WashU weekly Neuroscience publications

“It’s way more than just writing a prescription”: A qualitative study of preferences for integrated versus non-integrated treatment models among individuals with opioid use disorder
(2021) Addiction Science and Clinical Practice, 16 (1), art. no. 8, . 

Saunders, E.C.^a , Moore, S.K.^a , Walsh, O.^a , Metcalf, S.A.^a , Budney, A.J.^a , Cavazos-Rehg, P.^b , Scherer, E.^a , Marsch, L.A.^a

^a Center for Technology and Behavioral Health, Geisel School of Medicine At Dartmouth College, 46 Centerra Parkway, Suite 301, Lebanon, NH 03766, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Increasingly, treatment for opioid use disorder (OUD) is offered in integrated treatment models addressing both substance use and other health conditions within the same system. This often includes offering medications for OUD in general medical settings. It remains uncertain whether integrated OUD treatment models are preferred to non-integrated models, where treatment is provided within a distinct treatment system. This study aimed to explore preferences for integrated versus non-integrated treatment models among people with OUD and examine what factors may influence preferences. Methods: This qualitative study recruited participants (n = 40) through Craigslist advertisements and flyers posted in treatment programs across the United States. Participants were 18 years of age or older and scored a two or higher on the heroin or opioid pain reliever sections of the Tobacco, Alcohol, Prescription Medications, and Other Substances (TAPS) Tool. Each participant completed a demographic survey and a telephone interview. The interviews were coded and content analyzed. Results: While some participants preferred receiving OUD treatment from an integrated model in a general medical setting, the majority preferred non-integrated models. Some participants preferred integrated models in theory but expressed concerns about stigma and a lack of psychosocial services. Tradeoffs between integrated and non-integrated models were centered around patient values (desire for anonymity and personalization, fear of consequences), the characteristics of the provider and setting (convenience, perceived treatment effectiveness, access to services), and the patient-provider relationship (disclosure, trust, comfort, stigma). Conclusions: Among this sample of primarily White adults, preferences for non-integrated versus integrated OUD treatment were mixed. Perceived benefits of integrated models included convenience, potential for treatment personalization, and opportunity to extend established relationships with medical providers. Recommendations to make integrated treatment more patient-centered include facilitating access to psychosocial services, educating patients on privacy, individualizing treatment, and prioritizing the patient-provider relationship. This sample included very few minorities and thus findings may not be fully generalizable to the larger population of persons with OUD. Nonetheless, results suggest a need for expansion of both OUD treatment in specialty and general medical settings to ensure access to preferred treatment for all. © 2021, The Author(s).

Funding details
National Institute on Drug AbuseNIDAT32 DA037202
National Institute on Drug AbuseNIDAP30 DA029926

Activity competence among infants and toddlers with developmental disabilities: Rasch analysis of the Infant Toddler Activity Card Sort (ITACS)
(2021) Journal of Patient-Reported Outcomes, 5 (1), art. no. 14, . 

Hoyt, C.R.^a , L’Hotta, A.J.^a , Bauer, A.H.^a , Chang, C.-H.^a b c , Varughese, T.E.^a , Abel, R.A.^a c , King, A.A.^{a c d e f}

^a Program in Occupational Therapy, Washington University School of Medicine, 4444 Forest Park Blvd, MSC 8505-66-1, St. Louis, MO 63108, United States
^b Institute of Informatics, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^f Institute of Public Health, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Development is rapid in the first years of life. Developmental delays appearing during this critical period have the potential to persist throughout the child’s life. Available standardized assessments for this age record a child’s ability to successfully complete discrete skills but fail to capture whether the child incorporates those skills into daily routines that are meaningful to the child and family. The Infant Toddler Activity Card Sort (ITACS) is a newly developed photograph-based early intervention tool to measure the participation-related concept of activity competence using caregiver report. The purpose of the present study was to use Rasch analysis to determine if ITACS items comprehensively measure the construct of child activity competence. Results: A total of 60 child/caregiver dyads participated. The dichotomous caregiver-reported responses (present vs. absent) on the 40 individual ITACS items were used in Rasch analysis, and three iterations of the model were completed. The final model included 51 child/caregiver dyads and 67 ITACS assessments with a good spread of individual ability measure (6.47 logits). All items demonstrated adequate infit except for “sleeping” (range 0.68–1.54). Five items (sleeping, eating at restaurants, brushing teeth, crawling, and interact with pets) demonstrated high Mean Square (MNSQ) outfit statistics and one (take a bath) demonstrated low MNSQ outfit. ITACS items demonstrated a good spread of item difficulty measures (6.27 logits), and a clear ceiling was observed. Three activity items (smiling, breastfeeding, and playing with adults) were rarely endorsed as concerns. The activities most likely to be reported as challenging were “crying/communicating” and “going to school”. Person and item reliability statistics were adequate (0.79 and 0.80, respectively). The separation between individuals and between items were adequate to good (1.96 and 1.99, respectively). Conclusions: Findings indicate that ITACS items are measuring a unidimensional construct–activity competence in early childhood. The Rasch analysis of caregiver responses suggest that some activities are more likely to be considered challenging and may be important targets for intervention. These results provide evidence to further validate the ITACS as a caregiver report measure and support its use in the early intervention setting to facilitate caregiver driven goal development. © 2021, The Author(s).

Quantitative endophenotypes as an alternative approach to understanding genetic risk in neurodegenerative diseases
(2021) Neurobiology of Disease, 151, art. no. 105247, . 

Farias, F.H.G.^a b , Benitez, B.A.^a b , Cruchaga, C.^{a b c d e}

^a Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
^b NeuroGenomics and Informatics, Washington University, St. Louis, MO 63110, United States
^c Hope Center for Neurologic Diseases, Washington University, St. Louis, MO 63110, United States
^d The Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO 63110, United States
^e Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Endophenotypes, as measurable intermediate features of human diseases, reflect underlying molecular mechanisms. The use of quantitative endophenotypes in genetic studies has improved our understanding of pathophysiological changes associated with diseases. The main advantage of the quantitative endophenotypes approach to study human diseases over a classic case-control study design is the inferred biological context that can enable the development of effective disease-modifying treatments. Here, we summarize recent progress on biomarkers for neurodegenerative diseases, including cerebrospinal fluid and blood-based, neuroimaging, neuropathological, and clinical studies. This review focuses on how endophenotypic studies have successfully linked genetic modifiers to disease risk, disease onset, or progression rate and provided biological context to genes identified in genome-wide association studies. Finally, we review critical methodological considerations for implementing this approach and future directions. © 2021 The Author(s)

Funding details
National Institute of Neurological Disorders and StrokeNINDSR01NS118146

Morphologic Severity of Craniosynostosis: Implications for Speech and Neurodevelopment
(2021) Cleft Palate-Craniofacial Journal, . 

