Pannexin-1 channel inhibition alleviates opioid withdrawal in rodents by modulating locus coeruleus to spinal cord circuitry
(2024) Nature Communications, 15 (1), art. no. 6264, .
Kwok, C.H.T.a b , Harding, E.K.a b c , Burma, N.E.a b , Markovic, T.d , Massaly, N.d e , van den Hoogen, N.J.a b , Stokes-Heck, S.a b , Gambeta, E.c , Komarek, K.a b , Yoon, H.J.d , Navis, K.E.f , McAllister, B.B.a b , Canet-Pons, J.a b , Fan, C.a b , Dalgarno, R.a b , Gorobets, E.f , Papatzimas, J.W.f , Zhang, Z.c , Kohro, Y.a b , Anderson, C.L.g , Thompson, R.J.g , Derksen, D.J.f , Morón, J.A.d , Zamponi, G.W.c , Trang, T.a b
a Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
b Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
c Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
d Department of Anesthesiology, Washington University School of Medicine, Washington University Pain Center, St. Louis, MO, United States
e Department of Anesthesiology & amp; Perioperative Medicine, University of California Los Angeles, Los Angeles, CA, United States
f Department of Chemistry, University of Calgary, Calgary, AB, Canada
g Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
Abstract
Opioid withdrawal is a liability of chronic opioid use and misuse, impacting people who use prescription or illicit opioids. Hyperactive autonomic output underlies many of the aversive withdrawal symptoms that make it difficult to discontinue chronic opioid use. The locus coeruleus (LC) is an important autonomic centre within the brain with a poorly defined role in opioid withdrawal. We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal. Within the LC, we found that spinally projecting tyrosine hydroxylase (TH)-positive neurons (LCspinal) are hyperexcitable during morphine withdrawal, elevating cerebrospinal fluid (CSF) levels of norepinephrine. Pharmacological and chemogenetic silencing of LCspinal neurons or genetic ablation of Panx1 in microglia blunted CSF NE release, reduced LC neuron hyperexcitability, and concomitantly decreased opioid withdrawal behaviours in mice. Using probenecid as an initial lead compound, we designed a compound (EG-2184) with greater potency in blocking Panx1. Treatment with EG-2184 significantly reduced both the physical signs and conditioned place aversion caused by opioid withdrawal in mice, as well as suppressed cue-induced reinstatement of opioid seeking in rats. Together, these findings demonstrate that microglial Panx1 channels modulate LC noradrenergic circuitry during opioid withdrawal and reinstatement. Blocking Panx1 to dampen LC hyperexcitability may therefore provide a therapeutic strategy for alleviating the physical and aversive components of opioid withdrawal. © The Author(s) 2024.
Funding details
National Institutes of HealthNIH
Hotchkiss Brain InstituteHBI
Campus Alberta NeuroscienceCAN
Alberta InnovatesAI
Louise and Alan Edwards Foundation
R01-DA041781, R01-DA045463, R01-DA042499, R21-DA055057
Natural Sciences and Engineering Research Council of CanadaNSERCRGPIN06289-2019
Natural Sciences and Engineering Research Council of CanadaNSERC
Canada Research ChairsRGPIN-2017-04117
Canada Research Chairs
Canadian Institutes of Health ResearchCIHRPJ8-169697, PJT-173553
Canadian Institutes of Health ResearchCIHR
Document Type: Article
Publication Stage: Final
Source: Scopus
Distinct Mindfulness States Produce Dissociable Effects on Neural Markers of Emotion Processing: Evidence From the Late Positive Potential
(2024) Biological Psychiatry Global Open Science, 4 (5), art. no. 100357, .
Lin, Y.a , White, M.L.a , Wu, D.a , Viravan, N.b , Braver, T.S.a
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
b Department of Psychiatry, Faculty of Medicine Siriraj Hospital, Mahidol University, Thailand, Bangkok, Thailand
Abstract
Background: Mindfulness has long been theorized to benefit emotion regulation, but despite the ubiquity of the claim, there is little empirical evidence demonstrating how mindfulness modulates the neurophysiology of emotion processing. The current study aimed to fill this gap in knowledge by leveraging a novel research approach capable of discretizing mindfulness into distinct states of open monitoring (OM) and focused attention (FA) to distinguish their influence on multimodal subjective and objective measures of emotion processing. Methods: Utilizing a fully within-participant picture viewing state induction protocol (N = 30), we compared the effects of OM and FA, rigorously contrasted against an active control, on the visually evoked late positive potential (LPP), a neural index of motivated attention. Bayesian mixed modeling was used to distinguish OM versus FA effects on the early and late sustained LPP while evaluating the influence of subjective arousal ratings as a within-participant moderator of the state inductions. Results: When negative picture trials were retrospectively rated as more subjectively arousing, the OM induction reduced the late sustained LPP response, whereas the FA induction enhanced the LPP. Conclusions: Acute manipulation of OM and FA states may reduce and enhance motivated attention to aversive stimuli during conditions of high subjective arousal, respectively. Functional distinctions between different mindfulness states on emotion processing may be most dissociable after accounting for within-participant variability in how stimuli are appraised. These results support the future potential of the state induction protocol for parsing the neural affective mechanisms that underlie mindfulness training programs and interventions. © 2024 The Authors
Author Keywords
Arousal; EEG; Emotion; ERP; Late positive potential; Mindfulness
Funding details
National Institutes of HealthNIH
National Institute on AgingNIA
McDonnell Center for Systems Neuroscience
F32-AG069499
Document Type: Article
Publication Stage: Final
Source: Scopus
Generation of a gene-corrected human isogenic iPSC line from an Alzheimer’s disease iPSC line carrying the PSEN1 H163R mutation
(2024) Stem Cell Research, 79, art. no. 103495, .
