WashU weekly Neuroscience publications: March 7, 2022

Beta-amyloid moderates the relationship between cortical thickness and attentional control in middle- and older-aged adults
(2022) Neurobiology of Aging, 112, pp. 181-190. 

McKay, N.S.^a b , Dincer, A.^a b , Mehrotra, V.^e , Aschenbrenner, A.J.^b c , Balota, D.^b d , Hornbeck, R.C.^a b , Hassenstab, J.^b c d , Morris, J.C.^b c , Benzinger, T.L.S.^a b , Gordon, B.A.^a b d

^a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^b Knight Alzheimer’s Disease Research Center, Washington University in St. LouisMO, United States
^c Department of Neurology, Washington School of Medicine, St. Louis, MO, United States
^d Department of Psychological and Brain Sciences, Washington University in St. LouisMO, United States
^e Case Western School of Medicine, Cleveland, OH, United States

Abstract
Although often unmeasured in studies of cognition, many older adults possess Alzheimer disease (AD) pathologies such as beta-amyloid (Aβ) deposition, despite being asymptomatic. We were interested in examining whether the behavior-structure relationship observed in later life was altered by the presence of preclinical AD pathology. A total of 511 cognitively unimpaired adults completed magnetic resonance imaging and three attentional control tasks; a subset (n = 396) also underwent Aβ-positron emissions tomography. A vertex-wise model was conducted to spatially represent the relationship between cortical thickness and average attentional control accuracy, while moderation analysis examined whether Aβ deposition impacted this relationship. First, we found that reduced cortical thickness in temporal, medial- and lateral-parietal, and dorsolateral prefrontal cortex, predicted worse performance on the attention task composite. Subsequent moderation analyses observed that levels of Aβ significantly influence the relationship between cortical thickness and attentional control. Our results support the hypothesis that preclinical AD, as measured by Aβ deposition, is partially driving what would otherwise be considered general aging in a cognitively normal adult population. © 2022 Elsevier Inc.

Author Keywords
Alzheimer disease;  Amyloid;  Attention;  Cognition;  Control;  Free surfer;  Moderation

Funding details
National Institutes of HealthNIH1S10OD018091-01, 1S10RR022984-01A1, K01AG053474, P01AG003991, P01AG026276, P30 AG066444, P30NS098577, P50AG005681, R01EB009352, U19 AG024904, U19 AG032438
Alzheimer’s AssociationAA
Foundation for Barnes-Jewish HospitalFBJH

Racial and demographic disparities in emergency department utilization for mental health concerns before and during the COVID-19 pandemic
(2022) Psychiatry Research, 310, art. no. 114442, . 

Penner, F.^a b , Rajesh, A.^a c , Kinney, K.L.^a , Mabus, K.L.^a , Barajas, K.G.^a d , McKenna, K.R.^a e , Lim, C.S.^a

^a Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United States
^b Child Study Center, Yale School of Medicine, New Haven, CT, United States
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Psychiatry and Behavioral Medicine, Seattle Children’s Hospital, Seattle, WA, United States
^e VA Palo Alto Health Care System, Palo Alto, CA, United States

Abstract
This study investigated whether emergency department (ED) visits for mental health concerns increased during the COVID-19 pandemic, taking a health disparities lens. ED encounters from the only academic medical center in Mississippi were extracted from March-December 2019 and 2020, totaling 2,842 pediatric (ages 4–17) and 17,887 adult (ages 18–89) patients. Visits were coded based on primary ED diagnosis. For adults, there were fewer depression/anxiety ED visits during the pandemic, not moderated by any demographic factor, but no differences for serious mental illness or alcohol/substance use. For youth, there were significantly fewer ED visits for behavior problems during the pandemic among children in the lower socioeconomic status (SES) category; there were no differences for depression/anxiety. Regardless of year, adults in the lower SES category were more likely to visit the ED for mental health, Black adults were less likely to visit the ED for depression/anxiety or alcohol/substance use, and Black children were less likely to visit the ED for behavioral concerns. Results suggest that access to outpatient and telehealth services remains critical for mental health care during the pandemic and underline the importance of race- and SES-related factors in use of the ED for mental health concerns beyond the pandemic. © 2022 Elsevier B.V.

Author Keywords
Anxiety;  Child behavior problems;  Depression;  Health disparities;  Serious mental illness;  Southeastern United States;  Substance use

Funding details
National Institute of Mental HealthNIMHT32 MH018268

Glutamate in primary afferents is required for itch transmission
(2022) Neuron, 110 (5), pp. 809-823.e5. 

Cui, L.^a , Guo, J.^b , Cranfill, S.L.^a , Gautam, M.^a , Bhattarai, J.^a , Olson, W.^c , Beattie, K.^a , Challis, R.C.^d , Wu, Q.^a , Song, X.^a , Raabe, T.^e , Gradinaru, V.^d , Ma, M.^a , Liu, Q.^b , Luo, W.^a

^a Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^b Department of Anesthesiology, Center for the Study of Itch, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^c Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^d Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States
^e Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States

Abstract
Whether glutamate or itch-selective neurotransmitters are used to confer itch specificity is still under debate. We focused on an itch-selective population of primary afferents expressing MRGPRA3, which highly expresses Vglut2 and the neuropeptide neuromedin B (Nmb), to investigate this question. Optogenetic stimulation of MRGPRA3+ afferents triggers scratching and other itch-related avoidance behaviors. Using a combination of optogenetics, spinal cord slice recordings, Vglut2 conditional knockout mice, and behavior assays, we showed that glutamate is essential for MRGPRA3+ afferents to transmit itch. We further demonstrated that MRGPRA3+ afferents form monosynaptic connections with both NMBR+ and NMBR− neurons and that NMB and glutamate together can enhance the activity of NMBR+ spinal DH neurons. Moreover, Nmb in MRGPRA3+ afferents and NMBR+ DH neurons are required for chloroquine-induced scratching. Together, our results establish a new model in which glutamate is an essential neurotransmitter in primary afferents for itch transmission, whereas NMB signaling enhances its activities. © 2021 Elsevier Inc.

Author Keywords
behavior assays;  glutamate;  high-speed imaging;  itch-selective neurotransmitter;  MRGPRA3+ afferents;  NMB;  optogenetic stimulation;  spinal cord slice recordings;  VGLUT2

Funding details
National Institutes of HealthNIHAI125743, AI163146, EY024704, NS083702, NS094224
National Institute of Neurological Disorders and StrokeNINDS

Longitudinal and cross-sectional validation of the WERCAP screen for assessing psychosis risk and conversion
(2022) Schizophrenia Research, 241, pp. 201-209. 