Tandon, D.^a , Skolnick, G.B.^a , Naidoo, S.D.^a , Grames, L.M.^b , Cradock, M.M.^c , Smyth, M.D.^d , Patel, K.B.^a

^a Division of Plastic and Reconstructive Surgery, Washington University in St. LouisMO, United States
^b Cleft Palate and Craniofacial Institute, St. Louis Children’s HospitalMO, United States
^c Department of Psychology, St. Louis Children’s HospitalMO, United States
^d Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Single-suture craniosynostosis (SSC) can be associated with neurodevelopmental deficits. We examined the correlation between morphologic severity and incidence of speech-language or psychological concerns. Methods: In 62 patients (33 sagittal, 17 metopic, and 12 unicoronal), morphologic severity was determined via preoperative computed tomography (CT). Severity metrics for sagittal, metopic, and unicoronal synostosis were adjusted cephalic index (aCI), interfrontal angle (IFA), and anterior cranial fossa area ratio (ACFR), respectively. Speech-language and psychological concerns were assessed at age ≥4.5 years and defined as recommendation for therapy or monitoring. Results: Mean assessment age was 5.7 years; 32% had a speech-language concern and 44% had a psychological concern; 44% had neither. Sagittal: Mean aCI of those with a speech-language concern (0.62) and those without (0.62) were equivalent (P =.580), as were mean aCI of those with a psychological concern (0.62) and those without (0.62; P =.572). Metopic: Mean IFA with (117.9) and without (125.2) a speech-language concern were equivalent (P =.326), as were mean IFA with (120.2) and without (123.2) a psychological concern (P =.711). Unicoronal: Mean ACFR with (0.65) and without (0.69) a psychological concern (P =.423) were equivalent. However, mean ACFR with (0.74) and without (0.63) a speech-language concern were not (P =.022*). Bivariate rank correlation showed significant association between morphologic severity and speech-language score only for unicoronal synostosis (ρ =.722; P =.008*). Conclusion: A significant portion of patients with SSC had speech-language or psychological concerns. We found no correlation between morphologic severity and incidence of speech-language or psychological concerns for patients with sagittal or metopic synostosis. Morphological severity did correlate with speech concerns in patients with unicoronal synostosis. © 2021, American Cleft Palate-Craniofacial Association.

Funding details
School of Medicine
Washington University in St. LouisWUSTL

Child and Adolescent Psychiatry Fellowship Program Website Content and Accessibility
(2021) Academic Psychiatry, . 

Bernstein, S.A.^a , Gu, A.^b , Bernstein, S.L.^c , Wei, C.^b , Vogel, A.C.^a , Gold, J.A.^a

^a Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO, United States
^b George Washington University School of Medicine and Health Sciences, Washington, DC, United States
^c University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States

Abstract
Objective: When child and adolescent psychiatry fellowship applicants are applying to programs, many will use fellowship websites to gather information. This study assesses the accessibility and content available on child and adolescent fellowship websites. Methods: Using the Electronic Residency Application Service (ERAS) list of child and adolescent fellowship programs for 2020, 139 child and adolescent fellowship training websites were compiled. Information on websites was evaluated within the following three categories: program overview, application information and recruitment, and educational opportunities. A total of 22 criteria were evaluated within these three categories. Descriptive statistics were used to analyze the websites. Results: A list provided by ERAS and a Google search identified child and adolescent fellowship program websites. Analysis of content revealed most websites included an overview of the program (97.8%), but fewer included information such as the number of fellowship spots (51.5%), salary (45.5%), application deadline (41.0%), and call responsibility (19.4%). Conclusion: Results suggest there is room for improvement in the comprehensiveness and accessibility of child and adolescent fellowship websites. Especially during a time when much of the programmatic information will be obtained virtually due to COVID-19, it is critical that fellowship websites are uniformly curated so applicants can more easily find information about programs. © 2021, Academic Psychiatry.

Serotonin 5-HT1B receptor-mediated behavior and binding in mice with the overactive and dysregulated serotonin transporter Ala56 variant
(2021) Psychopharmacology, . 

O’Reilly, K.C.^a , Connor, M.^b c , Pierson, J.^d , Shuffrey, L.C.^a , Blakely, R.D.^e , Ahmari, S.E.^d , Veenstra-VanderWeele, J.^a c

^a Department of Psychiatry, New York State Psychiatric Institute, Columbia University, 1051 Riverside Dr., Unit 78, New York, NY 10032, United States
^b Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Vanderbilt University, Nashville, TN 37232, United States
^d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15219, United States
^e Brain Institute and Department of Biomedical Science, Florida Atlantic University, Jupiter, FL 33458, United States

Abstract
Rationale: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. Objectives: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. Methods: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. Results: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. Conclusions: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.

Funding details
National Institutes of HealthNIHMH081066, MH114296, T32MH016434, MH094604

Herpesvirus Infections and Risk of Parkinson’s Disease
(2021) Neurodegenerative Diseases, . 

