social advantage, or psychosocial stress. Conclusions: Three distinct neurobehavioral profiles were identified in healthy, full-term infants with hypotonic and fussy neurobehavioral features related to neonatal brain volumes and head circumference, but not prenatal exposure to socioeconomic or psychosocial adversity. Follow-up beyond the neonatal period will determine if identified profiles at birth are associated with subsequent clinical or developmental outcomes. © 2022 Elsevier Inc.

Author Keywords
latent profile analysis;  neonatal brain volumes;  psychological stress;  socioeconomic status

Funding details
P50 HD103525
National Institute of Mental HealthNIMHR01 MH113883, T32 MH100019
March of Dimes FoundationMDF
Children’s Discovery InstituteCDIMI-II-2018-725

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

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium
(2022) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, . 

Sun, D.^a c , Rakesh, G.^a c , Clarke-Rubright, E.K.^a c , Haswell, C.C.^a c , Logue, M.W.^e f g h , O’Leary, E.N.^d , Cotton, A.S.^d , Xie, H.^d , Dennis, E.L.^i q r w , Jahanshad, N.^q , Salminen, L.E.^q , Thomopoulos, S.I.^q , Rashid, F.M.^q , Ching, C.R.K.^q , Koch, S.B.J.^bd bf , Frijling, J.L.^bd , Nawijn, L.^bd be , van Zuiden, M.^bd , Zhu, X.^x y , Suarez-Jimenez, B.^x y z , Sierk, A.^bk , Walter, H.^bk , Manthey, A.^bk , Stevens, J.S.^aa , Fani, N.^aa , van Rooij, S.J.H.^aa , Stein, M.B.^t , Bomyea, J.^t , Koerte, I.^i bl , Choi, K.^u , van der Werff, S.J.A.^bg bh , Vermeiren, R.R.J.M.^bg , Herzog, J.I.^bm , Lebois, L.A.M.^j k , Baker, J.T.ⁿ , Ressler, K.J.^j k aa , Olson, E.A.^j l , Straube, T.^bn , Korgaonkar, M.S.^bo , Andrew, E.^bp , Zhu, Y.^br bs , Li, G.^br bs , Ipser, J.^bt , Hudson, A.R.^bv , Peverill, M.^ab , Sambrook, K.^ac , Gordon, E.^{ad ae af bc} , Baugh, L.A.^ah ai ak , Forster, G.^ah ai bw , Simons, R.M.^ai aj , Simons, J.S.^ai aj , Magnotta, V.A.^al , Maron-Katz, A.^s , du Plessis, S.^bu , Disner, S.G.^am an , Davenport, N.D.^am an , Grupe, D.^ao , Nitschke, J.B.^ap , deRoon-Cassini, T.A.^ar , Fitzgerald, J.^as , Krystal, J.H.^au av , Levy, I.^au av , Olff, M.^bd bi , Veltman, D.J.^bd , Wang, L.^br bs , Neria, Y.^x y , De Bellis, M.D.^b , Jovanovic, T.^aa aw , Daniels, J.K.^bj , Shenton, M.E.^i o , van de Wee, N.J.A.^bg bh , Schmahl, C.^bm , Kaufman, M.L.^j m , Rosso, I.M.^j l , Sponheim, S.R.^am an , Hofmann, D.B.^bn , Bryant, R.A.^bq , Fercho, K.A.^{ah ai ak ay} , Stein, D.J.^bt , Mueller, S.C.^bv bx , Phan, K.L.^az ba , McLaughlin, K.A.^p , Davidson, R.J.^ao ap aq , Larson, C.^at , May, G.^{ad ae af ag} , Nelson, S.M.^{ad ae af ag} , Abdallah, C.G.^au av , Gomaa, H.^bb , Etkin, A.^s v , Seedat, S.^bu , Harpaz-Rotem, I.^au av , Liberzon, I.^ax , Wang, X.^d , Thompson, P.M.^q , Morey, R.A.^a c