Mamah, D.^a , Mutiso, V.N.^b , Ndetei, D.M.^b c

^a Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States
^b Africa Mental Health Research and Training Foundation, Nairobi, Kenya
^c Department of Psychiatry, University of Nairobi, Kenya

Abstract
Background: The Washington Early Recognition Center Affectivity and Psychosis (WERCAP) Screen was developed to assess risk for developing psychosis. Its validity has not been investigated in a large population-based study or with longitudinal analyses. Methods: 825 participants, aged 14–25, were recruited from Kenya. Symptoms were assessed using the WERCAP Screen, as experienced over the prior 3-months (3MO), 12-months (12MO) or lifetime (LIF). ROC curve analysis was used to determine the validity of the WERCAP Screen against the Structured Interview of Psychosis-Risk Syndromes. Longitudinal validity was assessed by comparing baseline p-WERCAP scores in psychotic disorder converters and non-converters, and using ROC curve analysis. Relationship of the p-WERCAP was examined against clinical variables. Results: ROC curve analyses against SIPS showed an AUC of 0.83 for 3MO, 0.79 for 12MO and 0.65 for LIF psychosis scores. The optimal cut-point on 3MO was a score of >12 (sens: 0.78; spec: 0.77; ppv: 0.41), and >32 for 12MO (sens: 0.71; spec: 0.74; ppv: 0.24). Baseline 3MO scores (but not LIF scores) were higher in converters compared to high-risk non-converters (p = 0.02). 3MO scores against conversion status had an AUC of 0.75, with an optimal cutoff point of >16 (sens: 1.0; spec: 0.53). All p-WERCAP scores significantly correlated with substance use and stress severity. 12 MO scores were most related to cognitive impairment. Conclusions: The WERCAP Screen is a valid instrument for assessing psychosis severity and conversion risk. It can be used in the community to identify those who may require clinical assessment and care, and for recruitment in psychosis-risk research. © 2022 The Authors

Author Keywords
Kenya;  Psychosis;  Risk;  Stress screen;  Validation;  WERCAP

Funding details
National Institute of Mental HealthNIMHR21 MH095645, R56 MH111300

Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex
(2022) Epilepsy Research, 181, art. no. 106890, . 

Nguyen, L.H.^a b , Leiser, S.C.^c , Song, D.^c , Brunner, D.^d , Roberds, S.L.^d , Wong, M.^e , Bordey, A.^a b

^a Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
^b Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
^c Department of Translational EEG, PsychoGenics, Inc, Paramus, NJ, United States
^d Tuberous Sclerosis Alliance, Silver Spring, MD, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC. © 2022 Elsevier B.V.

Author Keywords
Epilepsy;  MAPK;  MEK inhibitor;  MEK-ERK signaling;  Seizures;  Tuberous sclerosis complex

Funding details
National Institute of Neurological Disorders and StrokeNINDSR01 NS056872, R01 NS086329
American Epilepsy SocietyAES
Tuberous Sclerosis AllianceTSA
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDF32 HD095567

Labor induction with oxytocin in pregnant rats is not associated with oxidative stress in the fetal brain
(2022) Scientific Reports, 12 (1), p. 3143. 

Giri, T.^a , Jiang, J.^a b , Xu, Z.^a c , McCarthy, R.^d , Halabi, C.M.^e , Tycksen, E.^f , Cahill, A.G.^g , England, S.K.^d , Palanisamy, A.^a d

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, USA
^b Department of Anesthesiology, Beijing Chaoyang Hospital, Capital Medical UniversityBeijing, China
^c Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, 63110, USA
^d Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, 63110, USA
^e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
^f Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
^g Department of Women’s Health, Dell Medical School, University of Texas at Austin, TX, Austin, United States

Abstract
Despite the widespread use of oxytocin for induction of labor, mechanistic insights into fetal/neonatal wellbeing are lacking because of the absence of an animal model that recapitulates modern obstetric practice. Here, we create and validate a hi-fidelity pregnant rat model that mirrors labor induction with oxytocin in laboring women. The model consists of an implantable preprogrammed microprocessor-controlled infusion pump that delivers a gradually escalating dose of intravenous oxytocin to induce birth at term gestation. We validated the model with molecular biological experiments on the uterine myometrium and telemetry-supported assessment of changes in intrauterine pressure. Finally, we applied this model to test the hypothesis that labor induction with oxytocin would be associated with oxidative stress in the newborn brain. Analysis of biomarkers of oxidative stress and changes in the expression of associated genes were no different between oxytocin-exposed and saline-treated pups, suggesting that oxytocin-induced labor was not associated with oxidative stress in the developing brain. Collectively, we provide a viable and realistic animal model for labor induction and augmentation with oxytocin that would enable new lines of investigation related to the impact of perinatal oxytocin exposure on the mother-infant dyad. © 2022. The Author(s).

Electrocochleography and cognition are important predictors of speech perception outcomes in noise for cochlear implant recipients
(2022) Scientific Reports, 12 (1), p. 3083. 

Walia, A., Shew, M.A., Kallogjeri, D., Wick, C.C., Durakovic, N., Lefler, S.M., Ortmann, A.J., Herzog, J.A., Buchman, C.A.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St. Louis, 660 S. Euclid Ave, Campus Box 8115, St. Louis, MO, 63110, USA

Abstract
Although significant progress has been made in understanding outcomes following cochlear implantation, predicting performance remains a challenge. Duration of hearing loss, age at implantation, and electrode positioning within the cochlea together explain ~ 25% of the variability in speech-perception scores in quiet using the cochlear implant (CI). Electrocochleography (ECochG) responses, prior to implantation, account for 47% of the variance in the same speech-perception measures. No study to date has explored CI performance in noise, a more realistic measure of natural listening. This study aimed to (1) validate ECochG total response (ECochG-TR) as a predictor of performance in quiet and (2) evaluate whether ECochG-TR explained variability in noise performance. Thirty-five adult CI recipients were enrolled with outcomes assessed at 3-months post-implantation. The results confirm previous studies showing a strong correlation of ECochG-TR with speech-perception in quiet (r = 0.77). ECochG-TR independently explained 34% of the variability in noise performance. Multivariate modeling using ECochG-TR and Montreal Cognitive Assessment (MoCA) scores explained 60% of the variability in speech-perception in noise. Thus, ECochG-TR, a measure of the cochlear substrate prior to implantation, is necessary but not sufficient for explaining performance in noise. Rather, a cognitive measure is also needed to improve prediction of noise performance. © 2022. The Author(s).

Effect of obstructive sleep apnea on glucose metabolism
(2022) European Journal of Endocrinology, 186 (4), pp. 457-467. 

Koh, H.-C.E.^a , van Vliet, S.^a , Cao, C.^a , Patterson, B.W.^a , Reeds, D.N.^a , Laforest, R.^b , Gropler, R.J.^b , Ju, Y.-E.S.^c d , Mittendorfer, B.^a

^a Center for Human Nutrition, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, St. Louis, MO, United States
^c Department of Neurology, St. Louis, MO, United States
^d Hope Center for Neurological Disorders at Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Obstructive sleep apnea (OSA) is prevalent in people with obesity and is a major risk factor for type 2 diabetes (T2D). The effect of OSA on metabolic function and the precise mechanisms (insulin resistance, β-cell dysfunction, or both) responsible for the increased T2D risk in people with OSA are unknown. Design and methods: We used a two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose and palmitate tracer infusions and 18F-fluorodeoxyglucose injection and positron emission tomography to quantify multi-organ insulin action and oral and intravenous tolerance tests to evaluate glucose-stimulated insulin secretion in fifteen people with obesity and OSA and thirteen people with obesity without OSA. Results: OSA was associated with marked insulin resistance of adipose tissue triglyceride lipolysis and glucose uptake into both skeletal muscles and adipose tissue, whereas there was no significant difference between the OSA and control groups in insulin action on endogenous glucose production, basal insulin secretion, and glucose-stimulated insulin secretion during both intravenous and oral glucose tolerance tests. Conclusions: These data demonstrate that OSA is a key determinant of insulin sensitivity in people with obesity and underscore the importance of taking OSA status into account when evaluating metabolic function in people with obesity. These findings may also have important clinical implications because disease progression and the risk of diabetes-related complications vary by T2D subtype (i.e. severe insulin resistance vs insulin deficiency). People with OSA may benefit most from the targeted treatment of peripheral insulin resistance and early screening for complications associated with peripheral insulin resistance.

Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter
(2022) Fluids and Barriers of the CNS, 19 (1), p. 17. 

Garcia-Bonilla, M.^a , Castaneyra-Ruiz, L.^a , Zwick, S.^a , Talcott, M.^a b , Otun, A.^a , Isaacs, A.M.^c , Morales, D.M.^a , Limbrick, D.D., Jr^a , McAllister, J.P., 2nd^a

^a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA
^b Division of Comparative Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA
^c Division of Neurosurgery, Department of Clinical Neurosciences, University of CalgaryAB T2N 2T9, Canada

Abstract
BACKGROUND: Hydrocephalus is a neurological disease with an incidence of 80-125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants. METHODS: Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19-40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF. RESULTS: The expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF. CONCLUSION: The induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation. © 2022. The Author(s).

Author Keywords
Kaolin-induced hydrocephalus;  Neuroinflammation;  Pig model;  Subventricular zone reduction;  Ventriculomegaly;  White matter alteration

Care team and practice-level implementation strategies to optimize pediatric collaborative care: study protocol for a cluster-randomized hybrid type III trial
(2022) Implementation Science: IS, 17 (1), p. 20. 

Kolko, D.J.^a , McGuier, E.A.^a , Turchi, R.^b , Thompson, E.^c , Iyengar, S.^d , Smith, S.N.^e , Hoagwood, K.^f , Liebrecht, C.^g , Bennett, I.M.^h , Powell, B.J.^i j , Kelleher, K.^k l , Silva, M.^m , Kilbourne, A.M.^g n

^a Department of Psychiatry, University of Pittsburgh School of Medicine, PA, Pittsburgh, United States
^b Department of Pediatrics, Drexel University College of Medicine and St. Christopher’s Hospital for Children, PA, Philadelphia, United States
^c PA Medical Home Program, PA Chapter, American Academy of Pediatrics, PA, Media, United States
^d Department of Statistics, University of Pittsburgh, PA, Pittsburgh, United States
^e Department of Health Management & Policy, School of Public Health, University of Michigan, MI, Ann Arbor, United States
^f Department of Child and Adolescent Psychiatry, New York University Langone Health, NY, NY, United States
^g Department of Learning Health Sciences, University of Michigan Medical School, MI, Ann Arbor, United States
^h Departments of Family Medicine and Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
ⁱ Center for Mental Health Services Research, Brown School, Washington University in St. Louis, One Brookings Drive, St. Louis, MO, 63130, USA
^j Division of Infectious Diseases, John T. Milliken Department of Medicine, Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
^k Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
^l Nationwide Children’s Hospital Research Institute, Columbus, OH, USA
^m Allegheny Family Network, PA, Pittsburgh, United States
ⁿ MI, VA Ann Arbor Healthcare System, Ann Arbor, United States

Abstract
BACKGROUND: Implementation facilitation is an effective strategy to support the implementation of evidence-based practices (EBPs), but our understanding of multilevel strategies and the mechanisms of change within the “black box” of implementation facilitation is limited. This implementation trial seeks to disentangle and evaluate the effects of facilitation strategies that separately target the care team and leadership levels on implementation of a collaborative care model in pediatric primary care. Strategies targeting the provider care team (TEAM) should engage team-level mechanisms, and strategies targeting leaders (LEAD) should engage organizational mechanisms. METHODS: We will conduct a hybrid type 3 effectiveness-implementation trial in a 2 × 2 factorial design to evaluate the main and interactive effects of TEAM and LEAD and test for mediation and moderation of effects. Twenty-four pediatric primary care practices will receive standard REP training to implement Doctor-Office Collaborative Care (DOCC) and then be randomized to (1) Standard REP only, (2) TEAM, (3) LEAD, or (4) TEAM + LEAD. Implementation outcomes are DOCC service delivery and change in practice-level care management competencies. Clinical outcomes are child symptom severity and quality of life. DISCUSSION: This statewide trial is one of the first to test the unique and synergistic effects of implementation strategies targeting care teams and practice leadership. It will advance our knowledge of effective care team and practice-level implementation strategies and mechanisms of change. Findings will support efforts to improve common child behavioral health conditions by optimizing scale-up and sustainment of CCMs in a pediatric patient-centered medical home. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04946253 . Registered June 30, 2021. © 2022. The Author(s).

Author Keywords
Collaborative care model;  Facilitation;  Implementation strategies;  Leadership;  Mechanisms;  Team

EML1 is essential for retinal photoreceptor migration and survival
(2022) Scientific Reports, 12 (1), p. 2897. 

Poria, D.^a b , Sun, C.^a , Santeford, A.^a , Kielar, M.^c , Apte, R.S.^a d e , Kisselev, O.G.^f g , Chen, S.^a d , Kefalov, V.J.^a b h

^a Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 S. Euclid Ave, Box 8096, Saint Louis, MO, 63110, USA
^b Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, 2121 Gillespie|837 Health Sciences Rd, Irvine, CA, 92697, USA
^c Unité Facultaire d’anatomie et de morphologie, Lausanne University Hospital, Lausanne, Switzerland
^d Department of Developmental Biology, Washington University in St. Louis School of Medicine, MO, Saint Louis, United States
^e Department of Medicine, Washington University in St. Louis School of Medicine, MO, Saint Louis, United States
^f Department of Ophthalmology, Saint Louis University School of Medicine, MO, Saint Louis, United States
^g Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO, Saint Louis, United States
^h Department of Physiology and Biophysics, University of California, Irvine, CA, USA

Abstract
Calcium regulates the response sensitivity, kinetics and adaptation in photoreceptors. In striped bass cones, this calcium feedback includes direct modulation of the transduction cyclic nucleotide-gated (CNG) channels by the calcium-binding protein CNG-modulin. However, the possible role of EML1, the mammalian homolog of CNG-modulin, in modulating phototransduction in mammalian photoreceptors has not been examined. Here, we used mice expressing mutant Eml1 to investigate its role in the development and function of mouse photoreceptors using immunostaining, in-vivo and ex-vivo retinal recordings, and single-cell suction recordings. We found that the mutation of Eml1 causes significant changes in the mouse retinal structure characterized by mislocalization of rods and cones in the inner retina. Consistent with the fraction of mislocalized photoreceptors, rod and cone-driven retina responses were reduced in the mutants. However, the Eml1 mutation had no effect on the dark-adapted responses of rods in the outer nuclear layer. Notably, we observed no changes in the cone sensitivity in the Eml1 mutant animals, either in darkness or during light adaptation, ruling out a role for EML1 in modulating cone CNG channels. Together, our results suggest that EML1 plays an important role in retina development but does not modulate phototransduction in mammalian rods and cones. © 2022. The Author(s).

Elucidating the molecular mechanisms associated with TARS2-related mitochondrial disease
(2022) Human Molecular Genetics, 31 (4), pp. 523-534. 