Camacho-Soto, A.^a , Faust, I.^a , Racette, B.A.^a b , Clifford, D.B.^a , Checkoway, H.^c d , Searles Nielsen, S.^a

^a Department of Neurology, Washington University, School of Medicine, Campus Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, Parktown, South Africa
^c Department of Family Medicine and Public Health, University of California, San Diego, CA, United States
^d Department of Neurosciences, University of California, San Diego, CA, United States

Abstract
Introduction: Herpesviruses might play a role in the pathogenesis of neurodegenerative disorders. We sought to examine a possible association between alpha herpesvirus infections and Parkinson’s disease. Methods: We conducted a population-based case-control study of incident Parkinson’s disease in 2009 Medicare beneficiaries age 66-90 years (89,790 cases, 118,095 randomly selected comparable controls). We classified beneficiaries with any diagnosis code for “herpes simplex”and/or “herpes zoster”in the previous 5 years as having had the respective alpha herpesviruses. In beneficiaries with Part D prescription coverage, we also identified those prescribed anti-herpetic medications. We calculated odds ratios (OR) and 95% CI between alpha herpesvirus diagnosis/treatment and Parkinson’s disease with logistic regression, with adjustment for age, sex, race/ethnicity, smoking, and use of medical care. Results: Parkinson’s disease risk was inversely associated with herpes simplex (OR 0.79, 95% CI 0.74-0.84), herpes zoster (OR 0.88, 95% CI 0.85-0.91), and anti-herpetic medications (OR 0.87, 95% CI 0.80-0.96). Conclusion: Herpesvirus infection or treatment might reduce risk of Parkinson’s disease, but future studies will be required to explore whether this inverse association is causal. © 2021 Cambridge University Press. All rights reserved.

Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study
(2021) Neuropsychopharmacology, . 

Harnett, N.G.^a b , van Rooij, S.J.H.^c , Ely, T.D.^c , Lebois, L.A.M.^a b , Murty, V.P.^d , Jovanovic, T.^e , Hill, S.B.^a , Dumornay, N.M.^a , Merker, J.B.^a , Bruce, S.E.^f , House, S.L.^g , Beaudoin, F.L.^h , An, X.ⁱ , Zeng, D.^j , Neylan, T.C.^k , Clifford, G.D.^l m , Linnstaedt, S.D.ⁱ , Germine, L.T.ⁿ , Bollen, K.A.^o , Rauch, S.L.^p , Lewandowski, C.^q , Hendry, P.L.^r , Sheikh, S.^r , Storrow, A.B.^s , Musey, P.I., Jr.^t , Haran, J.P.^u , Jones, C.W.^v , Punches, B.E.^w , Swor, R.A.^x , McGrath, M.E.^y , Pascual, J.L.^z aa , Seamon, M.J.^ab , Mohiuddin, K.^ac , Chang, A.M.^ad , Pearson, C.^ae , Peak, D.A.^af , Domeier, R.M.^ag , Rathlev, N.K.^ah , Sanchez, L.D.^ai aj , Pietrzak, R.H.^ak al , Joormann, J.^am , Barch, D.M.^an , Pizzagalli, D.A.^a b , Sheridan, J.F.^ao ap , Harte, S.E.^aq ar , Elliott, J.M.^as at au , Kessler, R.C.^av , Koenen, K.C.^aw , Mclean, S.^i ax , Ressler, K.J.^a b , Stevens, J.S.^c

^a Division of Depression and Anxiety, McLean Hospital, Belmont, MA, United States
^b Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^c Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, United States
^d Department of Psychology, Temple University, Philadelphia, PA, United States
^e Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
^f Department of Psychological Sciences, University of Missouri – St. Louis, Springfield, MO, United States
^g Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Emergency Medicine & Health Services, Policy, and Practice, Rhode Island Hospital and The Miriam Hospital, The Alpert Medical School of Brown University, Providence, RI, United States
ⁱ Institute of Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^j Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^k Departments of Psychiatry and Neurology, University of California at San Francisco, San Francisco, CA, United States
^l Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA, United States
^m Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, United States
ⁿ Institute for Technology in Psychiatry, McLean Hospital, Belmont, MA, United States
^o Department of Psychology and Neuroscience, Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^p Department of Psychiatry, McLean Hospital, Belmont, MA, United States
^q Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^r Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, FL, United States
^s Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^t Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^u Department of Emergency Medicine, University of Massachusetts Medical School, Worcester, MA, United States
^v Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
^w Department of Emergency Medicine, College of Medicine & College of Nursing, University of Cincinnati, Cincinnati, OH, United States
^x Department of Emergency Medicine, Oakland University William Beaumont School of Medicine, Rochester, MI, United States
^y Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
^z Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^aa Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^ab Division of Traumatology, Surgical Critical Care and Emergency Surgery, University of Pennsylvania, Philadelphia, PA, United States
^ac Department of Emergency Medicine, Einstein Medical Center, Philadelphia, PA, United States
^ad Department of Emergency Medicine, Jefferson University Hospitals, Philadelphia, PA, United States
^ae Department of Emergency Medicine, Wayne State University, Detroit, MI, United States
^af Department of Emergency Medicine, Massachusetts General Hospital, Massachusetts, MA, United States
^ag Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ann Arbor, MI, United States
^ah Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MO, United States
^ai Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
^aj Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^ak Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^al U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, United States
^am Department of Psychology, Yale University, New Haven, CT, United States
^an Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^ao Department of Biosciences and Neuroscience, OSU Wexner Medical Center, Columbus, OH, United States
^ap Institute for Behavioral Medicine Research, OSU Wexner Medical Center, Columbus, OH, United States
^aq Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^ar Department of Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
^as The Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, Camperdown, NSW, Australia
^at Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia
^au Physical Therapy & Human Movement Sciences, Feinberg School of Medicine at Northwestern University, Chicago, IL, United States
^av Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^aw Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^ax Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Abstract
Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma. © 2021, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.

Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institutes of HealthNIHR01HD079076, R03HD094577
National Center for Medical Rehabilitation ResearchNCMRR
Roche
Blue Cross and Blue Shield of Florida Foundation
AstraZeneca
Janssen Biotech
National Institute of Mental HealthNIMHK00 MH119603, U01 MH110925, K01 MH118467
R33AG05654, JAX- ASCENT

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
(2021) Molecular Psychiatry, . 