^a Brain Imaging and Analysis Center, Duke University, Durham, North Carolina
^b Healthy Childhood Brain Development Developmental Traumatology Research Program, Department of Psychiatry and Behavioral Sciences, Duke University, Durham, North Carolina
^c Department of Veteran Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina
^d Department of Psychiatry, University of Toledo, Toledo, Ohio
^e National Center for PTSD, VA Boston Healthcare System, Boston, Massachusetts
^f Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts
^g Biomedical Genetics, Boston University School of Medicine, Boston, Massachusetts
^h Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts
ⁱ Psychiatry Neuroimaging Laboratory, Brigham & Women’s Hospital, Boston, Massachusetts
^j Department of Psychiatry, Harvard Medical School, Boston, Massachusetts
^k Division of Depression and Anxiety Disorders, McLean Hospital, Harvard University, Belmont, Massachusetts
^l Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard University, Belmont, Massachusetts
^m Division of Women’s Mental Health, McLean Hospital, Harvard University, Belmont, Massachusetts
ⁿ Institute for Technology in Psychiatry, McLean Hospital, Harvard University, Belmont, Massachusetts
^o VA Boston Healthcare System, Brockton Division, Brockton, Massachusetts
^p Department of Psychology, Harvard University, Cambridge, Massachusetts
^q Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, California
^r Stanford Neurodevelopment, Affect, and Psychopathology Laboratory, Stanford, California
^s Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California
^t Department of Psychiatry, University of California San Diego, San Diego, California
^u Health Services Research Center, University of California San Diego, San Diego, California
^v VA Palo Alto Health Care System, Palo Alto, California
^w Department of Neurology, University of Utah, Salt Lake City, Utah
^x Department of Psychiatry, Columbia University Medical Center, New York, New York
^y New York State Psychiatric Institute, New York, New York
^z University of Rochester Medical Center, Rochester, New York
^aa Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Georgia, Atlanta, Georgia
^ab Department of Psychology, University of Washington, Seattle, WA, United States
^ac Department of Radiology, University of Washington, Seattle, WA, United States
^ad Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
^ae Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
^af Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas
^ag Department of Psychiatry and Behavioral Science, Texas A&M University Health Science Center, Bryan, Texas
^ah Division of Basic Biomedical Sciences, Sanford School of Medicine, Vermillion, SD, United States
^ai Center for Brain and Behavior Research, University of South Dakota, Vermillion, SD, United States
^aj Department of Psychology, University of South Dakota, Vermillion, SD, United States
^ak Sioux Falls VA Health Care System, Sioux Falls, SD, United States
^al Department of Radiology, Psychiatry, and Biomedical Engineering, University of Iowa, Iowa City, IA, United States
^am Minneapolis VA Health Care System, University of Minnesota, Minneapolis, MN, United States
^an Department of Psychiatry, University of Minnesota, Minneapolis, MN, United States
^ao Center for Healthy Minds, University of Wisconsin-Madison, Madison, WI, United States
^ap Department of Psychiatry, University of Wisconsin-Madison, Madison, WI, United States
^aq Department of Psychology, University of Wisconsin-Madison, Madison, WI, United States
^ar Division of Trauma and Acute Care Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, United States
^as Department of Psychology, Marquette University, Milwaukee, WI, United States
^at Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
^au Division of Clinical Neuroscience, National Center for PTSD, West Haven, CT, United States
^av Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
^aw Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine, Detroit, MI, United States
^ax Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
^ay Civil Aerospace Medical Institute, US Federal Aviation Administration, Oklahoma City, OK, United States
^az Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois
^ba Mental Health Service Line, Jesse Brown VA Chicago Health Care System, Chicago, Illinois
^bb Department of Psychiatry, Pennsylvania State University, State CollegePennsylvania
^bc Washington University School of Medicine, St. Louis, Missouri
^bd Department of Psychiatry, Amsterdam University Medical Centers, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands
^be Department of Psychiatry, Amsterdam University Medical Centers, VU University Medical Center, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^bf Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, Netherlands
^bg Department of Psychiatry, Leiden University Medical Center, Leiden, Netherlands
^bh Leiden Institute for Brain and Cognition, Leiden, Netherlands
^bi ARQ National Psychotrauma Centre, Diemen, Netherlands
^bj Department of Clinical Psychology, University of Groningen, Groningen, Netherlands
^bk University Medical Centre Charité, Berlin, Germany
^bl Department of Child and Adolescent Psychiatry, Psychosomatics, and Psychotherapy, Ludwig-Maximilians-Universität, Munich, Germany
^bm Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany
^bn Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany
^bo Brain Dynamics Centre, Westmead Institute of Medical Research, Westmead, NSW, Australia
^bp Department of Psychology, University of Sydney, Westmead, NSW, Australia
^bq School of Psychology, University of New South Wales, Sydney, NSW, Australia
^br Laboratory for Traumatic Stress Studies, Chinese Academy of Sciences Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
^bs Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
^bt SA MRC Unit on Risk & Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
^bu Department of Psychiatry, Stellenbosch University, Cape Town, South Africa
^bv Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium
^bw Brain Health Research Centre, Department of Anatomy, University of Otago, Dunedin, New Zealand
^bx Department of Personality, Psychological Assessment and Treatment, University of Deusto, Bilbao, Spain

