WashU weekly Neuroscience publications: March 21, 2022

Nonmedical use of gabapentin and opioid agonist medications in treatment-seeking individuals with opioid use disorder
(2022) Drug and Alcohol Dependence, 234, art. no. 109400, . 

Ellis, M.S.^a , Buttram, M.E.^b , Kasper, Z.A.^a

^a Washington University in St. Louis, School of Medicine. Department of Psychiatry, St. Louis, MO, United States
^b University of Arkansas, Department of Health, Human Performance & Recreation, Fayetteville, AR, United States

Abstract
Background: As prescriptions for gabapentin have increased in recent years, nonmedical use and risk of adverse outcomes (e.g., hospitalizations and overdose) have been identified, particularly in association with opioids, including opioid agonist medications (OAMs) buprenorphine and methadone. However, there is a lack of systematic, nationwide data assessing the relationship between the nonmedical use of gabapentin and OAMs. Methods: Data were sourced from two nationwide opioid surveillance programs of treatment-seeking individuals with opioid use disorder (OUD). Both programs utilized an identical serial, cross sectional survey of 12,792 new entrants to one of 163 substance use treatment programs for OUD in 46 states and the District of Columbia from January 2019 to December 2020. Results: Past month nonmedical use of gabapentin was endorsed by 9.3% of the sample. Of those using gabapentin nonmedically, 64.1% also endorsed nonmedical use of an OAM, including concomitant use of methadone (35.3%), and buprenorphine (49.0%). Concomitant nonmedical use of gabapentin and OAMs was more prevalent (versus nonmedical use of gabapentin alone) in the Southern region, among those living in a street dwelling, those with chronic pain and healthcare professionals. Conclusions: Nonmedical use of gabapentin in people with OUD appears to frequently coincide with nonmedical use of OAMs. As prescriptions and off-label use of gabapentin increase, provider education should include the risks of concomitant gabapentin and OAM use, particularly amongst buprenorphine prescribers. Future research should investigate motivations (e.g., OUD self-management) for nonmedical use of gabapentin and OAMs within the context of OUD treatment access and retention. © 2022 Elsevier B.V.

Author Keywords
Buprenorphine;  Gabapentin;  Methadone;  Nonmedical use;  Opioid agonist medications;  Opioid use disorder

Resolving and characterizing the incidence of millihertz EEG modulation in critically ill children
(2022) Clinical Neurophysiology, 137, pp. 84-91. 

Loe, M.E.^a b , Khanmohammadi, S.^a , Morrissey, M.J.^c d , Landre, R.^d , Tomko, S.R.^c , Guerriero, R.M.^c , Ching, S.^a

^a Department of Electrical and Systems Engineering, Washington University in St. Louis, United States
^b Medical Scientist Training Program, Washington University School of Medicine, United States
^c Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, United States
^d St. Louis Children’s Hospital, United States

Abstract
Objective: We analyze a slow electrographic pattern, Macroperiodic Oscillations (MOs), in the EEG from a cohort of young critical care patients (n = 43) with continuous EEG monitoring. We construct novel quantitative methods to quantify and understand MOs. Methods: We applied a nonparametric bilevel spectral analysis to identify MOs, a millihertz (0.004–0.01 Hz) modulation of 5–15 Hz activity in two separate ICU patient cohorts (n = 195 total). We also developed a rigorous measure to quantify MOs strength and spatial expression, which was validated against surrogate noise data. Results: Strong or spatially widespread MOs appear in both high clinical suspicion and a general ICU population. In the former, patients with strong or spatially widespread MOs tended to have worse clinical outcomes. Intracranial pressure and heart rate data from one patient provide insight into a potential broader physiological mechanism for MOs. Conclusions: We quantified millihertz EEG modulation (MOs) in cohorts of critically ill pediatric patients. We demonstrated high incidence in two patient populations. In a high suspicion cohort, MOs are associated with poor outcome, suggesting future potential as a diagnostic and prognostic aid. Significance: These results support the existence of EEG dynamics across disparate time-scales and may provide insight into brain injury physiology in young children. © 2022 International Federation of Clinical Neurophysiology

Author Keywords
Brain monitoring;  EEG oscillations;  Pediatric neurology;  quantitative EEG;  Spectral analysis

Funding details
National Science FoundationNSF1,653,589 – SC
Burroughs Wellcome FundBWF
Institute of Clinical and Translational SciencesICTSUL1TR002345 – RMG

Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease
(2022) Neurology(R) Neuroimmunology & Neuroinflammation, 9 (3), . 

Wang, Q.^a , Chen, G.^a , Schindler, S.E.^a , Christensen, J.^a , McKay, N.S.^b , Liu, J.^a , Wang, S.^a , Sun, Z.^a , Hassenstab, J.^a , Su, Y.^a , Flores, S.^a , Hornbeck, R.^a , Cash, L.^a , Cruchaga, C.^a , Fagan, A.M.^a , Tu, Z.^a , Morris, J.C.^a , Mintun, M.A.^a , Wang, Y.^a , Benzinger, T.L.S.^a