Jia, X.^a , Goes, F.S.^b , Locke, A.E.^c , Palmer, D.^d , Wang, W.^e , Cohen-Woods, S.^f g , Genovese, G.^d , Jackson, A.U.^h , Jiang, C.ⁱ , Kvale, M.^j , Mullins, N.^k , Nguyen, H.^e , Pirooznia, M.^l , Rivera, M.^g m , Ruderfer, D.M.ⁿ , Shen, L.ⁱ , Thai, K.ⁱ , Zawistowski, M.^h , Zhuang, Y.^h , Abecasis, G.^h , Akil, H.^o , Bergen, S.^p , Burmeister, M.^o q r s , Champion, S.^d , DelaBastide, M.^t , Juréus, A.^p , Kang, H.M.^h , Kwok, P.-Y.^j , Li, J.Z.^q r , Levy, S.E.^u , Monson, E.T.^v , Moran, J.^w , Sobell, J.^x , Watson, S.^o , Willour, V.^v , Zöllner, S.^h s , Adolfsson, R.^y , Blackwood, D.^z , Boehnke, M.^h , Breen, G.^g aa , Corvin, A.^ab , Craddock, N.^ac , DiFlorio, A.^ac , Hultman, C.M.^p , Landen, M.^p ad , Lewis, C.^g ae , McCarroll, S.A.^af , Richard McCombie, W.^t , McGuffin, P.^g , McIntosh, A.^z ag , McQuillin, A.^ah , Morris, D.^ab ai , Myers, R.M.^u , O’Donovan, M.^ac , Ophoff, R.^aj ak , Boks, M.^ak , Kahn, R.^al , Ouwehand, W.^am , Owen, M.^ac , Pato, C.^x an , Pato, M.^x ao , Posthuma, D.^ap aq , Potash, J.B.^b , Reif, A.^ar , Sklar, P.^e , Smoller, J.^d as , Sullivan, P.F.^at , Vincent, J.^au av , Walters, J.^ac , Neale, B.^d aw , Purcell, S.^ax ay , Risch, N.^j , Schaefer, C.ⁱ , Stahl, E.A.^e , Zandi, P.P.^b , Scott, L.J.^h

^a Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, United States
^b Department of Psychiatry and Behavioral Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21287, United States
^c Division of Genomics & Bioinformatics, Department of Medicine and McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63108, United States
^d Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
^e Division of Psychiatric Genomics, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^f Discipline of Psychology and Flinders Centre for Innovation in Cancer, Flinders University, Adelaide, SA, Australia
^g Medical Research Council Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^h Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, United States
ⁱ Division of Research, Kaiser Permanente Northern California, Oakland, CA 94611, United States
^j Institute for Human Genetics, University of California San Francisco, San Francisco, CA 94143, United States
^k Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^l Bioinformatics and Computational Core, National Heart, Lung, and Blood Institute, Bethesda, MD 20892, United States
^m Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, Spain
ⁿ Departments of Medicine, Psychiatry, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, United States
^o Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, United States
^p Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^q Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI 48109, United States
^r Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, United States
^s Department of Psychiatry, University of Michigan, Ann Arbor, MI 48109, United States
^t Division of Research, Cold Spring Harbor Laboratory, Cold Spring, Harbor, NY 11797, United States
^u HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, United States
^v Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 52242, United States
^w Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, United States
^x Department of Psychiatry and Behavioral Sciences, University of Southern California, Los Angeles, CA 90033, United States
^y Departments of Clinical Sciences and Psychiatry, Umea University, Umea, Sweden
^z Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom
^aa NIHR BRC for Mental Health, King’s College London, London, United Kingdom
^ab Department of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
^ac Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University School of Medicine, Cardiff, United Kingdom
^ad Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
^ae Department of Medical & Molecular Genetics, King’s College London, London, United Kingdom
^af Department of Genetics, Harvard Medical School, Boston, MA 02115, United States
^ag Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom
^ah Division of Psychiatry, University College London, London, United Kingdom
^ai Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland Galway, Galway, Ireland
^aj Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA 90095, United States
^ak Department of Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, Netherlands
^al Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
^am Department of Haematology, School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom
^an SUNY Downstate Medical Center, Brooklyn, NY 11203, United States
^ao Department of Psychiatry, SUNY Downstate Medical Center, Brooklyn, NY 11203, United States
^ap Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
^aq Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, Netherlands
^ar Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany
^as Department of Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, United States
^at Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, United States
^au Molecular Neuropsychiatry and Development Laboratory, Campbell Family Mental Health Research Institute, Center for Addiction & Mental Health, Toronto, ON, Canada
^av Department of Psychiatry and Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
^aw Analytical and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, United States
^ax Division of Sleep and Circadian Disorders, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, United States
^ay Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States

Abstract
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ. © 2021, The Author(s).

Funding details
Kaiser Permanente Washington Health Research InstituteKPWHRI
National Institutes of HealthNIHGERA RC2 AG036607, R01 MH 085543
National Institute of Mental HealthNIMHR01 MH 110437, R01 MH 094145, UO1 MH105653
Dalio Foundation
R01MH077139, R01 MH 087979, R01MH106531, R01MH106527, MH 087992, R01MH095034
Takeda Pharmaceuticals North AmericaTPNA

Choroid plexus NKCC1 mediates cerebrospinal fluid clearance during mouse early postnatal development
(2021) Nature Communications, 12 (1), art. no. 447, . 

Xu, H.^a , Fame, R.M.^a , Sadegh, C.^a b , Sutin, J.^c , Naranjo, C.^d , Della Syau^d , Cui, J.^a , Shipley, F.B.^a e , Vernon, A.^f g h , Gao, F.^f g h k , Zhang, Y.ⁱ , Holtzman, M.J.ⁱ , Heiman, M.^f g h , Warf, B.C.^j , Lin, P.-Y.^c , Lehtinen, M.K.^a e

^a Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, United States
^b Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, United States
^c Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, United States
^d Summer Honors Undergraduate Research Program, Division of Medical Sciences, Harvard Medical School, Boston, MA 02115, United States
^e Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, United States
^f Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
^g Picower Institute for Learning and Memory, Cambridge, MA 02139, United States
^h Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
ⁱ Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO 63110, United States
^j Department of Neurosurgery, Boston Children’s Hospital, Boston, MA 02115, United States
^k Bioinformatics Resource Center in the Beckman Institute at Caltech, Pasadena, CA 91125, United States

Abstract
Cerebrospinal fluid (CSF) provides vital support for the brain. Abnormal CSF accumulation, such as hydrocephalus, can negatively affect perinatal neurodevelopment. The mechanisms regulating CSF clearance during the postnatal critical period are unclear. Here, we show that CSF K+, accompanied by water, is cleared through the choroid plexus (ChP) during mouse early postnatal development. We report that, at this developmental stage, the ChP showed increased ATP production and increased expression of ATP-dependent K+ transporters, particularly the Na+, K+, Cl−, and water cotransporter NKCC1. Overexpression of NKCC1 in the ChP resulted in increased CSF K+ clearance, increased cerebral compliance, and reduced circulating CSF in the brain without changes in intracranial pressure in mice. Moreover, ChP-specific NKCC1 overexpression in an obstructive hydrocephalus mouse model resulted in reduced ventriculomegaly. Collectively, our results implicate NKCC1 in regulating CSF K+ clearance through the ChP in the critical period during postnatal neurodevelopment in mice. © 2021, The Author(s).