Abstract
Background: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). Methods: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2–85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis–Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2–148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. Results: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. Conclusions: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD. © 2022 Society of Biological Psychiatry

Author Keywords
Brain network;  Cortical thickness;  Depression;  PTSD;  Structural covariance;  Surface area

Funding details
110614
01J05415
National Science FoundationNSF
National Institutes of HealthNIHP41 EB015922, R01MH116147, R56AG058854, U54 EB020403
U.S. Department of DefenseDODW81XWH-10-1-0925, W81XWH-12-2-0012, W81XWH08-2-0159
National Institute of Mental HealthNIMH1R01MH110483, 1R21 MH098198, 1R21MH102634, F32 MH101976, F32MH109274, K01 MH118428, K01-MH092526, K23MH112873, K24MH71434, L30 MH114379, MH071537, MH098212, MH101380, R01 MH106574, R01 MH61744, R01 MH63407, R01-MH043454, R01-MH103291, R01MH105355, R01MH105535, R01MH111671, R01MH113574, R01MH117601, R21MH112956, T32-MH018931
National Institute on Alcohol Abuse and AlcoholismNIAAA5U01AA021681-08, DA028773, P50, R01 AA12479
National Institute on AgingNIA14848, R01AG059874
National Institute of Neurological Disorders and StrokeNINDSK99NS096116
National Institute of Child Health and Human DevelopmentNICHDP30-HD003352
Congressionally Directed Medical Research ProgramsCDMRPW81XWH-08–2–0038
National Center for Research ResourcesNCRRM01RR00039
U.S. Department of Veterans AffairsVACX001600
Bill and Melinda Gates FoundationBMGFOPP 1017641
Brain and Behavior Research FoundationBBRF
Dana FoundationDF
Amgen
Pfizer14/197,767, 14/306,382, 5,447,948, 8,778,979
AstraZeneca
Novartis
Biogen
Institute for Clinical and Translational Research, University of Wisconsin, MadisonUW ICTR
National Center for Advancing Translational SciencesNCATSUL1TR000454
Rehabilitation Research and Development ServiceRR&D1IK2RX000709, 1K1RX002325, 1K2RX002922, I01RX000622
AbbVie
Biomedical Laboratory Research and Development, VA Office of Research and DevelopmentBLR&D, ORDI01BX003477
Janssen Pharmaceuticals
Otsuka America PharmaceuticalOAPI
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDHD071982, HD085850
Sunovion
National Alliance for Research on Schizophrenia and DepressionNARSAD
Sage Therapeutics
Clinical Science Research and DevelopmentCSRD10/01/08 – 09/30/13, 1IK2CX001680
National Health and Medical Research CouncilNHMRC1073041
National Research FoundationNRF
South African Medical Research CouncilSAMRCMRC-RFA-FSP-01-2013 /SHARED ROOTS
Department of Science and Technology, Ministry of Science and Technology, Indiaडीएसटी
Deutsche ForschungsgemeinschaftDFGDA 1222/4-1, WA 1539/8-2
ZonMw40-00812-98-10041
Bundesministerium für Bildung und ForschungBMBF01KR1303A, C06
Astellas Pharma
H. Lundbeck A/S