Zheng, W.-Q.^a b , Pedersen, S.V.^c , Thompson, K.^d , Bellacchio, E.^e , French, C.E.^f , Munro, B.^g , Pearson, T.S.^h , Vogt, J.ⁱ , Diodato, D.^j , Diemer, T.^k , Ernst, A.^l , Horvath, R.^g , Chitre, M.^m , Ek, J.^c , Wibrand, F.^c , Grange, D.K.ⁿ , Raymond, L.^f , Zhou, X.-L.^a , Taylor, R.W.^d , Ostergaard, E.^c o

^a State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghai 200031, China
^b School of Life Science and Technology, ShanghaiTech UniversityShanghai 201210, China
^c Department of Clinical Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, 2100, Denmark
^d Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, United Kingdom
^e Area di Ricerca Genetica e Malattie Rare, Bambino Gesù Children’s Hospital, IRCCS, Rome, 00165, Italy
^f Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom
^g Department of Clinical Neurosciences, John Van Geest Centre for Brain Repair, School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom
^h Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
ⁱ West Midlands Regional Genetics Service, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham Women’s Hospital, Birmingham, B15 2TG, United Kingdom
^j Neuromuscular and Neurodegenerative Disease Unit, Children Hospital Bambino Gesù, Rome, 00165, Italy
^k Department of Clinical Genetics, Aalborg University Hospital, Aalborg, 9000, Denmark
^l Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, 9000, Denmark
^m Department of Paediatric Neurology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, United Kingdom
ⁿ Department of Pediatrics, Division Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
^o Department of Clinical Medicine, University of Copenhagen, Copenhagen, 2200, Denmark

Abstract
TARS2 encodes human mitochondrial threonyl tRNA-synthetase that is responsible for generating mitochondrial Thr-tRNAThr and clearing mischarged Ser-tRNAThr during mitochondrial translation. Pathogenic variants in TARS2 have hitherto been reported in a pair of siblings and an unrelated patient with an early onset mitochondrial encephalomyopathy and a combined respiratory chain enzyme deficiency in muscle. We here report five additional unrelated patients with TARS2-related mitochondrial diseases, expanding the clinical phenotype to also include epilepsy, dystonia, hyperhidrosis and severe hearing impairment. In addition, we document seven novel TARS2 variants-one nonsense variant and six missense variants-that we demonstrate are pathogenic and causal of the disease presentation based on population frequency, homology modeling and functional studies that show the effects of the pathogenic variants on TARS2 stability and/or function. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dynamics of Oddball Sound Processing: Trial-by-Trial Modeling of ECoG Signals
(2022) Frontiers in Human Neuroscience, 15, art. no. 794654, . 

Lecaignard, F.^a b , Bertrand, R.^a b , Brunner, P.^c d e , Caclin, A.^a b , Schalk, G.^e , Mattout, J.^a b

^a Lyon Neuroscience Research Center, CRNL, INSERM, CNRS, UMR 5292, Lyon, U1028, France
^b University Lyon 1, Lyon, France
^c Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Albany Medical College, Albany, NY, United States
^e National Center for Adaptive Neurotechnologies, Albany, NY, United States

Abstract
Recent computational models of perception conceptualize auditory oddball responses as signatures of a (Bayesian) learning process, in line with the influential view of the mismatch negativity (MMN) as a prediction error signal. Novel MMN experimental paradigms have put an emphasis on neurophysiological effects of manipulating regularity and predictability in sound sequences. This raises the question of the contextual adaptation of the learning process itself, which on the computational side speaks to the mechanisms of gain-modulated (or precision-weighted) prediction error. In this study using electrocorticographic (ECoG) signals, we manipulated the predictability of oddball sound sequences with two objectives: (i) Uncovering the computational process underlying trial-by-trial variations of the cortical responses. The fluctuations between trials, generally ignored by approaches based on averaged evoked responses, should reflect the learning involved. We used a general linear model (GLM) and Bayesian Model Reduction (BMR) to assess the respective contributions of experimental manipulations and learning mechanisms under probabilistic assumptions. (ii) To validate and expand on previous findings regarding the effect of changes in predictability using simultaneous EEG-MEG recordings. Our trial-by-trial analysis revealed only a few stimulus-responsive sensors but the measured effects appear to be consistent over subjects in both time and space. In time, they occur at the typical latency of the MMN (between 100 and 250 ms post-stimulus). In space, we found a dissociation between time-independent effects in more anterior temporal locations and time-dependent (learning) effects in more posterior locations. However, we could not observe any clear and reliable effect of our manipulation of predictability modulation onto the above learning process. Overall, these findings clearly demonstrate the potential of trial-to-trial modeling to unravel perceptual learning processes and their neurophysiological counterparts. Copyright © 2022 Lecaignard, Bertrand, Brunner, Caclin, Schalk and Mattout.

Author Keywords
Bayesian learning;  Bayesian model reduction;  general linear model;  mismatch negativity;  predictive coding;  single-trial analysis

Funding details
2019-ANR-LABX-02
National Institutes of HealthNIHP41-EB018783, P50-MH109429, R01-EB026439, U01-NS108916, U24-NS109103
Army Research OfficeAROW911NF-14-1-0440
Agence Nationale de la RechercheANR

A Real-World Observation of Antipsychotic Effects on Brain Volumes and Intrinsic Brain Activity in Schizophrenia
(2022) Frontiers in Neuroscience, 15, art. no. 749316, . 

Chen, Y.^a b c , Womer, F.Y.^d , Feng, R.^a e , Zhang, X.^b f , Zhang, Y.^g , Duan, J.^a b c , Chang, M.^a e , Yin, Z.^a , Jiang, X.^a , Wei, S.^a , Wei, Y.^a b c , Tang, Y.^a , Wang, F.^a b c

^a Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
^b Early Intervention Unit, Department of Psychiatry, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
^c Department of Radiology, The First Affiliated Hospital of China Medical University, Shenyang, China
^d Department of Psychiatry, Washington University School of Medicine, St. LouisMO, United States
^e School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
^f Nanjing Brain Hospital, Nanjing Medical University, Nanjing, China
^g Functional Brain Imaging Institute, Nanjing Medical University, Nanjing, China

Abstract
Background: The confounding effects of antipsychotics that led to the inconsistencies of neuroimaging findings have long been the barriers to understanding the pathophysiology of schizophrenia (SZ). Although it is widely accepted that antipsychotics can alleviate psychotic symptoms during the early most acute phase, the longer-term effects of antipsychotics on the brain have been unclear. This study aims to look at the susceptibility of different imaging measures to longer-term medicated status through real-world observation. Methods: We compared gray matter volume (GMV) with amplitude of low-frequency fluctuations (ALFFs) in 89 medicated-schizophrenia (med-SZ), 81 unmedicated-schizophrenia (unmed-SZ), and 235 healthy controls (HC), and the differences were explored for relationships between imaging modalities and clinical variables. We also analyzed age-related effects on GMV and ALFF values in the two patient groups (med-SZ and unmed-SZ). Results: Med-SZ demonstrated less GMV in the prefrontal cortex, temporal lobe, cingulate gyri, and left insula than unmed-SZ and HC (p < 0.05, family-wise error corrected). Additionally, GMV loss correlated with psychiatric symptom relief in all SZ. However, medicated status did not influence ALFF values: all SZ showed increased ALFF in the anterior cerebrum and decreased ALFF in posterior visual cortices compared with HC (p < 0.05, family-wise error corrected). Age-related GMV effects were seen in all regions, which showed group-level differences except fusiform gyrus. No significant correlation was found between ALFF values and psychiatric symptoms. Conclusion: GMV loss appeared to be pronounced to longer-term antipsychotics, whereby imbalanced alterations in regional low-frequency fluctuations persisted unaffected by antipsychotic treatment. Our findings may help to understand the disease course of SZ and potentially identify a reliable neuroimaging feature for diagnosis. Copyright © 2022 Chen, Womer, Feng, Zhang, Zhang, Duan, Chang, Yin, Jiang, Wei, Wei, Tang and Wang.