Hernández, D.a f , Morgan Schlicht, S.a , Elli Clarke, J.a , Daniszewski, M.a , Karch, C.M.b , Adams, S.e , Allegri, R.e , Araki, A.e , Barthelemy, N.e , Bateman, R.e , Bechara, J.e , Benzinger, T.e , Berman, S.e , Bodge, C.e , Brandon, S.e , (Bill) Brooks, W.e , Brosch, J.e , Buck, J.e , Buckles, V.e , Carter, K.e , Cash, L.e , Chen, C.e , Chhatwal, J.e , Chrem Mendez, P.e , Chua, J.e , Chui, H.e , Courtney, L.e , Cruchaga, C.e , Day, G.S.e , DeLaCruz, C.e , Denner, D.e , Diffenbacher, A.e , Dincer, A.e , Donahue, T.e , Douglas, J.e , Duong, D.e , Egido, N.e , Esposito, B.e , Fagan, A.e , Farlow, M.e , Feldman, B.e , Fitzpatrick, C.e , Flores, S.e , Fox, N.e , Franklin, E.e , Joseph-Mathurin, N.e , Fujii, H.e , Gardener, S.e , Ghetti, B.e , Goate, A.e , Goldberg, S.e , Goldman, J.e , Gonzalez, A.e , Gordon, B.e , Gr¨aber-Sultan, S.e , Graff-Radford, N.e , Graham, M.e , Gray, J.e , Gremminger, E.e , Grilo, M.e , Groves, A.e , Haass, C.e , H¨asler, L.e , Hassenstab, J.e , Hellm, C.e , Herries, E.e , Hoechst-Swisher, L.e , Hofmann, A.e , Holtzman, D.e , Hornbeck, R.e , Igor, Y.e , Ihara, R.e , Ikeuchi, T.e , Ikonomovic, S.e , Ishii, K.e , Jack, C.e , Jerome, G.e , Johnson, E.e , Jucker, M.e , Karch, C.e , K¨aser, S.e , Kasuga, K.e , Keefe, S.e , Klunk, W.e , Koeppe, R.e , Koudelis, D.e , Kuder-Buletta, E.e , Laske, C.e , Levey, A.e , Levin, J.e , Li, Y.e , Lopez, O.e , Marsh, J.e , Martins, R.e , Scott Mason, N.e , Masters, C.e , Mawuenyega, K.e , McCullough, A.e , McDade, E.e , Mejia, A.e , Morenas-Rodriguez, E.e , Morris, J.e , Mountz, J.e , Mummery, C.e , Nadkarni, N.e , Nagamatsu, A.e , Neimeyer, K.e , Niimi, Y.e , Noble, J.e , Norton, J.e , Nuscher, B.e , Obermüller, U.e , O’Connor, A.e , Patira, R.e , Perrin, R.e , Ping, L.e , Preische, O.e , Renton, A.e , Ringman, J.e , Salloway, S.e , Schofield, P.e , Senda, M.e , Seyfried, N.T.e , Shady, K.e , Shimada, H.e , Sigurdson, W.e , Smith, J.e , Smith, L.e , Snitz, B.e , Sohrabi, H.e , Stephens, S.e , Taddei, K.e , Thompson, S.e , V¨oglein, J.e , Wang, P.e , Wang, Q.e , Weamer, E.e , Xiong, C.e , Xu, J.e , Xu, X.e , Goate, A.M.c , Pébay, A.a d , Dominantly Inherited Alzheimer Network (DIAN)g
a Department of Anatomy and Physiology, the University of Melbourne, Parkville, VIC 3010, Australia
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Genetics and Genomic Sciences, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, United States
d Department of Surgery, Royal Melbourne Hospital, the University of Melbourne, Parkville, VIC 3010, Australia
f The Institute for Mental and Physical Health and Clinical Translation, Deakin University, GeelongVIC 3220, Australia
Abstract
We report the generation of a gene-edited human induced pluripotent stem cell (iPSC) line from an Alzheimer’s disease patient-derived iPSC line harbouring the PSEN1 H163R mutation. This line demonstrates pluripotent stem cell morphology, expression of pluripotency markers, and maintains a normal karyotype. © 2024 The Author(s)
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Japan Agency for Medical Research and DevelopmentAMED
Korea Health Industry Development InstituteKHIDI
National Health and Medical Research CouncilNHMRC1154389
Document Type: Article
Publication Stage: Final
Source: Scopus
Cross-sectional and longitudinal changes in mind-wandering in older adulthood
(2024) Psychology and Aging, 39 (5), pp. 495-509.