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

Mood and Behaviors of Adolescents With Depression in a Longitudinal Study Before and During the COVID-19 Pandemic
(2022) Journal of the American Academy of Child and Adolescent Psychiatry, . 

Sadeghi, N.^a , Fors, P.Q.^a , Eisner, L.^a b , Taigman, J.^a b , Qi, K.^a b , Gorham, L.S.^a c , Camp, C.C.^a d , O’Callaghan, G.^a , Rodriguez, D.^a b , McGuire, J.^a e , Garth, E.M.^a f , Engel, C.^a b , Davis, M.^a b , Towbin, K.E.^a b , Stringaris, A.^a g , Nielson, D.M.^a

^a Section of Clinical and Computational Psychiatry, National Institute of Mental Health, Bethesda, Maryland, United States
^b Emotion and Development Branch, National Institute of Mental Health, Bethesda, Maryland, United States
^c Medical Scientist Training Program, Washington University in St. Louis School of Medicine, St. Louis, Missouri, United States
^d Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut, United States
^e Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, Maryland, United States
^f Autoimmune Brain Disorders Program, National Institute of Mental Health, Bethesda, Maryland, United States
^g National and Kapodistrain University of Athens, Greece, and University College London, United Kingdom

Abstract
Objective: To investigate whether, compared to pre-pandemic levels, depressive and anxiety symptoms in adolescents with depression increased during the pandemic. Method: We used data from National Institute of Mental Health Characterization and Treatment of Depression (NIMH CAT-D) cohort, a longitudinal case-control study that started pre-pandemic. Most of the participants are from the states of Maryland and Virginia in the United States. We compared depressive symptoms (1,820 measurements; 519 measurements pre-pandemic and 1,302 during the pandemic) and anxiety symptoms (1,800 measurements; 508 measurements pre-pandemic and 1,292 ratings during the pandemic) of 166 adolescents (109 girls, 96 adolescents with depression) before and during the pandemic. Data were collected during yearly clinical visits, interim 4-month follow-up visits, inpatient stays, and weekly outpatient sessions, with additional data collection during the pandemic. Pre-pandemic, healthy volunteers (HVs) had a median of 1 depressive and anxiety rating (range, 1-3), and adolescents with depression had a median of 2 ratings (anxiety rating range, 1-25; depressive rating range, 1-26). During the pandemic, HVs had a median of 8 anxiety ratings and 9 depressive ratings (range, 1-13), and adolescents with depression had a median of 7 anxiety and depressive ratings (range, 1-29). We also analyzed adolescent- and parent-reported behaviors in the CoRonavIruS Health Impact Survey (CRISIS), totaling 920 self-reported measures for 164 adolescents (112 girls, 92 adolescents with depression). HVs had a median of 7 surveys (range, 1-8), and adolescents with depression had a median of 5 surveys (range, 1-8). Results: Pre-pandemic, adolescents with depression had a mean depressive score of 11.16 (95% CI = 10.10, 12.22) and HVs had a mean depressive score of 1.76 (95% CI = 0.40, 3.13), a difference of 9.40 points (95% CI = 7.78, 11.01). During the pandemic, this difference decreased by 22.6% (2.05 points, 95% CI = 0.71, 3.40, p = .003) due to 0.89 points decrease in severity of scores in adolescents with depression (95% CI = 0.08, 1.70, p = .032) and 1.16 points increase in HVs’ depressive symptoms (95% CI = 0.10, 2.23, p = .032). Compared to their pre-pandemic levels, adolescents with depression reported overall lower anxiety symptoms during the pandemic. Parent-on-child reports also were consistent with these results. Conclusion: Contrary to our hypothesis, we found that both depressive and anxiety symptoms were lower for adolescents with depression during the pandemic compared to before. In contrast, the depression scores for the HVs were higher during the pandemic relative to their pre-pandemic ratings; these scores remained much lower than those of adolescents with depression. Clinical trial registration information: Characterization and Treatment of Adolescent Depression; https://clinicaltrials.gov/; NCT03388606. © 2021 American Academy of Child and Adolescent Psychiatry