Author Keywords
amplitude of low frequency fluctuations;  antipsychotics;  gray matter volumes;  real-world observation;  schizophrenia

Funding details
LT2017007
3110117059, 3110118055
2015225018
National Natural Science Foundation of ChinaNSFC62176129
National Key Research and Development Program of ChinaNKRDPC2016YFC1306900, 2018YFC1311600
National Science Fund for Distinguished Young Scholars81725005
Liaoning Revitalization Talents Program1808036

Essential Functions of MLL1 and MLL2 in Retinal Development and Cone Cell Maintenance
(2022) Frontiers in Cell and Developmental Biology, 10, art. no. 829536, . 

Sun, C.^a , Zhang, X.^a , Ruzycki, P.A.^a , Chen, S.^a b

^a Department of Ophthalmology and Visual Sciences, St. Louis, MO, United States
^b Department of Developmental Biology, Washington University, St. Louis, MO, United States

Abstract
MLL1 (KMT2A) and MLL2 (KMT2B) are homologous members of the mixed-lineage leukemia (MLL) family of histone methyltransferases involved in epigenomic transcriptional regulation. Their sequence variants have been associated with neurological and psychological disorders, but little is known about their roles and mechanism of action in CNS development. Using mouse retina as a model, we previously reported MLL1’s role in retinal neurogenesis and horizontal cell maintenance. Here we determine roles of MLL2 and MLL1/MLL2 together in retinal development using conditional knockout (CKO) mice. Deleting Mll2 from Chx10+ retinal progenitors resulted in a similar phenotype as Mll1 CKO, but removal of both alleles produced much more severe deficits than each single CKO: 1-month double CKO mutants displayed null light responses in electroretinogram; thin retinal layers, including shorter photoreceptor outer segments with impaired phototransduction gene expression; and reduced numbers of M-cones, horizontal and amacrine neurons, followed by fast retinal degeneration. Despite moderately reduced progenitor cell proliferation at P0, the neurogenic capacity was largely maintained in double CKO mutants. However, upregulated apoptosis and reactive gliosis were detected during postnatal retinal development. Finally, the removal of both MLLs in fated rods produced a normal phenotype, but the CKO in M-cones impaired M-cone function and survival, indicating both cell non-autonomous and autonomous mechanisms. Altogether, our results suggest that MLL1/MLL2 play redundant roles in maintaining specific retinal neurons after cell fate specification and are essential for establishing functional neural networks. Copyright © 2022 Sun, Zhang, Ruzycki and Chen.

Author Keywords
conditional knockout;  functional maintenance;  gene expression;  histone modifications;  MLL1 (KMT2A);  MLL2 (KMT2B);  retinal development

Funding details
National Institutes of HealthNIHEY002687, EY012543
Research to Prevent BlindnessRPB

Isolation of Cardiac and Vascular Smooth Muscle Cells from Adult, Juvenile, Larval and Embryonic Zebrafish for Electrophysiological Studies
(2022) Journal of Visualized Experiments, 2022 (180), art. no. e63225, . 

Singareddy, S.S.^a , McClenaghan, C.^a , Roessler, H.I.^b , Tryon, R.^a , Nichols, C.G.^a

^a Department of Cell Biology and Physiology and Center for the Investigation of Membrane Excitability Diseases, Washington University in St. Louis, United States
^b Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Netherlands

Abstract
Zebrafish have long been used as a model vertebrate organism in cardiovascular research. The technical difficulties of isolating individual cells from the zebrafish cardiovascular tissues have been limiting in studying their electrophysiological properties. Previous methods have been described for dissection of zebrafish hearts and isolation of ventricular cardiac myocytes. However, the isolation of zebrafish atrial and vascular myocytes for electrophysiological characterization was not detailed. This work describes new and modified enzymatic protocols that routinely provide isolated juvenile and adult zebrafish ventricular and atrial cardiomyocytes, as well as vascular smooth muscle (VSM) cells from the bulbous arteriosus, suitable for patch-clamp experiments. There has been no literary evidence of electrophysiological studies on zebrafish cardiovascular tissues isolated at embryonic and larval stages of development. Partial dissociation techniques that allow patch-clamp experiments on individual cells from larval and embryonic hearts are demonstrated. © 2022 JoVE Journal of Visualized Experiments.

Funding details
National Institutes of HealthNIHHL140024, HL150277

Reward Deficiency Syndrome (RDS) Surprisingly Is Evolutionary and Found Everywhere: Is It “Blowin’ in the Wind”?
(2022) Journal of Personalized Medicine, 12 (2), art. no. 321, . 

Blum, K.^{a b c d e} , McLaughlin, T.^f , Bowirrat, A.^g , Modestino, E.J.^h , Baron, D.^a , Gomez, L.L.^c , Ceccanti, M.ⁱ , Braverman, E.R.^c , Thanos, P.K.^j k , Cadet, J.L.^l , Elman, I.^m n , Badgaiyan, R.D.^o p , Jalali, R.^c , Green, R.^c , Simpatico, T.A.^d , Gupta, A.^q , Gold, M.S.^r

^a Division of Addiction Research & Education, Center for Psychiatry, Medicine, & Primary Care (Office of the Provost), Graduate College, Western University of Health Sciences, Pomona, CA 91766, United States
^b Institute of Psychology, ELTE Eötvös Loránd University, Budapest, 1075, Hungary
^c Division of Nutrigenomics, The Kenneth Blum Behavioral Neurogenetic Institute, (Ivitalize, Inc.), Austin, TX 78701, United States
^d Department of Psychiatry, University of Vermont, Burlington, VT 05405, United States
^e Department of Psychiatry, Wright University Boonshoff School of Medicine, Dayton, OH 45324, United States
^f Column Health Clinic, Lawrence, MA 01843, United States
^g Department of Molecular Biology, Adelson School of Medicine, Ariel University, Ariel, 40700, Israel
^h Department of Psychology, Curry College, Milton, MA 02186, United States
ⁱ Alcohol Addiction Program, Latium Region Referral Center, Sapienza University of Rome, Roma, 00185, Italy
^j Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY 14203, United States
^k Department of Psychology, State University of New York at Buffalo, Buffalo, NY 14203, United States
^l Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, United States
^m Center for Pain and the Brain (PAIN Group), Department of Anesthesiology, Critical Care & Pain Medicine, Boston Children’s Hospital, Boston, MA 02115, United States
ⁿ Cambridge Health Alliance, Harvard Medical School, Cambridge, MA 02139, United States
^o Department of Psychiatry, South Texas Veteran Health Care System, Audie L. Murphy Memorial VA Hospital, Long School of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, United States
^p Department of Psychiatry, MT. Sinai School of Medicine, New York, NY 10003, United States
^q Future Biologics, Lawrenceville, GA 30043, United States
^r Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Reward Deficiency Syndrome (RDS) encompasses many mental health disorders, including a wide range of addictions and compulsive and impulsive behaviors. Described as an octopus of behavioral dysfunction, RDS refers to abnormal behavior caused by a breakdown of the cascade of reward in neurotransmission due to genetic and epigenetic influences. The resultant reward neurotransmission deficiencies interfere with the pleasure derived from satisfying powerful human physiological drives. Epigenetic repair may be possible with precision gene-guided therapy using formulations of KB220, a nutraceutical that has demonstrated pro-dopamine regulatory function in animal and human neuroimaging and clinical trials. Recently, large GWAS studies have revealed a significant dopaminergic gene risk polymorphic allele overlap between depressed and schizophrenic cohorts. A large volume of literature has also identified ADHD, PTSD, and spectrum disorders as having the known neurogenetic and psychological underpinnings of RDS. The hypothesis is that the true phenotype is RDS, and behavioral disorders are endophenotypes. Is it logical to wonder if RDS exists everywhere? Although complex, “the answer is blowin’ in the wind,” and rather than intangible, RDS may be foundational in species evolution and survival, with an array of many neurotransmitters and polymorphic loci influencing behavioral functionality. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Dopamine;  Genetic addiction risk severity (GARS) test;  Hypodopaminergia;  Pro-dopamine regulation (KB220)