^a From the Mallinckrodt Institute of Radiology (Q.W., G.C., J.C., S.F., R.H., Z.T., Y.W., T.L.S.B.), Washington University School of Medicine; Knight Alzheimer Disease Research Center (Q.W., G.C., S.E.S., J.H., L.C., A.M.F., J.C.M., T.L.S.B.), Washington University School of Medicine; Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Washington University School of Medicine; Department of Surgery (J.L.), Washington University School of Medicine; Department of Electrical and System Engineering (S.W., Y.W.), Washington University School of Med-icine; Department of Biomedical Engineering (Z.S., Y.W.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium (Y.S.), Phoenix, AZ; Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Avid Radiopharmaceuticals (M.A.M.), Philadelphia, PA; Department of Obstetrics and Gynecology (Y.W.), Washington University School of Medicine; and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO
^b From the Mallinckrodt Institute of Radiology (Q.W., G.C., J.C., S.F., R.H., Z.T., Y.W., T.L.S.B.), Washington University School of Medicine; Knight Alzheimer Disease Research Center (Q.W., G.C., S.E.S., J.H., L.C., A.M.F., J.C.M., T.L.S.B.), Washington University School of Medicine; Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Washington University School of Medicine; Department of Surgery (J.L.), Washington University School of Medicine; Department of Electrical and System Engineering (S.W., Y.W.), Washington University School of Med-icine; Department of Biomedical Engineering (Z.S., Y.W.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium (Y.S.), Phoenix, AZ; Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Avid Radiopharmaceuticals (M.A.M.), Philadelphia, PA; Department of Obstetrics and Gynecology (Y.W.), Washington University School of Medicine; and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO. wangyong@wustl.edu

Abstract
BACKGROUND AND OBJECTIVES: This study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline. METHODS: Twenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of Aβ42, Aβ42/Aβ40 ratio, tau phosphorylated at position 181 (p-tau181), and total tau (t-tau) were measured. Clinical and cognitive decline were examined with longitudinal CDR and cognitive composite scores (Global and Knight ADRC-Preclinical Alzheimer Cognitive Composite [Knight ADRC-PACC] Score). RESULTS: Participants in the progressor and symptomatic AD groups had significantly elevated [11C]PK11195 standard uptake value ratios (SUVRs) in the hippocampus but not in the precuneus region. In the subcohort with CSF biomarkers (16 of the 24), significant negative correlations between CSF Aβ42 or Aβ42/Aβ40 and [11C]PK11195 SUVR were observed in the hippocampus and precuneus. No correlations were observed between [11C]PK11195 SUVR and CSF p-tau181 or t-tau at baseline in those regions. Higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions predicted longitudinal decline on cognitive tests. DISCUSSION: Microglial activation is increased in individuals with brain amyloidosis and predicts worsening cognition in AD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with AD, higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions was associated with longitudinal decline on cognitive tests. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Magnetic resonance imaging adds prognostic value to EEG after pediatric cardiac arrest
(2022) Resuscitation, 173, pp. 91-100. 

Smith, A.E.^a , Ganninger, A.P.^a , Mian, A.Y.^b , Friess, S.H.^c , Guerriero, R.M.^a , Guilliams, K.P.^a b c

^a Division of Pediatric Neurology, Department of Neurology, Washington University in St. Louis, 660 S. Euclid Avenue, Campus Box 8111, St. Louis, MO 63110-1093, United States
^b Division of Neuroradiology, Mallinckrodt Institute of Radiology, Washington University in St. Louis, 510 South Kingshighway Boulevard, St. Louis, MO 63110-1093, United States
^c Division of Critical Care Medicine, Department of Pediatrics, Washington University in St. Louis, 660 S. Euclid Avenue, Campus Box 8208, St. Louis, MO 63110-1093, United States

Abstract
Aim: To investigate how combined electrographic and radiologic data inform outcomes in children after cardiac arrest. Methods: Retrospective observational study of children admitted to the pediatric intensive care unit (PICU) of a tertiary children’s hospital with diagnosis of cardiac arrest from 2009 to 2016. The first 20 min of electroencephalogram (EEG) background was blindly scored. Presence and location of magnetic resonance imaging (MRI) diffusion-weighted image (DWI) abnormalities were correlated with T2-weighted signal. Outcomes were categorized using Pediatric Cerebral Performance Category (PCPC) scores at hospital discharge, with “poor outcome” reflecting a PCPC score of 4–6. Logistic regression models examined the association of EEG and MRI variables with outcome. Results: 41 children met inclusion criteria and had both post-arrest EEG monitoring within 72 hours after ROSC and brain MRI performed within 8 days. Among the 19 children with poor outcome, 10 children did not survive to discharge. Severely abnormal EEG background (p < 0.0001) and any diffusion restriction (p < 0.0001) were associated with poor outcome. The area under the ROC curve (AUC) for identifying outcome based on EEG background alone was 0.86, which improved to 0.94 with combined EEG and MRI data (p = 0.02). Conclusion: Diffusion abnormalities on MRI within 8 days after ROSC add to the prognostic value of EEG background in children surviving cardiac arrest. © 2022 Elsevier B.V.

Author Keywords
EEG;  MRI;  Outcome;  Pediatric cardiac arrest

Funding details
National Institutes of HealthNIHK23 NS099472, R01 NS097721

Targeting IFN-λ Signaling Promotes Recovery from Central Nervous System Autoimmunity
(2022) Journal of immunology (Baltimore, Md.: 1950), 208 (6), pp. 1341-1351. 