Author Keywords
adolescence;  COVID-19;  depression;  longitudinal studies

Funding details
National Institutes of HealthNIHZIA-MH002957-01
National Institute of Mental HealthNIMH

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

Driving, Social Distancing, Protective, and Coping Behaviors of Older Adults Before and During COVID-19
(2022) Journal of Applied Gerontology, . 

Roe, C.M.^a , Bayet, S.^b c , Hicks, J.^d , Johnson, A.M.^e , Murphy, S.^d , Doherty, J.M.^d , Babulal, G.M.^d f g

^a Roe Research LLC, St. Louis, MO, United States
^b Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
^c Department of Geomatics Engineering, University of Calgary, Calgary, AB, Canada
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Center for Clinical Studies, Washington University School of Medicine, St. Louis, MO, United States
^f Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Psychology, Faculty of Humanities, University of Johannesburg, South Africa

Abstract
A thorough understanding of individual characteristics of older adults during the COVID-19 pandemic is critical for managing the ongoing pandemic course and planning for the future pandemics. Here, we explore the impact of the COVID-19 pandemic on driving, social distancing, protective, and coping behaviors of older adults. This study reports data on participants aged above 65 whose driving behaviors are being monitored using Global Positioning System (GPS) devices. Participants completed a COVID-19 survey in May 2020. We found that older adults decreased their number of days driving, number of trips per day, as well as average driving speed, and had fewer speeding incidents following COVID-19 onset. We also show that female and African American older adults engaged in more positive coping and cleaning behaviors, and had greater decreases in the number of days driving during the pandemic. The findings highlight the importance of considering older adults’ individual characteristics for an equitable response to the COVID-19 pandemic. © The Author(s) 2022.

Author Keywords
automobile driving;  COVID-19;  motor vehicles;  pandemic

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAAG056466, AG067428, AG068183
BrightFocus FoundationBFFA2021142S

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

MicroRNA Profiling in the Perilymph of Cochlear Implant Patients: Identifying Markers that Correlate to Audiological Outcomes
(2021) Journal of the American Academy of Audiology, 32 (10), pp. 627-635. 

Wichova, H.^a , Shew, M.^b , Nelson-Brantley, J.^c , Warnecke, A.^d , Prentiss, S.^e , Staecker, H.^f

^a House Ear Institute, Los Angeles, CA, United States
^b Department of Otolaryngology Head and Neck Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Anatomy and Cell Biology, School of Medicine, University of Kanas, Kansas City, KS, United States
^d Department of Otolaryngology Head and Neck Surgery, Hannover Medical School, Hannover, Germany
^e Department of Otolaryngology Head and Neck Surgery, University of Miami, School of Medicine, Miami, FL, United States
^f Department of Otolaryngology Head and Neck Surgery, University of Kansas, School of Medicine, Kansas City, KS, United States