Funding details
Human Frontier Science ProgramHFSPR01 NS088566, 0063/2018
National Institutes of HealthNIHT32 HL110852
Simons FoundationSF590293, R01 HD096693, 645596, R00 HD083512, R01 AI130591, R35 HL145242
Boston Children’s HospitalBCH
New York Stem Cell FoundationNYSCF1U54HD090255, P30EY012196
National Science FoundationNSF
Hydrocephalus AssociationHA

A predictable home environment may protect child mental health during the COVID-19 pandemic
(2021) Neurobiology of Stress, 14, art. no. 100291, . 

Glynn, L.M.^a , Davis, E.P.^b c , Luby, J.L.^d , Baram, T.Z.^e f g , Sandman, C.A.^c

^a Department of Psychology, Chapman University, United States
^b Department of Psychology University of Denver, United States
^c Department of Psychiatry & Human Behavior, University of California, Irvine, United States
^d Department of Psychiatry, Washington University in St. Louis, United States
^e Department of Anatomy/Neurobiology, University of California, Irvine, United States
^f Department of Pediatrics, University of California, Irvine, United States
^g Department of Neurology, University of California, Irvine, United States

Abstract
Objective: Information about the adverse effects of the COVID-19 pandemic on adolescent and adult mental health is growing, yet the impacts on preschool children are only emerging. Importantly, environmental factors that augment or protect from the multidimensional and stressful influences of the pandemic on emotional development of young children are poorly understood. Methods: Depressive symptoms in 169 preschool children (mean age 4.1 years) were assessed with the Preschool Feelings Checklist during a state-wide stay-at-home order in Southern California. Mothers (46% Latinx) also reported on externalizing behaviors with the Strengths & Difficulties Questionnaire. To assess the role of environmental factors in child mental health we examined household income, food insecurity, parental essential worker status and loss of parental job, as well as preservation of the structure of children’s daily experiences with the Family Routines Inventory. Results: Sixty-one percent of families’ incomes were below the living wage and 50% had at least one parent who was an essential worker. Overall, preschoolers’ depressive and externalizing symptoms were elevated compared to pre-COVID norms. Practice of family routines robustly predicted better child mental health, and this protective effect persisted after covarying income, dual-parent status and food insecurity as well as maternal depression and stress. Conclusion: The stress of the COVID-19 pandemic is exacting a significant toll on the mental health of preschool children. Importantly, maintaining a structured, predicable home environment by adherence to family routines appears to mitigate these adverse effects, providing empiric basis for public health recommendations. © 2020

Author Keywords
Child psychopathology;  Conduct disorders;  Depression;  Early life adversity;  Family routines;  Pandemic;  Resilience;  Stress;  Trauma

Funding details
National Institutes of HealthNIHMH096889

Multimodal examination of emotion processing systems associated with negative affectivity across early childhood
(2021) Developmental Cognitive Neuroscience, 48, art. no. 100917

Camacho, M.C.^a , Williams, E.M.^b , Ding, K.^b c , Perlman, S.B.^a b

^a Division of Biology and Biomedical Science (Neurosciences), Washington University in St. Louis, St. Louis, MO, United States
^b Division of Child and Adolescent Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Key Laboratory of Child Development & Learning Science, Ministry of Education, Department of Biomedical Engineering, Southeast University, Nanjing, China

Abstract
High Temperamental Negative Affectivity in early childhood has been found to predict later emotion dysregulation. While much work has been conducted to separately probe bio-behavioral systems associated with Negative Affectivity, very little work has examined the relations among multiple systems across age. In this study, we use multi-modal methods to index neurobiological systems associated with Negative Affectivity in 53 4-7-year-old children. Prefrontal activation during emotion regulation was measured using functional near-infrared spectroscopy over the lateral prefrontal cortex (PFC) while children played a game designed to elicit frustration in Social (Happy and Angry faces) and Nonsocial contexts. Gaze behaviors while free-viewing Happy and Angry faces were also measured. Finally, Negative Affectivity was indexed using a score composite based on factor analysis of parent-reported temperament. Using mixed-effects linear models, we found an age-dependent association between Negative Affectivity and both PFC activation during frustration and fixation duration on the mouth area of Happy faces, such that older children high in Negative Affectivity spent less time looking at the mouths of Happy faces and had lower PFC activation in response to frustration (ps<0.034). These results provide further insight to how Negative Affectivity may be associated with changes in affective neurobiological systems across early childhood. © 2021

Author Keywords
Early childhood;  Emotion regulation;  Eye tracking;  Functional near-infrared spectroscopy;  Temperament

Funding details
National Science FoundationNSFDGE-1745038
National Institutes of HealthNIHR01 MH107540

Network variants are similar between task and rest states
(2021) NeuroImage, 229, art. no. 117743, . 