Funding details
National Institutes of HealthNIHR01NS073884
National Institute on Drug AbuseNIDA
Howard University

Fractality of tics as a quantitative assessment tool for Tourette syndrome
(2022) Journal of the Royal Society, Interface, 19 (187), p. 20210742. 

Beeler, P.^a , Jensen, N.O.^b , Kim, S.^c , Robichaux-Viehoever, A.^d , Schlaggar, B.L.^e f , Greene, D.J.^g , Black, K.J.^c d h i , Chakrabarty, R.K.^a j

^a Center for Aerosol Science and Engineering, Department of Energy, Environmental and Chemical Engineering, Washington University in St Louis, St Louis, MO 63110, USA
^b Computational and Systems Biology Program, Division of Biology and Biomedical Sciences, Washington University in St Louis, St Louis, MO 63110, USA
^c Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63130, USA
^d Department of Neurology, Washington University School of Medicine, St Louis, MO 63130, USA
^e Kennedy Krieger Institute, Baltimore, MD 21205, United States
^f Departments of Neurology and Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
^g Department of Cognitive Science, University of California San Diego, La Jolla, CA, 92093, United States
^h Department of Radiology, Washington University School of Medicine, St Louis, MO 63130, USA
ⁱ Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63130, USA
^j Institute for Public Health, Washington University in St Louis, St Louis, MO 63110, USA

Abstract
Tics manifest as brief, purposeless and unintentional movements or noises that, for many individuals, can be suppressed temporarily with effort. Previous work has hypothesized that the chaotic temporal nature of tics could possess an inherent fractality, that is, have neighbour-to-neighbour correlation at all levels of timescale. However, demonstrating this phenomenon has eluded researchers for more than two decades, primarily because of the challenges associated with estimating the scale-invariant, power law exponent-called the fractal dimension Df-from fractional Brownian noise. Here, we confirm this hypothesis and establish the fractality of tics by examining two tic time series datasets collected 6-12 months apart in children with tics, using random walk models and directional statistics. We find that Df is correlated with tic severity as measured by the YGTTS total tic score, and that Df is a sensitive parameter in examining the effect of several tic suppression conditions on the tic time series. Our findings pave the way for using the fractal nature of tics as a robust quantitative tool for estimating tic severity and treatment effectiveness, as well as a possible marker for differentiating typical from functional tics.

Author Keywords
fractal;  tics;  Tourette syndrome;  ‌provisional tic disorder

Validity evidence for an instrument for cognitive load for virtual didactic sessions
(2022) AEM Education and Training, 6 (1), art. no. e10718, . 

Hickam, G.^a , Jordan, J.^b , Haas, M.R.C.^c , Wagner, J.^d , Manthey, D.^e , John Cico, S.^f , Wolff, M.^g , Santen, S.A.^h

^a Medical Education Fellow, Clinical Instructor, Department of Emergency Medicine, Virginia Commonwealth University, Richmond, VA, United States
^b of Clinical Emergency Medicine, of Residency Training Program, Vice-Chair, Acute Care College, Department of Emergency Medicine, David Geffen School of Medicine at UCLA, Ronald Reagan UCLA Medical Center, Los Angeles, CA, United States
^c Assistant Residency Director, Instructor, Department of Emergency Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
^d Residency Program Director, of Emergency Medicine, Washington University in St. Louis School of Medicine, Saint Louis, MO, United States
^e of Emergency Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States
^f Assistant Dean for Graduate Medical Education, of Clinical Emergency Medicine & Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
^g of Emergency Medicine and Pediatrics, University of Michigan, Ann Arbor, MI, United States
^h Senior Associate Dean, Assessment, Evaluation, and Scholarship and, Emergency Medicine, Virginia Commonwealth University School of Medicine, of Emergency Medicine and Medical Education, University of Cincinnati College of Medicine, Cincinnati, OH, United States

Abstract
Background: COVID necessitated the shift to virtual resident instruction. The challenge of learning via virtual modalities has the potential to increase cognitive load. It is important for educators to reduce cognitive load to optimize learning, yet there are few available tools to measure cognitive load. The objective of this study is to identify and provide validity evidence following Messicks’ framework for an instrument to evaluate cognitive load in virtual emergency medicine didactic sessions. Methods: This study followed Messicks’ framework for validity including content, response process, internal structure, and relationship to other variables. Content validity evidence included: (1) engagement of reference librarian and literature review of existing instruments; (2) engagement of experts in cognitive load, and relevant stakeholders to review the literature and choose an instrument appropriate to measure cognitive load in EM didactic presentations. Response process validity was gathered using the format and anchors of instruments with previous validity evidence and piloting amongst the author group. A lecture was provided by one faculty to four residency programs via ZoomTM. Afterwards, residents completed the cognitive load instrument. Descriptive statistics were collected; Cronbach’s alpha assessed internal consistency of the instrument; and correlation for relationship to other variables (quality of lecture). Results: The 10-item Leppink Cognitive Load instrument was selected with attention to content and response process validity evidence. Internal structure of the instrument was good (Cronbach’s alpha = 0.80). Subscales performed well-intrinsic load (α = 0.96, excellent), extrinsic load (α = 0.89, good), and germane load (α = 0.97, excellent). Five of the items were correlated with overall quality of lecture (p &lt; 0.05). Conclusions: The 10-item Cognitive Load instrument demonstrated good validity evidence to measure cognitive load and the subdomains of intrinsic, extraneous, and germane load. This instrument can be used to provide feedback to presenters to improve the cognitive load of their presentations. © 2021 Society for Academic Emergency Medicine.

Funding details
National Center for Advancing Translational SciencesNCATS
American Medical AssociationAMAUL1TR002649

The Association Between Patterns of Social Engagement and Conversion From Mild Cognitive Impairment to Dementia: Evidence From the Health and Retirement Study
(2022) Alzheimer Disease and Associated Disorders, 36 (1), pp. 7-14. 