Welhaf, M.S.a , Balota, D.A.a , Morris, J.C.b , Hassenstab, J.a , Aschenbrenner, A.J.b
a Department of Psychological and Brain Sciences, Washington University in St. Louis
b Department of Neurology, Washington University in St. Louis
Abstract
Age-related declines in the frequency of mind-wandering are well established. Theories of mind-wandering have attempted to explain why this decline occurs, but no one theory firmly predicts such changes. One problem with these theoretical views, and the studies that have grown out of them, is their reliance on cross-sectional methods, which do not account for within-person changes over time in mind-wandering, and it is well-documented that cross-sectional and longitudinal changes in some cognitive domains do not align. We present a novel analysis of longitudinal change in subjective and objective indicators of mind-wandering during a sustained attention task. Cognitively normal adults (N = 277, age range 42-94) completed a sustained attention task with thought probes to measure mind-wandering repeatedly over several years. Linear mixed effect models revealed baseline differences in subjective mind-wandering reports among middle-aged and older adults. However, longitudinally, middle-aged participants showed a significant increase in subjective mind-wandering, whereas older participants showed no change. Changes in mind-wandering could not be explained by attentional control ability or contemporaneous estimates of interest and perceived difficulty, but they were explained by baseline levels of conscientiousness. Objective measures of mind-wandering did not show these same patterns and were largely only associated with participants perceived difficulty. Our results build on previous cross-sectional research and suggest that incorporating longitudinal analyses into theories of ageing and mind-wandering and mind-wandering more broadly is important for refining these theories. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Document Type: Article
Publication Stage: Final
Source: Scopus
GABAA receptor subunit composition regulates circadian rhythms in rest-wake and synchrony among cells in the suprachiasmatic nucleus
(2024) Proceedings of the National Academy of Sciences of the United States of America, 121 (31), pp. e2400339121.
Granados-Fuentes, D.a , Lambert, P.b , Simon, T.a , Mennerick, S.b , Herzog, E.D.a
a Department of Biology, Washington University in St. Louis
b Department of Psychiatry, Washington University in St. Louis
Abstract
The mammalian circadian clock located in the suprachiasmatic nucleus (SCN) produces robust daily rhythms including rest-wake. SCN neurons synthesize and respond to γ-aminobutyric acid (GABA), but its role remains unresolved. We tested the hypothesis that γ2- and δ-subunits of the GABAA receptor in the SCN differ in their regulation of synchrony among circadian cells. We used two approaches: 1) shRNA to knock-down (KD) the expression of either γ2 or δ subunits in the SCN or 2) knock-in mice harboring a point mutation in the M2 domains of the endogenous GABAA γ2 or δ subunits. KD of either γ2 or δ subunits in the SCN increased daytime running and reduced nocturnal running by reducing their circadian amplitude by a third. Similarly, δ subunit knock-in mice showed decreased circadian amplitude, increased duration of daily activity, and decreased total daily activity. Reduction, or mutation of either γ2 or δ subunits halved the synchrony among, and amplitude of, circadian SCN cells as measured by firing rate or expression of the PERIOD2 protein, in vitro. Surprisingly, overexpression of the γ2 subunit rescued these phenotypes following KD or mutation of the δ subunit, and overexpression of the δ subunit rescued deficiencies due to γ2 subunit KD or mutation. We conclude that γ2 and δ GABAA receptor subunits play similar roles in maintaining circadian synchrony in the SCN and amplitude of daily rest-wake rhythms, but that modulation of their relative densities can change the duration and amplitude of daily activities.
Author Keywords
Gabrd; Gabrg2; SCN; γ2; δ
Document Type: Article
Publication Stage: Final
Source: Scopus
West Nile Virus-Induced Expression of Senescent Gene Lgals3bp Regulates Microglial Phenotype within Cerebral Cortex
(2024) Biomolecules, 14 (7), art. no. 808, .