Abstract
Hypothesis MicroRNA (miRNA) expression profiles from human perilymph correlate to post cochlear implantation (CI) hearing outcomes. Background The high inter-individual variability in speech perception among cochlear implant recipients is still poorly understood. MiRNA expression in perilymph can be used to characterize the molecular processes underlying inner ear disease and to predict performance with a cochlear implant. Methods Perilymph collected during CI from 17 patients was analyzed using microarrays. MiRNAs were identified and multivariable analysis using consonant-nucleus-consonant testing at 6 and 18 months post implant activation was performed. Variables analyzed included age, gender, preoperative pure tone average (PTA), and preoperative speech discrimination (word recognition [WR]). Gene ontology analysis was performed to identify potential functional implications of changes in the identified miRNAs. Results Distinct miRNA profiles correlated to preoperative PTA and WR. Patients classified as poor performers showed downregulation of six miRNAs that potentially regulate pathways related to neuronal function and cell survival. Conclusion Individual miRNA profiles can be identified in microvolumes of perilymph. Distinct non-coding RNA expression profiles correlate to preoperative hearing and postoperative cochlear implant outcomes. © 2021 American Academy of Audiology. All rights reserved.

Author Keywords
biomarker;  cochlear implant outcomes;  miRNA;  perilymph sampling

Funding details
P30 GM122731– 03, S10OD021743, UL1TR002366
National Institutes of HealthNIHU54 HD 090216
National Cancer InstituteNCIP30 CA168524
National Institute of General Medical SciencesNIGMSP20GM103418

Document Type: Article
Publication Stage: Final
Source: Scopus

Approaches to Treat Sensorineural Hearing Loss by Hair-Cell Regeneration: The Current State of Therapeutic Developments and Their Potential Impact on Audiological Clinical Practice
(2021) Journal of the American Academy of Audiology, 32 (10), pp. 661-669.

Hinton, A.S.^a , Yang-Hood, A.^b , Schrader, A.D.^b , Loose, C.^a , Ohlemiller, K.K.^b , McLean, W.J.^a c 

^a Frequency Therapeutics, Lexington, MA, United States
^b Department of Otolaryngology, Central Institute for the Deaf, Fay and Carl Simons Center for Hearing and Deafness, Washington University, School of Medicine, Saint Louis, MO, United States
^c Department of Surgery, University of Connecticut, School of Medicine, Farmington, CT, United States

Abstract
Sensorineural hearing loss (SNHL) is typically a permanent and often progressive condition that is commonly attributed to sensory cell loss. All vertebrates except mammals can regenerate lost sensory cells. Thus, SNHL is currently only treated with hearing aids or cochlear implants. There has been extensive research to understand how regeneration occurs in nonmammals, how hair cells form during development, and what limits regeneration in maturing mammals. These studies motivated efforts to identify therapeutic interventions to regenerate hair cells as a treatment for hearing loss, with a focus on targeting supporting cells to form new sensory hair cells. The approaches include gene therapy and small molecule delivery to the inner ear. At the time of this publication, early-stage clinical trials have been conducted to test targets that have shown evidence of regenerating sensory hair cells in preclinical models. As these potential treatments move closer to a clinical reality, it will be important to understand which therapeutic option is most appropriate for a given population. It is also important to consider which audiological tests should be administered to identify hearing improvement while considering the pharmacokinetics and mechanism of a given approach. Some impacts on audiological practice could include implementing less common audiological measures as standard procedure. As devices are not capable of repairing the damaged underlying biology, hair-cell regeneration treatments could allow patients to benefit more from their devices, move from a cochlear implant candidate to a hearing aid candidate, or move a subject to not needing an assistive device. Here, we describe the background, current state, and future implications of hair-cell regeneration research. © 2021 American Academy of Audiology. All rights reserved.

Author Keywords
hearing loss;  regeneration;  therapeutic

Document Type: Article
Publication Stage: Final
Source: Scopus