Kraus, B.T.^a , Perez, D.^a , Ladwig, Z.^b , Seitzman, B.A.^c , Dworetsky, A.^d , Petersen, S.E.^{c d e f g} , Gratton, C.^a b h

^a Department of Psychology, Northwestern University, Evanston, IL 60208, United States
^b Interdepartmental Neuroscience Program, Northwestern University, Chicago, IL 60611, United States
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
^f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63110, United States
^g Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO 63110, United States
^h Department of Neurology, Northwestern University, Chicago, IL 60611, United States

Abstract
Recent work has demonstrated that individual-specific variations in functional networks (termed “network variants”) can be identified in individuals using resting state functional magnetic resonance imaging (fMRI). These network variants exhibit reliability over time, suggesting that they may be trait-like markers of individual differences in brain organization. However, while networks variants are reliable at rest, is is still untested whether they are stable between task and rest states. Here, we use precision data from the Midnight Scan Club (MSC) to demonstrate that (1) task data can be used to identify network variants reliably, (2) these network variants show substantial spatial overlap with those observed in rest, although state-specific effects are present, (3) network variants assign to similar canonical functional networks in task and rest states, and (4) single tasks or a combination of multiple tasks produce similar network variants to rest. Together, these findings further reinforce the trait-like nature of network variants and demonstrate the utility of using task data to define network variants. © 2021

Funding details
Office of the University Provost, Arizona State University
Northwestern UniversityNU

Specialist approaches to prognostic counseling in isolated REM sleep behavior disorder
(2021) Sleep Medicine, 79, pp. 107-112. 

Teigen, L.N.^a b , Sharp, R.R.^c , Hirsch, J.R.^c , Campbell, E.^c d , Timm, P.C.^a b , Sandness, D.J.^a b , Feemster, J.C.^a b , Gossard, T.R.^a b , Faber, S.M.^a b , Steele, T.A.^a b e , Rivera, S.^a b e , Junna, M.R.^a b , Lipford, M.C.^a b , Tippmann-Peikert, M.^a b , Kotagal, S.^a b , Ju, Y.-E.^f , Howell, M.^g , Schenck, C.H.^h , Videnovic, A.ⁱ , Jennum, P.^j , Hogl, B.^k , Stefani, A.^k , Arnulf, I.^l , Heidbreder, A.^k m , Lewis, S.ⁿ , McCarter, S.J.^a b , Boeve, B.F.^a b , Silber, M.H.^a b , St Louis, E.K.^a b c

^a Mayo Center for Sleep Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, United States
^b Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, United States
^c Biomedical Ethics Research Program, Mayo Clinic College of Medicine and Science, Rochester, MN, United States
^d University of South Carolina, United States
^e University of Minnesota-Rochester, Rochester, MN, United States
^f Department of Neurology, Washington University, St. Louis, MO, United States
^g Department of Neurology, University of Minnesota, Minneapolis, MN, United States
^h Minnesota Regional Sleep Disorders Center, And Department of Psychiatry, Hennepin County Medical Center and University of Minnesota Medical School, Minneapolis, MN, USA, United States
ⁱ Massachusetts General Hospital and Harvard University, Boston, MA, United States
^j Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
^k Department of Neurology, University of Innsbruck, Innsbruck, Austria
^l Pitie Salpetriere Hopital and Sorbonne University, Paris, France
^m Department of Neurology with Institute of Translational Neurology, University of Muenster, Muenster, Germany
ⁿ Department of Neurology, University of Sidney, Sidney, Australia

Abstract
Objectives/background: Most middle-aged and older adult patients with isolated (idiopathic) REM sleep behavior disorder (RBD) eventually develop parkinsonism, dementia with Lewy bodies, or multiple system atrophy. We aimed to describe the current sleep medicine specialist approach toward RBD prognostic counseling, and to determine physician beliefs and characteristics that impact provision of counseling. Patients/methods: We surveyed 70 sleep medicine physicians with RBD expertise for demographic information, counseling practices, and their beliefs and understandings concerning the association between RBD and synucleinopathies, among other questions. Responses were summarized by descriptive statistics. Results: Among the 44 respondents (63% response rate), 41 (93.2%) regularly provided prognostic counseling for most RBD patients, but only 31.8% routinely asked about patient preferences on receiving counseling. 41.8% believed that the risk for developing overt synucleinopathy following RBD diagnosis was >80%, but only 15.9% routinely provided this detailed phenoconversion risk estimate to their patients. Most respondents were concerned that RBD prognostic counseling could adversely impact on the patient’s and family’s mental health. Conclusions: Most expert RBD sleep clinicians routinely counsel their patients regarding the high risk for phenoconversion to parkinsonism or dementia, yet relatively few routinely ask patients about their preferences for receiving this information, and fewer provide details concerning the known high risk estimates for developing a synucleinopathy. Future research should analyze patients’ values and preferences in RBD populations to inform approaches toward shared decision making for RBD prognostic counseling. © 2020

Author Keywords
Communication;  Counseling;  Ethics;  Physician–patient relationship;  Prognosis;  REM sleep behavior disorder

Funding details
UL1 TR002377
R34AG056639

The Pediatric Neurology 2020 Research Workforce Survey: Optimism in a Time of Challenge
(2021) Pediatric Neurology, 116, pp. 62-67. 

Bonkowsky, J.L.^a , Felling, R.J.^b , Grinspan, Z.M.^c , Guerriero, R.M.^d , Kosofsky, B.E.^e , Lyons-Warren, A.M.^f , deVeber, G.A.^g

^a Division of Pediatric Neurology, Department of Pediatrics, University of Utah School of Medicine;, Primary Children’s Hospital, Intermountain Healthcare, Salt Lake City, UT, United States
^b Division of Pediatric Neurology, Johns Hopkins School of Medicine, Baltimore, MD, United States
^c Departments of Population Health Sciences and Pediatrics, New York-Presbyterian/Weill Cornell Medicine, New York, NY, United States
^d Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Pediatrics, New York-Presbyterian/Weill Cornell Medicine, New York, NY, United States
^f Division of Child Neurology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, United States
^g Division of Neurology, Hospital for Sick Children, Toronto, ON, Canada