Amano, T.^a , Park, S.^b , Morrow-Howell, N.^b , Carpenter, B.^c

^a Department of Social Work, School of Arts and Sciences, Rutgers University-Newark
^b Brown School
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO

Abstract
OBJECTIVES: This study examined the association between patterns of social engagement and conversion from cognitive impairment, no dementia (CIND) to dementia. It also tested whether social engagement is associated with conversion independently from physical and cognitive engagements. METHOD: Data from 2 waves (2010 and 2014) of the Health and Retirement Study (HRS) were used. The sample consisted of 1227 people who had CIND in 2010. To identify the heterogeneity of social engagement, latent class analysis was utilized. Multinomial logistic regression analysis was utilized to investigate the association between patterns of social engagement and probability of conversion to dementia and death or dropout. RESULTS: The result showed that patterns of social engagement that represent higher level and more variety of social engagement were associated with lower probabilities of conversion to dementia in 4 years but not with probabilities of death or dropout. The relationship held after controlling for physical and cognitive engagements. DISCUSSION: Findings implied that promoting social engagement may be protective against developing dementia even for the high-risk group of people with CIND. Future studies should investigate the mechanism behind the relationship between patterns of social engagement and lower probabilities of conversion to dementia. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.

Racial differences in longitudinal Alzheimer’s disease biomarkers among cognitively normal adults
(2022) Alzheimer’s and Dementia, . 

Xiong, C.^a b , Luo, J.^a c d , Schindler, S.E.^b e , Fagan, A.M.^b e , Benzinger, T.^b f , Hassenstab, J.^b e , Balls-Berry, J.E.^b e , Agboola, F.^a b , Grant, E.^a b , Moulder, K.L.^b e , Morris, J.C.^b e g

^a Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^g Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Longitudinal changes in Alzheimer’s disease (AD) biomarkers, including cerebrospinal fluid (CSF) analytes, amyloid uptakes from positron emission tomography (PET), structural outcomes from magnetic resonance imaging (MRI), and cognition, have not been compared between Blacks and Whites. Methods: A total of 179 Blacks and 1180 Whites who were cognitively normal at baseline and had longitudinal data from at least one biomarker modality were analyzed for the annual rates of change. Results: CSF amyloid beta (Aβ)42/Aβ40 declined more slowly (P =.0390), and amyloid (PET) accumulated more slowly (P =.0157), in Blacks than Whites. CSF Aβ42 changed in opposite directions over time between Blacks and Whites (P =.0039). The annual increase in CSF total tau and phosphorylated tau181 for Blacks was about half of that for Whites. Discussion: Longitudinal racial differences in amyloid biomarkers are observed. It will be important to comprehensively and prospectively examine the effects of apolipoprotein E genotype and sociocultural factors on these differences. © 2022 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  cerebrospinal fluid biomarkers;  imaging biomarkers;  longitudinal;  racial difference

Funding details
National Institutes of HealthNIH
National Institute on AgingNIAP01 AG003991, P01AG026276, P30AG066444, R01 AG053550, R01 AG067505
Biogen

The complex relationship between depression and progression to incident cognitive impairment across race and ethnicity
(2022) Alzheimer’s and Dementia, . 

Babulal, G.M.^a b c f , Zhu, Y.^d e , Roe, C.M.^a , Hudson, D.L.^e f , Williams, M.M.ⁱ , Murphy, S.A.^a , Doherty, J.^a , Johnson, A.M.^h , Trani, J.-F.^e f g

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
^c Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, MO, United States
^d School of Social Work, Adelphi University, New York, United States
^e Brown School, Washington University in St. Louis, St. Louis, MO, United States
^f Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
^g Centre for Social Development in Africa, University of Johannesburg, Johannesburg, South Africa
^h Center for Clinical Studies, Washington University in St. Louis, Saint Louis, MO, United States
ⁱ New Horizons Living, St. Louis, MO, United States

Abstract
Introduction: We examined baseline differences in depression and antidepressant use among cognitively normal older adults in five ethnoracial groups and assessed whether depression predicted a faster progression to incident cognitive impairment across groups. Methods: Data from the National Alzheimer’s Coordinating Center (n = 8168) were used to examine differences between non-Hispanic Whites (nHW), African Americans (AA), Hispanics, Asians, and American Indian and Alaskan Natives in cross-sectional and longitudinal models. Results: AA had a lower risk of depression compared to nHW at baseline. No statistical interactions were noted between ethnoracial groups and depression. However, depression independently predicted a faster progression to incident cognitive impairment. Hispanics and Asian participants had a higher hazard for progression compared to nHW. Discussion: Previously established risk factors between depression and dementia were not found among AA and nHW participants. The relationship between depression and ethnoracial groups is complex and suggests differential effects on progression from cognitive normality to impairment. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  cognitive impairment;  depression;  disparities;  ethnicity;  race

Funding details
R01AG056466, R01AG067428, R01AG074302
National Institutes of HealthNIH
National Institute on AgingNIAR01AG068183

Effect of interventions on activity and participation outcomes for adults with brain injury: a scoping review
(2022) Brain Injury, . 

Kersey, J.^a , Hammel, J.^b , Baum, C.^c , Huebert, K.^a , Malagari, E.^a , Terhorst, L.^a , McCue, M.^d , Skidmore, E.R.^a

^a Department of Occupational Therapy, University of Pittsburgh, School of Health and Rehabilitation Science, Pittsburgh, PA, United States
^b Department of Occupational Therapy, University of Illinois at Chicago, Chicago, IL, United States
^c Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Rehabilitation Science and Technology, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Objective: To characterize the intervention elements associated with improvements in activity and participation outcomes for adults with brain injury. Data Sources: PubMed and PsycINFO/Ovid. Study Selection: We included RCTs that examined interventions for adults with acquired brain injury with an activity or participation outcome measure. Data Extraction: We classified intervention elements and extracted effect sizes. We examined patterns of effect sizes associated with each intervention element based on time of follow-up and level of outcome (home versus community). Data Synthesis: Thirty-nine articles were included. Outcomes focused on the performance of home and community activities. There was wide variation in effect sizes across all intervention elements, as well as by time and by outcome level (home versus community). Metacognitive interventions and daily life skills interventions showed the greatest promise for improving performance of home and community activities. Additionally, cognitive training interventions may play a role in improving home activity performance and social skills training interventions may play a role in community activity performance. Physical activity interventions showed the least promise for improving home and community activity performance. Conclusion: This study highlights the importance of interventions that incorporate explicit strategies and task-specific training, rather than only addressing specific injury-related impairments. © 2022 Taylor & Francis Group, LLC.

Author Keywords
Brain injury;  intervention;  Rehabilitation;  review

The dual-process perspective and the benefits of retrieval practice in younger and older adults
(2022) Memory, . 