Manivasagam, S.^a , Williams, J.L.^b , Vollmer, L.L.^a , Bollman, B.^c , Bartleson, J.M.^d , Ai, S.^a , Wu, G.F.^c d , Klein, R.S.^c d e

^a Department of Medicine, Washington University in St. Louis, St. Louis, MO
^b Department of Neurosciences, Cleveland Clinic, Cleveland, OH
^c Department of Neurology, Washington University in St. Louis, St. Louis, MO; and
^d Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO
^e Department of Medicine, Washington University in St. Louis, St. Louis, MO;

Abstract
Type III IFNs (IFNLs) are newly discovered cytokines, acting at epithelial and other barriers, that exert immunomodulatory functions in addition to their primary roles in antiviral defense. In this study, we define a role for IFNLs in maintaining autoreactive T cell effector function and limiting recovery in a murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. Genetic or Ab-based neutralization of the IFNL receptor (IFNLR) resulted in lack of disease maintenance during experimental autoimmune encephalomyelitis, with loss of CNS Th1 effector responses and limited axonal injury. Phenotypic effects of IFNLR signaling were traced to increased APC function, with associated increase in T cell production of IFN-γ and GM-CSF. Consistent with this, IFNL levels within lesions of CNS tissues derived from patients with MS were elevated compared with MS normal-appearing white matter. Furthermore, expression of IFNLR was selectively elevated in MS active lesions compared with inactive lesions or normal-appearing white matter. These findings suggest IFNL signaling as a potential therapeutic target to prevent chronic autoimmune neuroinflammation. Copyright © 2022 by The American Association of Immunologists, Inc.

Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
(2022) The Lancet, 399 (10329), pp. 1049-1058. Cited 1 time.

McDonald, C.M.^a , Marbán, E.^b , Hendrix, S.^c , Hogan, N.^c , Ruckdeschel Smith, R.^d , Eagle, M.^e , Finkel, R.S.^f g , Tian, C.^h , Janas, J.ⁱ , Harmelink, M.M.^j , Varadhachary, A.S.^k , Taylor, M.D.^h , Hor, K.N.^l , Mayer, O.H.^m , Henricson, E.K.^a , Furlong, P.ⁿ , Ascheim, D.D.^d , Rogy, S.^d , Williams, P.^d , Marbán, L.^d , Butterfield, R.^o , Connolly, A.^o , Muntoni, F.^o , Joyce, N.C.^o , Evans, M.^o , Abedi, M.^o , Surampudi, P.^o , Jhawar, S.^o , Dayan, J.G.^o , Anthonisen, C.^o , Goude, E.^o , Nicorici, A.^o , Sarwary, O.^o , Prasad, P.^o , Baek, J.^o , Newton, A.^o , Johnson, H.^o , Kusmik, K.^o , Filar, L.^o , Edmondson, A.^o , Rybalsky, I.^o , Chouteau, W.^o , Giordano, A.F.^o , Rodriguez, A.^o , Anderson, K.^o , Wezel, G.^o , Vega, M.^o , Duke, J.^o , Collado, J.^o , Civitello, M.^o , Wells, J.^o , Pyzik, E.^o , Rehborg, R.^o , Brown, M.^o , Van Eyk, J.^o , Rogers, R.G.^o , HOPE-2 Study Group^p

^a University of California Davis School of Medicine, Sacramento, CA, United States
^b Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States
^c Pentara, Millcreek, UT, United States
^d Capricor Therapeutics, Beverly Hills, CA, United States
^e Atom International, Newcastle upon Tyne, United Kingdom
^f Nemours Children’s Hospital, Orlando, FL, United States
^g St Jude Children’s Research Hospital, Memphis, TN, United States
^h Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, United States
ⁱ University of Colorado, Children’s Hospital Colorado, Denver, CO, United States
^j Medical College of Wisconsin, Milwaukee, WI, United States
^k Washington University School of Medicine, St Louis, MO, United States
^l Nationwide Children’s Hospital, Columbus, OH, United States
^m Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, United States
ⁿ Parent Project Muscular Dystrophy, Hackensack, NJ, United States

Abstract
Background: Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy. Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780. Findings: Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7–59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred. Interpretation: CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy. Funding: Capricor Therapeutics. © 2022 Elsevier Ltd

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
Muscular Dystrophy AssociationMDA
Biogen
Parent Project Muscular DystrophyPPMD
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRR
PTC TherapeuticsPTC
Sarepta TherapeuticsSRPT

Effect of Physiologic Point-of-Care Cardiopulmonary Resuscitation Training on Survival With Favorable Neurologic Outcome in Cardiac Arrest in Pediatric ICUs: A Randomized Clinical Trial
(2022) JAMA, 327 (10), pp. 934-945. 

Sutton, R.M.^a , Wolfe, H.A.^a , Reeder, R.W.^b , Ahmed, T.^c , Bishop, R.^d , Bochkoris, M.^e , Burns, C.^f , Diddle, J.W.^g , Federman, M.^h , Fernandez, R.ⁱ , Franzon, D.^j , Frazier, A.H.^k , Friess, S.H.^f , Graham, K.^a , Hehir, D.^a k , Horvat, C.M.^e , Huard, L.L.^h , Landis, W.P.^a , Maa, T.ⁱ , Manga, A.^f , Morgan, R.W.^a , Nadkarni, V.M.^a , Naim, M.Y.^a , Palmer, C.A.^b , Schneiter, C.^d , Sharron, M.P.^g , Siems, A.^g , Srivastava, N.^h , Tabbutt, S.^j , Tilford, B.^c , Viteri, S.^k , Berg, R.A.^a , Bell, M.J.^e g , Carcillo, J.A.^e , Carpenter, T.C.^d , Dean, J.M.^b , Fink, E.L.^e , Hall, M.ⁱ , McQuillen, P.S.^j , Meert, K.L.^c , Mourani, P.M.^d , Notterman, D.^l , Pollack, M.M.^g , Sapru, A.^h , Wessel, D.^g , Yates, A.R.ⁱ , Zuppa, A.F.^a , ICU-RESUS and Eunice Kennedy Shriver National Institute of Child Health^m , Human Development Collaborative Pediatric Critical Care Research Network Investigator Groupsⁿ