Abstract
Background: The past decades have seen a transformational shift in the understanding and treatment for neurological diseases affecting infants and children. These advances have been driven in part by the pediatric neurology physician-scientist workforce and its efforts. However, pediatric neurology research faces significant challenges from internal and external forces including work-life balance demands, COVID-19 pandemic effects, and research funding. Understanding the impact of these challenges on the perceptions, planning, and careers of pediatric neurology physician-scientists is needed to guide the research mission. Methods: Our objective was to survey the research challenges, goals, and priorities of pediatric neurologists. In 2020 we conducted a cross-sectional, 28-question survey emailed to 1,775 members of the Child Neurology Society. Results: One hundred fifty-one individuals responded to the survey. Most respondents were grant investigators (52%) and conducted clinical research (69%). Research areas included epilepsy (23%), neurodevelopmental and autism (16%), neurocritical care and stroke (11%), neurogenetics and neurometabolics (9%), neonatal neurology (8%), and others. The most common funding source was the National Institutes of Health (37%). Shared major research concerns were funding, utilization of remote technology, overcoming disparities, natural history and multicenter studies, global neurology, and diversification of the research portfolio. Commitment to continuing and increasing research efforts was evident. Conclusions: Our survey demonstrates obstacles for physician-scientist researchers in pediatric neurology, but it also shows optimism about continued opportunity. Creative approaches to address challenges will benefit the research mission, maximize the current and future pool of researchers, and help improve the lives of children with neurological disorders. © 2020

Author Keywords
Career;  Child neurology;  Funding;  Physician-scientist;  Survey;  Workforce

Funding details
Epilepsy FoundationEF
Pediatric Epilepsy Research FoundationPERF
Weill Cornell Medical College

The mixed kappa and delta opioid receptor agonist, MP1104, attenuates chemotherapy-induced neuropathic pain
(2021) Neuropharmacology, 185, art. no. 108445, . 

Atigari, D.V.^a , Paton, K.F.^a , Uprety, R.^b , Váradi, A.^b , Alder, A.F.^a , Scouller, B.^a , Miller, J.H.^a , Majumdar, S.^c , Kivell, B.M.^a

^a School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand
^b Molecular Pharmacology Program and Department of Neurology, Memorial Sloan Kettering Cancer Centre, New York, United States
^c Center of Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, United States

Abstract
Effective treatments for chronic pain without abuse liability are urgently needed. One in 5 adults suffer chronic pain and half of these patients report inefficient treatment. Mu opioid receptor agonists (MOP), including oxycodone, tramadol and morphine, are often prescribed to treat chronic pain, however, use of drugs targeting MOP can lead to drug dependency, tolerance and overdose deaths. Kappa opioid receptor (KOP) agonists have antinociceptive effects without abuse potential; however, they have not been utilised clinically due to dysphoria and sedation. We hypothesise that mixed opioid receptor agonists targeting the KOP and delta opioid receptor (DOP) would have a wider therapeutic index, with the rewarding effects of DOP negating the negative effects of KOP. MP1104, an analogue of 3-Iodobenzoyl naltrexamine, is a novel mixed opioid receptor agonist with potent antinociceptive effects mediated via KOP and DOP in mice without rewarding or aversive effects. In this study, we show MP1104 has potent, long-acting antinociceptive effects in the warm-water tail-withdrawal assay in male and female mice and rats; and is longer acting than morphine. In the paclitaxel-induced neuropathic pain model in mice, MP1104 reduced both mechanical and cold allodynia and unlike morphine, did not produce tolerance when administered daily for 23 days. Moreover, MP1104 did not induce sedative effects in the open-field locomotor activity test, respiratory depression in mice using whole-body plethysmography, or have cross-tolerance with morphine. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOP/DOP agonists, as non-addictive pain medications with reduced tolerance. © 2020

Author Keywords
Mixed opioid receptor agonist;  Neuropathic pain;  Paclitaxel;  Respiratory depression;  Tail-withdrawal;  Tolerance

Funding details
Victoria University of WellingtonWGTN
W81XWH-17-1-0256
P30 CA008748
National Institute on Alcohol Abuse and AlcoholismNIAAAAA026949
Office of the Assistant Secretary for HealthOASH
National Institute on Drug AbuseNIDADA045884, DA046487

Effects of dietary restriction on neuroinflammation in neurodegenerative diseases
(2021) The Journal of Experimental Medicine, 218 (2), . 

Fontana, L.^a b c , Ghezzi, L.^d e , Cross, A.H.^d , Piccio, L.^d f

^a Charles Perkins Center, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
^b Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, Australia
^c Department of Clinical and Experimental Sciences, Brescia University, Brescia, Italy
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO
^e University of Milan, Milan, Italy
^f Brain and Mind Centre, School of Medical Sciences, University of Sydney, Sydney, NSW, Australia

Abstract
Recent and accumulating work in experimental animal models and humans shows that diet has a much more pervasive and prominent role than previously thought in modulating neuroinflammatory and neurodegenerative mechanisms leading to some of the most common chronic central nervous system (CNS) diseases. Chronic or intermittent food restriction has profound effects in shaping brain and peripheral metabolism, immunity, and gut microbiome biology. Interactions among calorie intake, meal frequency, diet quality, and the gut microbiome modulate specific metabolic and molecular pathways that regulate cellular, tissue, and organ homeostasis as well as inflammation during normal brain aging and CNS neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis, among others. This review discusses these findings and their potential application to the prevention and treatment of CNS neuroinflammatory diseases and the promotion of healthy brain aging. © 2021 Fontana et al.

Cognitive impairment in Parkinson’s disease is associated with Default Mode Network subsystem connectivity and cerebrospinal fluid Aβ
(2021) Parkinsonism and Related Disorders, 83, pp. 71-78. 

Zarifkar, P.^a b , Kim, J.^a , La, C.^a , Zhang, K.^a , YorkWilliams, S.^a c , Levine, T.F.^a d , Tian, L.^e , Borghammer, P.^b , Poston, K.L.^a f

^a Department of Neurology and Neurological Sciences, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, United States
^b Department of Nuclear Medicine and PET, Aarhus University Hospital, Denmark
^c Department of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309, United States
^d Department of Psychological & Brain Sciences, Washington University, 1 Brookings Drive, St. Louis, MO 63130, United States
^e Department of Biomedical Data Science, Stanford University School of Medicine, 150 Governor’s Lane, Stanford, CA 94305, United States
^f Department of Neurosurgery, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, United States