Shaffer, R.A.^a , McDermott, K.B.^a b

^a Department of Psychological Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
The testing effect is often considered a recollection-related phenomenon. However, recent work has observed a benefit of testing to both recollection and familiarity on immediate and delayed final tests. Further, although aging populations show marked declines in recollection, older and younger adults often benefit similarly from testing. This finding suggests that the testing effect in older adults may function via relatively preserved familiarity and lends further support to the hypothesis that the testing effect does not function solely via recollection-related processes. The current study builds on this work to better understand the mechanisms from the dual-process perspective that underlie the testing effect in both younger and older adults. To this end, younger (18–22 year old) and older (65–82 year old) adults studied words, took cued-recall tests on half of the words, and took a final Remember-Know recognition test on all words immediately or after a 1-day delay. At both delays, older and younger adults exhibited a testing effect in both recollection and familiarity, although the magnitude of the testing effect in recollection was reduced for older relative to younger adults. Implications for theories of the testing effect and its application in older adult populations are explored. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
aging;  Dual-process;  familiarity;  recollection;  retrieval practice

Decoupling of regional neural activity and inter-regional functional connectivity in Alzheimer’s disease: a simultaneous PET/MR study
(2022) European Journal of Nuclear Medicine and Molecular Imaging, . 

Maleki Balajoo, S.^a b c , Rahmani, F.^d , Khosrowabadi, R.^e , Meng, C.^f , Eickhoff, S.B.^b c , Grimmer, T.^g , Zarei, M.^a h i , Drzezga, A.^j k l , Sorg, C.^g m n , Tahmasian, M.^a b c

^a Institute of Medical Science and Technology, Shahid Beheshti University, Tehran, Iran
^b Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
^c Institute of Neuroscience and Medicine, Brain & Behaviour (INM-7), Research Centre Jülich, Jülich, Germany
^d Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Institute for Cognitive and Brain Sciences, Shahid Beheshti University, Tehran, Iran
^f The Clinical Hospital of Chengdu Brain Science Institute, MOE Key Laboratory for Neuroinformation, Center for Information in Medicine, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, 611731, China
^g Department of Psychiatry and Psychotherapy, Klinikum Rechts Der Isar, Technical University of Munich, Munich, Germany
^h Department of Neurology, Odense University Hospital, Odense, Denmark
ⁱ Department of Clinical Research, University of Southern Denmark, Odense, Denmark
^j Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
^k German Center for Neurodegenerative Diseases (DZNE), Bonn-Cologne, Germany
^l Institute of Neuroscience and Medicine (INM-2), Molecular Organization of the Brain, Forschungszentrum Jülich, Jülich, Germany
^m Department of Neuroradiology, Klinikum Rechts Der Isar, Technische Universität München, Munich, Germany
ⁿ Klinikum Rechts Der Isar, TUM-Neuroimaging Center (TUM-NIC), TechnischeUniversitätMünchen, Munich, Germany

Abstract
Purpose: Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are characterized by both aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). However, the effect of AD/MCI on the coupling between regional neural activity (measured by regional fluorodeoxyglucose imaging (rFDG)) and inter-regional FC (measured by resting-state functional magnetic resonance imaging (rs-fMRI)) is poorly understood. Methods: We scanned 19 patients with MCI, 33 patients with AD, and 26 healthy individuals by simultaneous FDG-PET/rs-fMRI and assessed rFDG and inter-regional FC metrics (i.e., clustering coefficient and degree centrality). Next, we examined the potential moderating effect of disease status (MCI or AD) on the link between rFDG and inter-regional FC metrics using hierarchical moderated multiple regression analysis. We also tested this effect by considering interaction between disease status and inter-regional FC metrics, as well as interaction between disease status and rFDG. Results: Our findings revealed that both rFDG and inter-regional FC metrics were disrupted in MCI and AD. Moreover, AD altered the relationship between rFDG and inter-regional FC metrics. In particular, we found that AD moderated the effect of inter-regional FC metrics of the caudate, parahippocampal gyrus, angular gyrus, supramarginal gyrus, frontal pole, inferior temporal gyrus, middle frontal, lateral occipital, supramarginal gyrus, precuneus, and thalamus on predicting their rFDG. On the other hand, AD moderated the effect of rFDG of the parietal operculum on predicting its inter-regional FC metric. Conclusion: Our findings demonstrated that AD decoupled the link between regional neural activity and functional segregation and global connectivity across particular brain regions. © 2022, The Author(s).

Author Keywords
Alzheimer’s disease;  Functional connectivity;  Graph analysis;  Mild cognitive impairment;  Neural activity;  PET/MR

The Worldwide Alzheimer’s Disease Neuroimaging Initiative: ADNI-3 updates and global perspectives
(2021) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 7 (1), art. no. e12226, . 

Weber, C.J.^a , Carrillo, M.C.^a , Jagust, W.^b , Jack, C.R., Jr.^c , Shaw, L.M.^d , Trojanowski, J.Q.^e , Saykin, A.J.^f , Beckett, L.A.^g , Sur, C.^h , Rao, N.P.ⁱ , Mendez, P.C.^j , Black, S.E.^k , Li, K.^l , Iwatsubo, T.^m , Chang, C.-C.ⁿ , Sosa, A.L.^o , Rowe, C.C.^p , Perrin, R.J.^q , Morris, J.C.^r , Healan, A.M.B.^s , Hall, S.E.^a , Weiner, M.W.^t

^a Alzheimer’s Association, Chicago, IL, United States
^b School of Public Health and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, United States
^c Department of Radiology, Mayo Clinic, Rochester, MN, United States
^d Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^e Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Institute on Aging, Perelman School of Medicine, Alzheimer’s Disease Core Center, Perelman School of Medicine, Udall Parkinson’s Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Department of Radiology and Imaging Sciences and the Indiana Alzheimer’s Disease Research Center, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^g Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, United States
^h Merck Research Laboratories, Merck, Kenilworth, NJ, United States
ⁱ Department of Psychiatry, National Institute of Mental Health and Neurosciences, Karnataka, Bengaluru, India
^j Centro de Memoria, FLENI, Montañeses, 2325 (C1428AQK), Bs As, Buenos Aires, Argentina
^k Department of Medicine (Neurology), Hurvitz Brain Sciences Program, Canadian Partnership for Stroke Recovery, and LC Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
^l Department of Radiology, Xuanwu Hospital of Capital Medical University, Beijing, China
^m Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
ⁿ Department of General Neurology and Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
^o National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
^p Department of Molecular Imaging and Therapy, Austin Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
^q Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Pathology and Immunology, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^r Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^s Independent Science Writer and Editor, Nashville, TN, United States
^t Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, Department of Radiology, Department of Medicine, Department of Psychiatry, Department of Neurology, University of California, San Francisco, CA, United States

Abstract
The Worldwide Alzheimer’s Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer’s disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI-1, ADNI-GO, ADNI-2, and ADNI-3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW-ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer’s Association convened WW-ADNI researchers who shared updates from ADNI-3 and their vision for ADNI-4. © 2021 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  amyloid;  biomarkers;  cerebrospinal fluid;  cognitive impairment;  MRI;  neuroimaging;  PET;  Tau

Funding details
005441
U24 AG021886
National Institutes of HealthNIH
Mayo Clinic
Roche
Biogen
AbbVie
Alzheimer’s Disease Research Center, Emory UniversityADRCP30AG010124
Alzheimer’s Disease Neuroimaging InitiativeADNIP30 AG010133, R01 AG019771, R01 AG057739, R01 AG068193, R01 LM013463, U01 AG024904, U01 AG068057
Campbell Foundation
Cosmetic Surgery FoundationCSFU19AG024904
GHR FoundationGHR
Canadian Institutes of Health ResearchIRSC112246, 142381, 159910
National Health and Medical Research CouncilNHMRC
Eisai