^a Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, United States
^b Department of Pediatrics, University of Utah, Salt Lake City, United States
^c Department of Pediatrics, Children’s Hospital of Michigan, Central Michigan University, Detroit, United States
^d Department of Pediatrics, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, United States
^e Department of Critical Care Medicine, UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, United States
^f Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^g Department of Pediatrics, Children’s National Hospital, George Washington University School of Medicine, DCWA
^h Department of Pediatrics, Mattel Children’s Hospital, University of California. Los Angeles
ⁱ Department of Pediatrics, Ohio State University, Nationwide Children’s Hospital, Columbus, United States
^j Department of Pediatrics, Benioff Children’s Hospital, University of California, San Francisco, Mexico
^k Department of Pediatrics, Nemours/Alfred I. duPont Hospital for Children and Thomas Jefferson University, Wilmington, DE, United States
^l Department of Molecular Biology, Princeton University, Princeton, NJ, United States

Abstract
Importance: Approximately 40% of children who experience an in-hospital cardiac arrest survive to hospital discharge. Achieving threshold intra-arrest diastolic blood pressure (BP) targets during cardiopulmonary resuscitation (CPR) and systolic BP targets after the return of circulation may be associated with improved outcomes. Objective: To evaluate the effectiveness of a bundled intervention comprising physiologically focused CPR training at the point of care and structured clinical event debriefings. Design, Setting, and Participants: A parallel, hybrid stepped-wedge, cluster randomized trial (Improving Outcomes from Pediatric Cardiac Arrest-the ICU-Resuscitation Project [ICU-RESUS]) involving 18 pediatric intensive care units (ICUs) from 10 clinical sites in the US. In this hybrid trial, 2 clinical sites were randomized to remain in the intervention group and 2 in the control group for the duration of the study, and 6 were randomized to transition from the control condition to the intervention in a stepped-wedge fashion. The index (first) CPR events of 1129 pediatric ICU patients were included between October 1, 2016, and March 31, 2021, and were followed up to hospital discharge (final follow-up was April 30, 2021). Intervention: During the intervention period (n = 526 patients), a 2-part ICU resuscitation quality improvement bundle was implemented, consisting of CPR training at the point of care on a manikin (48 trainings/unit per month) and structured physiologically focused debriefings of cardiac arrest events (1 debriefing/unit per month). The control period (n = 548 patients) consisted of usual pediatric ICU management of cardiac arrest. Main Outcomes and Measures: The primary outcome was survival to hospital discharge with a favorable neurologic outcome defined as a Pediatric Cerebral Performance Category score of 1 to 3 or no change from baseline (score range, 1 [normal] to 6 [brain death or death]). The secondary outcome was survival to hospital discharge. Results: Among 1389 cardiac arrests experienced by 1276 patients, 1129 index CPR events (median patient age, 0.6 [IQR, 0.2-3.8] years; 499 girls [44%]) were included and 1074 were analyzed in the primary analysis. There was no significant difference in the primary outcome of survival to hospital discharge with favorable neurologic outcomes in the intervention group (53.8%) vs control (52.4%); risk difference (RD), 3.2% (95% CI, -4.6% to 11.4%); adjusted OR, 1.08 (95% CI, 0.76 to 1.53). There was also no significant difference in survival to hospital discharge in the intervention group (58.0%) vs control group (56.8%); RD, 1.6% (95% CI, -6.2% to 9.7%); adjusted OR, 1.03 (95% CI, 0.73 to 1.47). Conclusions and Relevance: In this randomized clinical trial conducted in 18 pediatric intensive care units, a bundled intervention of cardiopulmonary resuscitation training at the point of care and physiologically focused structured debriefing, compared with usual care, did not significantly improve patient survival to hospital discharge with favorable neurologic outcome among pediatric patients who experienced cardiac arrest in the ICU. Trial Registration: ClinicalTrials.gov Identifier: NCT02837497.

Evaluating risk for alcohol use disorder: Polygenic risk scores and family history
(2022) Alcoholism: Clinical and Experimental Research, 46 (3), pp. 374-383. 

Lai, D.^a , Johnson, E.C.^b , Colbert, S.^b , Pandey, G.^c , Chan, G.^d e , Bauer, L.^d , Francis, M.W.^f , Hesselbrock, V.^d , Kamarajan, C.^c , Kramer, J.^e , Kuang, W.^c , Kuo, S.^g , Kuperman, S.^e , Liu, Y.^a , McCutcheon, V.^b , Pang, Z.^h , Plawecki, M.H.ⁱ , Schuckit, M.^j , Tischfield, J.^k , Wetherill, L.^a , Zang, Y.^l , Edenberg, H.J.^a m , Porjesz, B.^c , Agrawal, A.^b , Foroud, T.^a