Arutyunov, A.a b , Durán-Laforet, V.c , Ai, S.a b , Ferrari, L.c , Murphy, R.c , Schafer, D.P.c , Klein, R.S.d
a Center for Neuroimmunology & Neuroinfectious Diseases, St. Louis, MO 63110, United States
b Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655, United States
d Department of Microbiology & Immunology, Western Institute of Neuroscience, Schulich School of Medicine & Dentistry, University of Western Ontario, 100 Perth Dr, London, ON N6A 5K8, Canada
Abstract
Microglia, the resident macrophages of the central nervous system, exhibit altered gene expression in response to various neurological conditions. This study investigates the relationship between West Nile Virus infection and microglial senescence, focusing on the role of LGALS3BP, a protein implicated in both antiviral responses and aging. Using spatial transcriptomics, RNA sequencing and flow cytometry, we characterized changes in microglial gene signatures in adult and aged mice following recovery from WNV encephalitis. Additionally, we analyzed Lgals3bp expression and generated Lgals3bp-deficient mice to assess the impact on neuroinflammation and microglial phenotypes. Our results show that WNV-activated microglia share transcriptional signatures with aged microglia, including upregulation of genes involved in interferon response and inflammation. Lgals3bp was broadly expressed in the CNS and robustly upregulated during WNV infection and aging. Lgals3bp-deficient mice exhibited reduced neuroinflammation, increased homeostatic microglial numbers, and altered T cell populations without differences in virologic control or survival. These data indicate that LGALS3BP has a role in regulating neuroinflammation and microglial activation and suggest that targeting LGALS3BP might provide a potential route for mitigating neuroinflammation-related cognitive decline in aging and post-viral infections. © 2024 by the authors.
Author Keywords
aging; CD8 T cell; flavivirus encephalitis; Lgals3; Lgals3bp; microglia; microglia transcriptomics; neurodegeneration; neuroinfectious disease; senescence; West Nile virus
Funding details
National Institute of Neurological Disorders and StrokeNINDS
Simons Foundation Autism Research InitiativeSFARI
Dr. Miriam and Sheldon G. Adelson Medical Research FoundationAMRF
R35NS122310
Alzheimer’s AssociationAAAARF-22-923219
Document Type: Article
Publication Stage: Final
Source: Scopus
Age-Based Developmental Biomarkers in Eye Movements: A Retrospective Analysis Using Machine Learning
(2024) Brain Sciences, 14 (7), art. no. 686, .
Hunfalvay, M.a b , Bolte, T.a , Singh, A.a , Greenstein, E.c , Murray, N.P.d , Carrick, F.R.e f g h
a RightEye LLC., 6107A, Suite 400, Rockledge Drive, BethesdaMD 20814, United States
b Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States
c Washington University in St. Louis, 1 Brookings Dr., St. Louis, MO 63130, United States
d Visual Motor Laboratory, Department of Kinesiology, East Carolina University, Greenville, NC 27858, United States
e Neurology, University of Central Florida College of Medicine, Orlando, FL 23816, United States
f Centre for Mental Health Research in Association with University of Cambridge, Cambridge, CB3 9AJ, United Kingdom
g MGH Institute of Health Professions, Boston, MA 02129, United States
h Carrick Institute Neurology, Cape Canaveral, FL 32920, United States
Abstract
This study aimed to identify when and how eye movements change across the human lifespan to benchmark developmental biomarkers. The sample size comprised 45,696 participants, ranging in age from 6 to 80 years old (M = 30.39; SD = 17.46). Participants completed six eye movement tests: Circular Smooth Pursuit, Horizontal Smooth Pursuit, Vertical Smooth Pursuit, Horizontal Saccades, Vertical Saccades, and Fixation Stability. These tests examined all four major eye movements (fixations, saccades, pursuits, and vergence) using 89 eye-tracking algorithms. A semi-supervised, self-training, machine learning classifier was used to group the data into age ranges. This classifier resulted in 12 age groups: 6–7, 8–11, 12–14, 15–25, 26–31, 32–38, 39–45, 46–53, 54–60, 61–68, 69–76, and 77–80 years. To provide a descriptive indication of the strength of the self-training classifier, a series of multiple analyses of variance (MANOVA) were conducted on the multivariate effect of the age groups by test set. Each MANOVA revealed a significant multivariate effect on age groups (p < 0.001). Developmental changes in eye movements across age categories were identified. Specifically, similarities were observed between very young and elderly individuals. Middle-aged individuals (30s) generally showed the best eye movement metrics. Clinicians and researchers may use the findings from this study to inform decision-making on patients’ health and wellness and guide effective research methodologies. © 2024 by the authors.
Author Keywords
eye movements; eye tracking; lifespan development; machine learning
Document Type: Article
Publication Stage: Final
Source: Scopus
Electroencephalogram Alpha Oscillations in Stroke Recovery: Insights into Neural Mechanisms from Combined Transcranial Direct Current Stimulation and Mirror Therapy in Relation to Activities of Daily Life
(2024) Bioengineering, 11 (7), art. no. 717, .