Abstract
Introduction: To identify clinically implementable biomarkers of cognitive impairment in Parkinson’s Disease (PD) derived from resting state-functional MRI (rs-fMRI) and CSF protein analysis. Methods: In this single-center longitudinal cohort study, we analyzed rs-fMRI and CSF biomarkers from 50 PD patients (23 cognitively normal, 18 mild cognitive impairment, 9 dementia) and 19 controls, who completed comprehensive neuropsychological testing. A subgroup of participants returned for follow-up cognitive assessments three years later. From rs-fMRI, we studied the connectivity within two distinct Default Mode Network subsystems: left-to-right hippocampus (LHC-RHC) and medial prefrontal cortex-to-posterior cingulate cortex (mPFC-PCC). We used regression analyses to determine whether imaging (LHC-RHC, mPFC-PCC), clinical (CSF Aβ-42:40, disease duration), and demographic (age, sex, education) variables were associated with global and domain-specific cognitive impairments. Results: LHC-RHC (F3,67 = 3.41,p=0.023) and CSF Aβ-42:40 (χ2(3) = 8.77,p = 0.033) were reduced across more cognitively impaired PD groups. Notably, LHC-RHC connectivity was significantly associated with all global and domain-specific cognitive impairments (attention/executive, episodic memory, visuospatial, and language) at the baseline visit. In an exploratory longitudinal analysis, mPFC-PCC was associated with future global and episodic memory impairment. Conclusion: We used biomarker techniques that are readily available in clinical and research facilities to shed light on the pathophysiologic basis of cognitive impairment in PD. Our findings suggest that there is a functionally distinct role of the hippocampal subsystem within the DMN resting state network, and that intrinsic connectivity between the hippocampi is critically related to a broad range of cognitive functions in PD. © 2021 The Authors

Author Keywords
Biomarkers;  CSF;  Default mode network;  Dementia;  Mild cognitive impairment;  Parkinson’s disease/Parkinsonism;  rs-fMRI

Funding details
Jascha Fonden
Novo Nordisk17–12-1981
Sanofi
National Institutes of HealthNIH
Lundbeckfonden
Novo Nordisk FondenNNF
National Institute of Neurological Disorders and StrokeNINDSNS075097, NS062684
Michael J. Fox Foundation for Parkinson’s ResearchMJFF6440, 6440.01
Novo Nordisk
National Institutes of HealthNIH
National Institute on AgingNIAAG047366

Macrophages Respond Rapidly to Ototoxic Injury of Lateral Line Hair Cells but Are Not Required for Hair Cell Regeneration
(2021) Frontiers in Cellular Neuroscience, 14, art. no. 613246, . 

Warchol, M.E.^a b , Schrader, A.^a , Sheets, L.^a c

^a Department of Otolaryngology, Washington University School of Medicine, St. LouisMO, United States
^b Department of Neuroscience, Washington University School of Medicine, St. LouisMO, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. LouisMO, United States

Abstract
The sensory organs of the inner ear contain resident populations of macrophages, which are recruited to sites of cellular injury. Such macrophages are known to phagocytose the debris of dying cells but the full role of macrophages in otic pathology is not understood. Lateral line neuromasts of zebrafish contain hair cells that are nearly identical to those in the inner ear, and the optical clarity of larval zebrafish permits direct imaging of cellular interactions. In this study, we used larval zebrafish to characterize the response of macrophages to ototoxic injury of lateral line hair cells. Macrophages migrated into neuromasts within 20 min of exposure to the ototoxic antibiotic neomycin. The number of macrophages in the near vicinity of injured neuromasts was similar to that observed near uninjured neuromasts, suggesting that this early inflammatory response was mediated by “local” macrophages. Upon entering injured neuromasts, macrophages actively phagocytosed hair cell debris. The injury-evoked migration of macrophages was significantly reduced by inhibition of Src-family kinases. Using chemical-genetic ablation of macrophages before the ototoxic injury, we also examined whether macrophages were essential for the initiation of hair cell regeneration. Results revealed only minor differences in hair cell recovery in macrophage-depleted vs. control fish, suggesting that macrophages are not essential for the regeneration of lateral line hair cells. © Copyright © 2021 Warchol, Schrader and Sheets.

Author Keywords
hair cell;  inner ear;  lateral line;  macrophage;  ototoxicity;  regeneration;  zebrafish

Bright light shows promise in improving sleep, depression, and quality of life in women with breast cancer during chemotherapy: findings of a pilot study
(2021) Chronobiology International, . 

Wu, H.-S.^a , Davis, J.E.^b , Chen, L.^c

^a College of Nursing, Michigan State University, East Lansing, United States
^b College of Nursing, University of South Carolina, Columbia, United States
^c Division of Biostatistics, Washington University School of Medicine, St. Louis, United States

Abstract
Sleep and fatigue-associated symptoms are prominent during chemotherapy. The purpose of this pilot study was to examine bright light effects on sleep disruption, fatigue, daytime sleepiness, depression, and quality of life (QOL) in women with stage I–III breast cancer undergoing chemotherapy. In this 2-group randomized controlled trial (NCT02658708), participants were randomized to receive either blue-green light of 12,000 lux (experimental) or dim red light of 5 lux (control). Light therapy was self-administered using a light visor cap at home. Both groups received 30-minute daily light therapy for 21 consecutive days following the 2nd cycle of chemotherapy. Sleep quality, fatigue, daytime sleepiness, depression, and QOL were self-reported, and nocturnal sleep was monitored by ambulatory polysomnography before the initiation of chemotherapy (baseline) and following the light intervention (posttest). Relative change was assessed at posttest controlling for pretest scores. At posttest, the experimental group self-reported significantly shorter sleep latency than controls (10 vs. 20 min, p = .045) consistent with polysomnography findings (14 vs. 63 min). Polysomnography also revealed longer total sleep time (467 vs. 315 min) and higher sleep efficiency (74% vs. 58%) in experimental vs. controls. Participants receiving bright light experienced a 30% relative decrease in depression, while there was a 24% increase in the controls. The experimental group reported substantially fewer increases in symptom intensity than controls (33% vs. 166%). These findings suggest that bright light likely improved sleep quality and depression and mitigated worsening intensity of symptoms during the first three cycles of chemotherapy. However, features of bright light, e.g., treatment duration, frequency, and timing in relation to chemotherapy treatment require further investigation. © 2021 Taylor & Francis Group, LLC.

Author Keywords
Bright light;  cancer;  depression;  fatigue;  quality of life;  sleep quality