^a Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^b Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^c Henri Begleiter Neurodynamics Lab, Department of Psychiatry, Downstate Medical Center, State University of New York, Brooklyn, NY, United States
^d Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^e Department of Psychiatry, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, IA, United States
^f The Brown School of Social Work, Washington University School of Medicine, St Louis, MO, United States
^g Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^h Department of Neuroscience and Cell Biology, Child Health Institute of New Jersey, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, United States
ⁱ Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^j Department of Psychiatry, University of California, San Diego Medical School, San Diego, CA, United States
^k Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, United States
^l Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States
^m Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
Background: Early identification of individuals at high risk for alcohol use disorder (AUD) coupled with prompt interventions could reduce the incidence of AUD. In this study, we investigated whether Polygenic Risk Scores (PRS) can be used to evaluate the risk for AUD and AUD severity (as measured by the number of DSM-5 AUD diagnostic criteria met) and compared their performance with a measure of family history of AUD. Methods: We studied individuals of European ancestry from the Collaborative Study on the Genetics of Alcoholism (COGA). DSM-5 diagnostic criteria were available for 7203 individuals, of whom 3451 met criteria for DSM-IV alcohol dependence or DSM-5 AUD and 1616 were alcohol-exposed controls aged ≥21 years with no history of AUD or drug dependence. Further, 4842 individuals had a positive first-degree family history of AUD (FH+), 2722 had an unknown family history (FH?), and 336 had a negative family history (FH−). PRS were derived from a meta-analysis of a genome-wide association study of AUD from the Million Veteran Program and scores from the problem subscale of the Alcohol Use Disorders Identification Test in the UK Biobank. We used mixed models to test the association between PRS and risk for AUD and AUD severity. Results: AUD cases had higher PRS than controls with PRS increasing as the number of DSM-5 diagnostic criteria increased (p-values ≤ 1.85E−05) in the full COGA sample, the FH+ subsample, and the FH? subsample. Individuals in the top decile of PRS had odds ratios (OR) for developing AUD of 1.96 (95% CI: 1.54 to 2.51, p-value = 7.57E−08) and 1.86 (95% CI: 1.35 to 2.56, p-value = 1.32E−04) in the full sample and the FH+ subsample, respectively. These values are comparable to previously reported ORs for a first-degree family history (1.91 to 2.38) estimated from national surveys. PRS were also significantly associated with the DSM-5 AUD diagnostic criterion count in the full sample, the FH+ subsample, and the FH? subsample (p-values ≤6.7E−11). PRS remained significantly associated with AUD and AUD severity after accounting for a family history of AUD (p-values ≤6.8E−10). Conclusions: Both PRS and family history were associated with AUD and AUD severity, indicating that these risk measures assess distinct aspects of liability to AUD traits. © 2022 by the Research Society on Alcoholism

Author Keywords
alcohol use disorders;  DSM-5 alcohol use disorder diagnostic criterion count;  family history of AUD;  polygenic risk scores

Funding details
National Institutes of HealthNIHU10AA008401
National Institute on Drug AbuseNIDAK01DA051759, K02DA32573, MH109532, T32DA015035
National Institute on Alcohol Abuse and AlcoholismNIAAA
Indiana UniversityIU
State University of New YorkSUNY
Washington University in St. LouisWUSTL
Icahn School of Medicine at Mount SinaiISMMS
University of Connecticut
University of California, San DiegoUCSD
University of IowaUI
Virginia Commonwealth UniversityVCU
Rutgers, The State University of New JerseyRU
Howard University

Global Disability Trajectories over the First Decade Following Combat Concussion
(2022) Journal of Head Trauma Rehabilitation, 37 (2), pp. 63-70. 

Donald, C.L.M.^a , Barber, J.^a , Johnson, A.^b , Patterson, J.^a , Temkin, N.^a

^a University of Washington School of Medicine, Seattle, United States
^b Washington University, Saint Louis, MO, United States

Abstract
Objective: To examine global disability trajectories in US military with and without traumatic brain injury (TBI) over the first decade following deployment to identify risk profiles for better intervention stratification, hopefully reducing long-term cost. Setting: Patients and participants were enrolled in combat or directly following medical evacuation at the time of injury and followed up every 6 months for 10 years. Participants: There are 4 main groups (n = 475), 2 primary and 2 exploratory: (1) combat-deployed controls without a history of blast exposure “non-blast- control” (n = 143), (2) concussive blast TBI “‘blast-TBI” (n = 236) (primary), (3) combat-deployed controls with a history of blast exposure “blast-control” (n = 54), and (4) patients sustaining a combat concussion not from blast “non-blast-TBI” (n = 42) (exploratory). Design: Prospective, observational, longitudinal study. Main Measures: Combat concussion, blast exposure, and subsequent head injury exposure over the first decade post-deployment. Global disability measured by the Glasgow Outcome Scale Extended (GOSE). Results: Latent class growth analysis identified 4 main trajectories of global outcome, with service members sustaining combat concussion 37 to 49 times more likely to be in the worse disability trajectories than non-blast-controls (blast-TBI: odds ratio [OR] = 49.33; CI, 19.77-123.11; P <.001; non-blast-TBI: OR = 37.50; CI, 10.01-140.50; P <.001). Even blast-exposed-controls were 5 times more likely to be in these worse disability categories compared with non-blast-controls (OR = 5.00; CI, 1.59-15.99; P =.007). Adjustment for demographic factors and subsequent head injury exposure did not substantially alter these odds ratios. Conclusions: Very high odds of poor long-term outcome trajectory were identified for those who sustained a concussion in combat, were younger at the time of injury, had lower education, and enlisted in the Army above the risk of deployment alone. These findings help identify a risk profile that could be used to target early intervention and screen for poor long-term outcome to aid in reducing the high public health cost and enhance the long-term quality of life for these service members following deployment. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
concussion;  global disability;  long-term outcome;  military;  trajectory analysis;  veteran

Funding details
National Institutes of HealthNIH1R01NS091618

What Can Brinley Plots Tell Us About Cognitive Aging? Exploring Simulated Data and Modified Brinley Plots
(2022) Frontiers in Psychology, 13, art. no. 797583, . 

Nicosia, J.^a , Cohen-Shikora, E.R.^b , Strube, M.J.^b

^a Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
Cognitive aging researchers have been challenged with demonstrating age-related effects above and beyond global slowing ever since Cerella raised this issue in 1990. As the literature has made clear, this has indeed proved to be a difficult task and continues to plague the field. One way that researchers have attempted to test for disproportionate age differences across task conditions is by using Brinley plots, or plotting the mean response latencies of older adults against the mean latencies for younger adults. The simplicity and large proportion of variance accounted for by these models has led to the widespread use of Brinley plots over the years. However, as systematically tested here through eight cases of simulated data, it is clear that the Brinley technique is not well suited to either identify or display the underlying structure of datasets examining age-related differences in attentional control. Some of the problems with conventional Brinley plots can be resolved by using a modified Brinley plot that includes study-specific slopes linking trial types and a no-age-difference reference line. Multilevel models find all of the relevant effects, especially if applied to trial-level data, and have the advantage of incorporating study-level moderators that might account for slope heterogeneity. Ultimately, we encourage fellow cognitive aging researchers to access the code and data for this project on OSF (https://osf.io/zxus8/) and employ the use of multilevel models over Brinley plots. Copyright © 2022 Nicosia, Cohen-Shikora and Strube.