Liu, C.-L.a , Tu, Y.-W.b , Li, M.-W.b , Chang, K.-C.c d e , Chang, C.-H.f g h , Chen, C.-K.e i , Wu, C.-Y.a i j
a Department of Occupational Therapy, Chang Gung University, Taoyuan, 33302, Taiwan
b Department of Physical Medicine and Rehabilitation, Sijhih Cathay General Hospital, New Taipei221, Taiwan
c Division of Cerebrovascular Diseases, Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 80756, Taiwan
d Long-Term Care Service Center, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, 80756, Taiwan
e Department of Medicine, Chang Gung University College of Medicine, Taoyuan, 33302, Taiwan
f Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63108, United States
g Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
h Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63130, United States
i Department of Physical Medicine and Rehabilitation, Chang Gung Memorial Hospital at Linkou, Taoyuan, 33302, Taiwan
j Healthy Aging Research Center, Chang Gung University, Taoyuan, 333, Taiwan
Abstract
The goal of stroke rehabilitation is to establish a robust protocol for patients to live independently in community. Firstly, we examined the impact of 3 hybridized transcranial direct current stimulation (tDCS)-mirror therapy interventions on activities of daily life (ADL) in stroke patients. Secondly, we explored the underlying therapeutic mechanisms with theory-driven electroencephalography (EEG) indexes in the alpha band. This was achieved by identifying the unique contributions of alpha power in motor production to ADL in relation to the premotor cortex (PMC), primary cortex (M1), and Sham tDCS with mirror therapy. The results showed that, although post-intervention ADL improvement was comparable among the three tDCS groups, one of the EEG indexes differentiated the interventions. Neural-behavioral correlation analyses revealed that different types of ADL improvements consistently corresponded with alpha power in the temporal lobe exclusively in the PMC tDCS group (all rs > 0.39). By contrast, alterations in alpha power in the central-frontal region were found to vary, with ADL primarily in the M1 tDCS group (r = −0.6 or 0.7), with the benefit depending on the complexity of the ADL. In conclusion, this research suggested two potential therapeutic mechanisms and demonstrated the additive benefits of introducing theory-driven neural indexes in explaining ADL. © 2024 by the authors.
Author Keywords
activities of daily function; EEG oscillatory activity; neurorehabilitation; stroke; tDCS
Funding details
Chang Gung Memorial HospitalCGMHBMRP553, CMRPD1M0043
NSTC 111-2314-B-182-037-MY3
URRPD1P0181
National Health Research InstitutesNHRINHRI-EX113-11105PI
Document Type: Article
Publication Stage: Final
Source: Scopus
Effects of Aerobic Exercise on Brain Age and Health in Middle-Aged and Older Adults: A Single-Arm Pilot Clinical Trial
(2024) Life, 14 (7), art. no. 855, .
Ouyang, A.a b c d , Zhang, C.a b c , Adra, N.a b c , Tesh, R.A.a b c , Sun, H.a b c , Lei, D.a b c , Jing, J.b c , Fan, P.e , Paixao, L.b c f , Ganglberger, W.a b c , Briggs, L.c , Salinas, J.g , Bevers, M.B.c h , Wrann, C.D.a c i , Chemali, Z.a b c j , Fricchione, G.a b c , Thomas, R.J.c k , Rosand, J.a b c , Tanzi, R.E.a b c , Westover, M.B.a b c
a Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA 02114, United States
b Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, United States
c Harvard Medical School, Boston, MA 02115, United States
d Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA 02131, United States
e Department of Physical Therapy & Human Movement Science, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, United States
f Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
g Department of Neurology, New York University Grossman School of Medicine, New York, NY 10016, United States
h Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, United States
i Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, United States
j Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, United States
k Department of Medicine, Division of Pulmonary, Critical Care & Sleep, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
Abstract