Author Keywords
attention;  Brinley plots;  cognitive aging;  multi-level model;  Stroop

A Digital Mental Health Intervention in an Orthopedic Setting for Patients With Symptoms of Depression and/or Anxiety: Feasibility Prospective Cohort Study
(2022) JMIR Formative Research, 6 (2), art. no. e34889, . 

Leo, A.J.^a , Schuelke, M.J.^b , Hunt, D.M.^c , Metzler, J.P.^c , Miller, J.P.^b , Areán, P.A.^d , Armbrecht, M.A.^c , Cheng, A.L.^c

^a Washington University in St Louis School of Medicine, St Louis, MO, United States
^b Division of Biostatistics, Washington University in St Louis School of Medicine, St Louis, MO, United States
^c Division of Physical Medicine and Rehabilitation, Department of Orthopedic Surgery, Washington University in St Louis School of Medicine, St Louis, MO, United States
^d Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States

Abstract
Background: Symptoms of depression and anxiety commonly coexist with chronic musculoskeletal pain, and when this occurs, standard orthopedic treatment is less effective. However, mental health intervention is not yet a routine part of standard orthopedic treatment, in part because of access-related barriers. Digital mental health intervention is a potential scalable resource that could be feasibly incorporated into orthopedic care. Objective: This study’s primary purpose was to assess the feasibility of introducing a digital mental health intervention (Wysa) in an outpatient orthopedic setting to patients with coexisting symptoms of depression and/or anxiety. The secondary purpose was to perform a preliminary effectiveness analysis of the intervention. Methods: In this single-arm, prospective cohort study, participants included adult patients (18 years and older) who presented to a nonsurgical orthopedic specialist at a single tertiary care academic center for evaluation of a musculoskeletal condition and who self-reported symptoms of depression and/or anxiety (Patient-Reported Outcomes Measurement Information System [PROMIS] Depression and/or Anxiety score ≥55). Face-to-face enrollment was performed by a research coordinator immediately after the participant’s encounter with an orthopedic clinician. Participants were provided 2 months of access to a mobile app called Wysa, which is an established, multicomponent digital mental health intervention that uses chatbot technology and text-based access to human counselors to deliver cognitive behavioral therapy, mindfulness training, and sleep tools, among other features. For this study, Wysa access also included novel, behavioral activation.based features specifically developed for users with chronic pain. Primary feasibility outcomes included the study recruitment rate, retention rate, and engagement rate with Wysa (defined as engagement with a therapeutic Wysa tool at least once during the study period). Secondary effectiveness outcomes were between-group differences in mean longitudinal PROMIS mental and physical health score changes at 2-month follow-up between high and low Wysa users, defined by a median split. Results: The recruitment rate was 29.3% (61/208), retention rate was 84% (51/61), and engagement rate was 72% (44/61). Compared to low users, high users reported greater improvement in PROMIS Anxiety scores (between-group difference -4.2 points, 95% CI -8.1 to -0.2; P=.04) at the 2-month follow-up. Between-group differences in PROMIS Depression (-3.2 points, 95% CI -7.5 to 1.2; P=.15) and Pain Interference scores (-2.3 points, 95% CI -6.3 to 1.7; P=.26) favored high users but did not meet statistical significance. Improvements in PROMIS Physical Function scores were comparable between groups. Conclusions: Delivery of a digital mental health intervention within the context of orthopedic care is feasible and has the potential to improve mental health and pain-related impairment to a clinically meaningful degree. Participants’ engagement rates exceeded industry standards, and additional opportunities to improve recruitment and retention were identified. Further pilot study followed by a definitive, randomized controlled trial is warranted. © 2022 Ashwin J Leo, Matthew J Schuelke, Devyani M Hunt, John P Metzler, J Philip Miller, Patricia A Areán, Melissa A Armbrecht, Abby L Cheng.

Author Keywords
Anxiety;  Chronic pain;  Depression;  Digital health;  Health intervention;  Mental health;  Mobile phone;  Musculoskeletal;  Orthopedic;  Pain management

Funding details
National Institutes of HealthNIHK23AR074520
Doris Duke Charitable FoundationDDCF

COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab
(2022) Neurology and Therapy, . 

Cross, A.H.^a , Delgado, S.^b , Habek, M.^c , Davydovskaya, M.^d , Ward, B.J.^e , Cree, B.A.C.^f , Totolyan, N.^g , Pingili, R.^h , Mancione, L.^h , Hu, X.^h , Sullivan, R.^h , Su, W.^h , Zielman, R.ⁱ , Gupta, A.D.^j , Montalban, X.^k , Winthrop, K.^l

^a Department of Neurology, Washington University, St. Louis, MO, United States
^b University of Miami Miller School of Medicine, Miami, FL, United States
^c University Hospital Center Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
^d Moscow State Public Healthcare InsCity Clinical Hospital 24, Moscow, Russian Federation
^e Infectious Diseases Division, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
^f UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States
^g First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
^h Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
ⁱ Novartis Pharma B.V., Amsterdam, Netherlands
^j Novartis Healthcare Private Limited, Hyderabad, India
^k Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain
^l School of Public Health at Oregon Health and Science University, Portland, OR, United States

Abstract
Introduction: The SARS-CoV-2 pandemic necessitated better understanding of the impact of disease-modifying therapies on COVID-19 outcomes and vaccination. We report characteristics of COVID-19 cases and vaccination status in ofatumumab-treated relapsing multiple sclerosis (RMS) patients. Methods: COVID-19 data analyzed were from the ongoing, open-label, long-term extension phase 3b ALITHIOS study from December 2019 (pandemic start) and post-marketing cases from August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and breakthrough infection were evaluated. Results: As of 25 September 2021, 245 of 1703 patients (14.3%) enrolled in ALITHIOS receiving ofatumumab (median exposure: 2.45 years) reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or moderate (46.5%) severity, but 9% had severe/life-threatening COVID-19. There were 24 serious cases (9.8%) with 23 patients were hospitalized; 22 recovered and 2 died. At study cut-off, 241 patients (98.4%) had recovered or were recovering or had recovered with sequelae and 2 (0.8%) had not recovered. Ofatumumab was temporarily interrupted in 39 (15.9%) patients. Before COVID-19 onset, IgG levels were within the normal range in all COVID-19–affected patients, while IgM was < 0.4 g/l in 23 (9.4%) patients. No patient had a reinfection. Overall, 559 patients were vaccinated (full, 476; partial, 74; unspecified, 9). Breakthrough infection was reported in 1.5% (7/476) patients, and 11 reported COVID-19 after partial vaccination. As of 25 September 2021, the Novartis Safety Database (~ 4713 patient-treatment years) recorded 90 confirmed COVID-19 cases receiving ofatumumab. Most cases were non-serious (n = 80), and ten were serious (1 medically significant, 9 hospitalized, 0 deaths). Among 36 of 90 cases with outcomes reported, 30 recovered and 6 did not recover. Conclusion: COVID-19 in RMS patients on ofatumumab was primarily of mild/moderate severity and non-serious in these observational data. Most recovered from COVID-19 without treatment interruption. Two people died with COVID-19. Breakthrough COVID-19 despite being fully/partially vaccinated was uncommon. © 2022, The Author(s).

Author Keywords
ALITHIOS;  Anti-CD20 therapy;  B-cell therapy;  COVID-19;  Ofatumumab;  Post-marketing;  Relapsing multiple sclerosis;  SARS-CoV-2;  Vaccination

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Multiple Sclerosis SocietyNMSS
Conrad N. Hilton FoundationCNHF
Novartis
Roche
Biogen
Novartis Pharma
TG Therapeutics

Subjective Fatigue in Children With Unaided and Aided Unilateral Hearing Loss
(2022) Laryngoscope, . 

Bakkum, K.H.E.^a , Teunissen, E.M.^a , Janssen, A.M.^a , Lieu, J.E.C.^b , Hol, M.K.S.^a c d

^a Department of Otorhinolaryngology, Radboud University Medical Centre, Nijmegen, Netherlands
^b Department of Otolaryngology—Head and Neck Surgery, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Otorhinolaryngology/Head and Neck Surgery, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
^d Research School of Behavioral and Cognitive Neurosciences, Graduate School of Medical Sciences, University of Groningen, Groningen, Netherlands

Abstract
Objectives: Fatigue is frequently observed in children with chronic diseases and can affect the quality of life (QoL). However, research in children with unilateral hearing loss (UHL) is scarce. Subsequently, no studies investigated the effects of hearing aids on fatigue in children. This study investigates subjective fatigue and hearing-related QoL in children with UHL. Furthermore, it evaluates the influence of hearing aids, subject-specific factors, and respondent-type on subjective fatigue. Study Design: A cross-sectional study was conducted from June 2020 until September 2020 at the department of otorhinolaryngology in a tertiary referral center. Methods: The primary outcome was the difference in subjective fatigue and hearing-related QoL between children with unaided UHL, aided UHL, and normal hearing. Subjective fatigue and hearing-related QoL were measured using the Pediatric Quality of Life Inventory™ Multidimensional Fatigue Scale (PedsQL™-MFS) and Hearing Environments and Reflection on Quality of Life (HEAR-QL™) questionnaires. Results: Along with 36 aided children with UHL, 34 unaided and 36 normal-hearing children were included. Child reports revealed significantly more cognitive fatigue in children with aided UHL than children with normal hearing (median difference 12.5, P =.013). Parents reported more fatigue in children with UHL compared to normal-hearing siblings. Especially children with aided UHL seemed at increased risk for fatigue. Children with UHL scored lower on hearing-related QoL than children with normal hearing. No apparent differences were found in fatigue and QoL between children with unaided and aided UHL. Conclusion: Children with unaided and even aided UHL seem to experience more subjective fatigue and lower hearing-related QoL than children with normal hearing. Prospective longitudinal studies are required to investigate the influence of hearing aids on fatigue and QoL in individual patients. Level of Evidence: Level 3 Laryngoscope, 2021 Laryngoscope, 2022. © 2022 The Authors. The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
bone conduction device;  fatigue;  hearing aid;  quality of life;  Unilateral hearing loss

Funding details
Radboud Universitair Medisch CentrumRUNMC

Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease
(2022) Alzheimer’s and Dementia, . 