Backgrounds: Sleep disturbances are prevalent among elderly individuals. While polysomnography (PSG) serves as the gold standard for sleep monitoring, its extensive setup and data analysis procedures impose significant costs and time constraints, thereby restricting the long-term application within the general public. Our laboratory introduced an innovative biomarker, utilizing artificial intelligence algorithms applied to PSG data to estimate brain age (BA), a metric validated in cohorts with cognitive impairments. Nevertheless, the potential of exercise, which has been a recognized means of enhancing sleep quality in middle-aged and older adults to reduce BA, remains undetermined. Methods: We conducted an exploratory study to evaluate whether 12 weeks of moderate-intensity exercise can improve cognitive function, sleep quality, and the brain age index (BAI), a biomarker computed from overnight sleep electroencephalogram (EEG), in physically inactive middle-aged and older adults. Home wearable devices were used to monitor heart rate and overnight sleep EEG over this period. The NIH Toolbox Cognition Battery, in-lab overnight polysomnography, cardiopulmonary exercise testing, and a multiplex cytokines assay were employed to compare pre- and post-exercise brain health, exercise capacity, and plasma proteins. Results: In total, 26 participants completed the initial assessment and exercise program, and 24 completed all procedures. Data are presented as mean [lower 95% CI of mean, upper 95% CI of mean]. Participants significantly increased maximal oxygen consumption (Pre: 21.11 [18.98, 23.23], Post 22.39 [20.09, 24.68], mL/kg/min; effect size: −0.33) and decreased resting heart rate (Pre: 66.66 [63.62, 67.38], Post: 65.13 [64.25, 66.93], bpm; effect size: −0.02) and sleeping heart rate (Pre: 64.55 [61.87, 667.23], Post: 62.93 [60.78, 65.09], bpm; effect size: −0.15). Total cognitive performance (Pre: 111.1 [107.6, 114.6], Post: 115.2 [111.9, 118.5]; effect size: 0.49) was significantly improved. No significant differences were seen in BAI or measures of sleep macro- and micro-architecture. Plasma IL-4 (Pre: 0.24 [0.18, 0.3], Post: 0.33 [0.24, 0.42], pg/mL; effect size: 0.49) was elevated, while IL-8 (Pre: 5.5 [4.45, 6.55], Post: 4.3 [3.66, 5], pg/mL; effect size: −0.57) was reduced. Conclusions: Cognitive function was improved by a 12-week moderate-intensity exercise program in physically inactive middle-aged and older adults, as were aerobic fitness (VO2max) and plasma cytokine profiles. However, we found no measurable effects on sleep architecture or BAI. It remains to be seen whether a study with a larger sample size and more intensive or more prolonged exercise exposure can demonstrate a beneficial effect on sleep quality and brain age. © 2024 by the authors.
Author Keywords
brain health; EEG; exercise; intervention trial; sleep
Funding details
Harvard University
Cure Alzheimer’s FundCAF
Glenn Foundation for Medical ResearchGFMR
American Federation for Aging ResearchAFAR
American Academy of Sleep MedicineAASM
U.S. Department of DefenseDOD
R01AG062989, R01NS107291, R01AG073410, R01NS102190, RF1AG064312, R01NS102574
2014431
Document Type: Article
Publication Stage: Final
Source: Scopus
Association of maternal fish consumption and ω-3 supplement use during pregnancy with child autism-related outcomes: results from a cohort consortium analysis
(2024) American Journal of Clinical Nutrition, .
Lyall, K.a , Westlake, M.b , Musci, R.J.c , Gachigi, K.d , Barrett, E.S.e , Bastain, T.M.f , Bush, N.R.g , Buss, C.h , Camargo, C.A., Jr.i , Croen, L.A.j , Dabelea, D.k , Dunlop, A.L.l , Elliott, A.J.m n , Ferrara, A.j , Ghassabian, A.o , Gern, J.E.p , Hare, M.E.q , Hertz-Picciotto, I.r , Hipwell, A.E.s , Hockett, C.W.m n , Karagas, M.R.t , Lugo-Candelas, C.u , O’Connor, T.G.v , Schmidt, R.J.r , Stanford, J.B.w , Straughen, J.K.x , Shuster, C.L.y , Wright, R.O.z , Wright, R.J.z , Zhao, Q.q , Oken, E.aa , Smith, P.B.ab , Newby, K.L.ab , Jacobson, L.P.ac , Catellier, D.J.ad , Gershon, R.ae , Cella, D.ae , Alshawabkeh, A.N.af , Cordero, J.ag , Meeker, J.ah , Aschner, J.ai , Teitelbaum, S.L.aj , Stroustrup, A.aj ak , Mansbach, J.M.al , Spergel, J.M.am , Samuels-Kalow, M.E.an , Stevenson, M.D.ao , Bauer, C.S.ap , Koinis Mitchell, D.aq , Deoni, S.aq , D’Sa, V.aq , Duarte, C.S.ar , Monk, C.as , Posner, J.at , Canino, G.au , Seroogy, C.av , Bendixsen, C.av , Hertz-Picciotto, I.aw , Keenan, K.ax , Karr, C.ay , Tylavsky, F.az , Mason, A.az , Zhao, Q.az , Sathyanarayana, S.ba , LeWinn, K.Z.bb , Lester, B.bc , Carter, B.bd , Pastyrnak, S.be , Neal, C.bf , Smith, L.bg , Helderman, J.bh , Weiss, S.T.bi , Litonjua, A.bj , O’Connor, G.bk , Zeiger, R.bl , Bacharier, L.bm , Volk, H.bn , Ozonoff, S.aw , Schmidt, R.bo , Simhan, H.bp , Kerver, J.M.bq , Barone, C.br , Fussman, C.bs , Paneth, N.bq , Elliott, M.ah , Ruden, D.bt , Porucznik, C.bu , Giardino, A.bu , Innocenti, M.bv , Silver, R.bu , Conradt, E.bu , Bosquet-Enlow, M.al , Huddleston, K.bw , Nguyen, R.bx , Trasande, L.by , Swan, S.aj , program collaborators for Environmental influences on Child Health Outcomesbz , ECHO Componentsbz , Coordinating Centerbz , Data Analysis Centerbz , Person-Reported Outcomes Corebz , ECHO Awardees and Cohortsbz
a AJ Drexel Autism Institute, Drexel University, Philadelphia, PA, United States
b RTI International, Raleigh, NC, United States
c Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
d Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
e Department of Biostatistics and Epidemiology, Rutgers University School of Public Health, Environmental and Occupational Health Sciences Institute, Piscataway, NJ, United States
f Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, United States
g Department of Psychiatry and Behavioral Sciences, Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
h UC Irvine Medical Center, Orange, CA, United States
i Department of Emergency Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
j Division of Research, Kaiser Permanente Northern California, Oakland, CA, United States
k Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
l Department of Gynecology & Obstetrics, Emory University School of Medicine, Atlanta, GA, United States
m Avera Research Institute, Sioux Falls, SD, United States
n Department of Pediatrics, University of South Dakota Sanford School of Medicine, Vermillion, SD, United States
o Department of Pediatrics, New York University Grossman School of Medicine, New York, NY, United States
p Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
q Department of Preventive Medicine, College of Medicine, University of Health Science Center, Memphis, TN, United States
r Department of Public Health Sciences, University of California Davis, Davis, CA, United States
s Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
t Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States
u New York State Psychiatric Institute, Columbia University Irving Medical Center, New York, NY, United States
v Departments of Psychiatry, Psychology, Neuroscience, Obstetrics and Gynecology, University of Rochester, Rochester, NY, United States
w Department of Family and Preventative Medicine, University of Utah, Salt Lake City, UT, United States
x Department of Public Health Sciences, Henry Ford Health, Detroit, MI, United States
y Brown Center for the Study of Children at Risk, Women and Infants Hospital, Providence, RI, United States
z Department of Environmental Medicine and Public Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
aa Division of Chronic Disease Research Across the Lifecourse, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
ab Duke Clinical Research Institute, Durham, NC, United States
ac Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
ad Research Triangle Institute, Durham, NC, United States
ae Northwestern University, Evanston, IL, United States
af Northeastern University, Boston, MA, United States
ag University of Georgia, Athens, GA, United States
ah University of Michigan, Ann Arbor, MI, United States
ai Albert Einstein College of Medicine, Bronx, NY, United States
aj Icahn School of Medicine at Mount Sinai, New York, NY, United States
ak Cohen Children’s Medical Center, Northwell Health, New Hyde Park, NY, United States
al Boston Children’s Hospital, Boston, MA, United States
am Children’s Hospital of Philadelphia, Philadelphia, PA, United States
an Massachusetts General Hospital, Boston, MA, United States
ao Norton Children’s Hospital, Louisville, KY, United States
ap Phoenix Children’s Hospital, Phoenix, AZ, United States
aq Rhode Island Hospital, Providence, RI, United States
ar New York State Psychiatric Institute, New York, NY, United States
as Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States
at Duke University Department of Psychiatry and Behavioral Sciences, Durham, NC, United States
au University of Puerto Rico, Rio Piedras, PR, United States
av Marshfield Clinic Research Institute, Marshfield, WI, United States
aw University of California Davis Health, MIND Institute, Sacramento, CA, United States
ax University of Chicago, Chicago, IL, United States
ay University of Washington, Department of Environmental and Occupational Health Sciences, Seattle, WA, United States
az University of Tennessee Health Science Center, Memphis, TN, United States
ba Seattle Children’s Research Institute, Seattle, WA, United States
bb University of California, San Francisco, San Francisco, CA, United States
bc Women & Infants Hospital of Rhode Island, Providence, RI, United States
bd Children’s Mercy, Kansas City, MO, United States
be Corewell Health, Helen DeVos Children’s Hospital, Grand Rapids, MI, United States
bf Kapiolani Medical Center for Women and Children, Providence, RI, United States
bg Los Angeles Biomedical Research Institute at Harbour–UCLA Medical Center, Los Angeles, CA, United States
bh Wake Forest University School of Medicine, Winston Salem, NC, United States
bi Brigham and Women’s Hospital, Boston, MA, United States
bj Golisano Children’s Hospital, Rochester, NY, United States
bk Boston University Medical Center, Boston, MA, United States
bl Kaiser Permanente, Southern California, San Diego, CA, United States
bm Washington University of St. Louis, St Louis, MO, United States
bn John Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
bo University of California Davis Health, MIND Institute, Davis, CA, United States
bp University of Pittsburgh Medical Center, Magee Women’s Hospital, Pittsburgh, PA, United States