Levin, J.^a b c , Vöglein, J.^a b , Quiroz, Y.T.^d e , Bateman, R.J.^f , Ghisays, V.^g , Lopera, F.^e , McDade, E.^f , Reiman, E.^g , Tariot, P.N.^g , Morris, J.C.^f

^a Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^b German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^c Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^d Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, United States
^e Grupo de Neurociencias, Universidad de Antioquia, Antioquia, Colombia
^f Washington University School of Medicine, Saint Louis, MO, United States
^g Banner Alzheimer’s Institute, Phoenix, AZ, United States

Abstract
Objective: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. Background: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. Updated Hypothesis: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. Major Challenges for the Hypothesis: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common “sporadic” late-onset AD. Linkage to Other Major Theories: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others. © 2022 the Alzheimer’s Association

Author Keywords
Alzheimer disease;  amyloid hypothesis;  autosomal dominant Alzheimer disease;  preclinical;  prevention;  therapy

Funding details
R01AG054671
National Institutes of HealthNIHR01NS065667, R1AG046179, U01AG042791‐S1, UF1AG032438
Foundation for the National Institutes of HealthFNIHR01/R56 AG053267
National Institute on AgingNIA
NIH Office of the DirectorODDP5OD019833
Alzheimer’s AssociationAA
Abbott Laboratories
Eli Lilly and Company
Pfizer
Genentech
Novartis
Roche
Massachusetts General HospitalMGH1200‐228010, 1200‐228767
Biogen
BrightFocus FoundationBFF
AbbVie
Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS)
University of RochesterURP01AG003991, P01AG026276, P50AG005681
Janssen Pharmaceuticals
Banner Alzheimer’s Foundation
ACADIA PharmaceuticalsACADIA
GHR FoundationGHR
NOMIS Stiftung

Increased Perceptions of Autonomy Through Choice Fail to Enhance Motor Skill Retention
(2022) Journal of Experimental Psychology: Human Perception and Performance, . 

Germain, L.S.^a , Williams, A.^a , Balbaa, N.^a , Poskus, A.^a , Leshchyshen, O.^a , Lohse, K.R.^b , Carter, M.J.^a

^a Department of Kinesiology, McMaster University, Canada
^b Program in Physical Therapy, Department of Neurology, Washington University School of Medicine, Saint Louis, United States

Abstract
There has been growing research interest in the effects that motivation plays in motor learning, and specifically how autonomy, competence, and social relatedness may directly benefit the learning process. Here, we present a preregistered manipulation of autonomy-support by providing learners with choice during the practice of a speed cup-stacking task. One group was given control over when a video demonstration was provided and the viewing speed. A yoked control group received an identical demonstration schedule, but without choice (as their schedule was matched to a participant with choice). Critically, we addressed a gap in the literature by adding a yoked group who was explicitly told that they were being denied choice and that their schedule was chosen by another participant. We found no statistically significant learning differences between groups, despite finding evidence that providing choice increased perceived autonomy. Equivalence tests further showed that although the groups were not statistically equivalent, the effect size is likely too small to practically study the effects of autonomy-support through choice in most motor learning labs. These findings add to a growing body of research that questions a causal role of autonomy-support on motor learning, and the robustness of the so-called self-controlled learning advantage. © 2022. American Psychological Association

Author Keywords
Motor learning;  Observation;  Preregistered;  Self-controlled

Neighborhood cognitive amenities? A mixed-methods study of intellectually-stimulating places and cognitive function among older Americans
(2021) Wellbeing, Space and Society, 2, art. no. 100040, . 

Finlay, J.^a b , Yu, W.^a c , Clarke, P.^a b , Li, M.^a c , Judd, S.^d , Esposito, M.^a e

^a Social Environment and Health, Survey Research Center, Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, MI 48104, United States
^b Center for Social Epidemiology and Population Health, Department of Epidemiology, School of Public Health, University of Michigan, 1415 Washington Heights, Ann Arbor, MI 48109, United States
^c Survey Methodology Program, Institute for Social Research, University of Michigan, 426 Thompson Street, Ann Arbor, MI 48104, United States
^d School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL 35233, United States
^e Department of Sociology, Washington University of St. Louis, St. Louis, MO 63130, United States

Abstract
Neighborhoods structure health and wellbeing in later life. Local spaces can encourage physically active and socially engaged aging in place, and may also nurture opportunities for cognitively-stimulating creative and complex activities such as reading; playing and listening to music; learning; and engagement in galleries, performing arts, and museums. These activities are associated with better cognitive health outcomes. In this exploratory sequential mixed-methods study, thematic analysis of interviews and ethnographic fieldwork with 125 diverse older adults in the Minneapolis (MN) metropolitan area (mean age 71 years) explored how and where older adults participated in intellectually-stimulating neighborhood activities. Thematic analysis indicated that libraries, higher education campuses, and sites of arts and culture were frequented intellectually-stimulating places, with racial differences in perception and usage. The qualitative findings informed quantitative investigation of associations between these amenities and cognitive function in a large national sample of aging Black and white Americans (n = 21,165, mean age 67 years) in the Reasons for Geographic and Racial Differences in Stroke Study. We used multilevel linear regression models to examine whether living in a neighborhood with higher kernel densities of libraries, higher education campuses, and arts/cultural sites had a net positive effect on cognitive function. Analysis identified statistically significant positive associations between arts/cultural sites and cognitive function, with a significantly larger effect size for white versus Black participants. The study contributes new evidence to the emerging ecological model of cognitive health. It critically considers racial disparities in access to health-promoting neighborhood infrastructure and opportunities to age well in place. © 2021 The Authors

Author Keywords
Aging;  Cognitive function;  Intellectual stimulation;  Mixed-methods;  Neighborhood;  Wellbeing

Funding details
F32 AG064815–01, UL1 TR002240–02
National Institutes of HealthNIH1RF1AG057540–01
U.S. Department of Health and Human ServicesHHS
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDS
Michigan Institute for Clinical and Health ResearchMICHRF32 AG064815