bq Michigan State University, East Lansing, MI, United States
br Henry Ford Health, Detroit, MI, United States
bs Michigan Department of Health and Human Services, Lansing, MI, United States
bt Wayne State University, Detroit, MI, United States
bu University of Utah, Salt Lake City, UT, United States
bv Utah State University, Logan, UT, United States
bw George Mason University, Fairfax, VA, United States
bx University of Minnesota, Minneapolis, MN, United States
by New York University Grossman School of Medicine, New York, NY, United States
Abstract
Background: Prenatal fish intake is a key source of omega-3 (ω-3) polyunsaturated fatty acids needed for brain development, yet intake is generally low, and studies addressing associations with autism spectrum disorder (ASD) and related traits are lacking. Objective: This study aimed to examine associations of prenatal fish intake and ω-3 supplement use with both autism diagnosis and broader autism-related traits. Methods: Participants were drawn from 32 cohorts in the Environmental influences on Child Health Outcomes Cohort Consortium. Children were born between 1999 and 2019 and part of ongoing follow-up with data available for analysis by August 2022. Exposures included self-reported maternal fish intake and ω-3/fish oil supplement use during pregnancy. Outcome measures included parent report of clinician-diagnosed ASD and parent-reported autism-related traits measured by the Social Responsiveness Scale (SRS)-second edition (n = 3939 and v3609 for fish intake analyses, respectively; n = 4537 and n = 3925 for supplement intake analyses, respectively). Results: In adjusted regression models, relative to no fish intake, fish intake during pregnancy was associated with reduced odds of autism diagnosis (odds ratio: 0.84; 95% confidence interval [CI]: 0.77, 0.92), and a modest reduction in raw total SRS scores (β: −1.69; 95% CI: −3.3, −0.08). Estimates were similar across categories of fish consumption from “any” or “less than once per week” to “more than twice per week.” For ω-3 supplement use, relative to no use, no significant associations with autism diagnosis were identified, whereas a modest relation with SRS score was suggested (β: 1.98; 95% CI: 0.33, 3.64). Conclusions: These results extend previous work by suggesting that prenatal fish intake, but not ω-3 supplement use, may be associated with lower likelihood of both autism diagnosis and related traits. Given the low-fish intake in the United States general population and the rising autism prevalence, these findings suggest the need for better public health messaging regarding guidelines on fish intake for pregnant individuals. © 2024 The Author(s)
Author Keywords
autism; fish; pregnancy; quantitative traits; ω-3 supplement
Funding details
Office of Behavioral and Social Sciences ResearchOBSSRUH3OD023347, OD023244, UH3 OD023275, UH3OD023365, UH3OD023279, UH3 OD023287, UH3OD023313, UH3OD023249, UH3OD023268, UH3 OD023282, UH3OD023320, UH3OD023289, UH3OD023328, UH3OD023305, UH3OD023286, UH3OD023285, UH3OD023253, UH3 OD023248, OD0233337, UH3OD023271, UH3 OD023349, UH3OD023318, UH3OD023251, UH3OD023342
National Institutes of HealthNIHU24OD023319, U2COD023375, U24OD023382
31,34,35, 33,38, 34,35
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Exploring the Experience of Community Participation Among Individuals With Serious Mental Illness
(2024) OTJR: Occupational Therapy Journal of Research, .
Randolph, S.B.a , Barch, D.M.a , Ben-Zeev, D.b , Moran, E.K.a
a Washington University in St. LouisMO, United States
b University of Washington, Seattle, United States
Abstract
People with serious mental illness (SMI) encounter restrictions in the quantity of their community participation. Less is known about the quality of their participation. We aimed to explore the relationship between symptoms of SMI and the daily experience (i.e., loneliness and enjoyment) of community participation. We examined daily community participation among people with SMI using ecological momentary assessment surveys. We built multilevel models to examine the associations between symptoms of SMI and loneliness or enjoyment during community participation. Our analysis included 183 people among four participant groups: bipolar disorder (n = 44), major depressive disorder (n = 46), schizophrenia/schizoaffective disorder (n = 40), and control (n = 53). People with schizophrenia engaged in more unstructured activities (e.g., socializing) than people among other groups. Symptom association varied across diagnostic groups. To support tailored intervention development, researchers and practitioners should consider the context of participation and the clinical characteristics of the client. © The Author(s) 2024.
Author Keywords
community participation; mental health; schizophrenia
Funding details
R01-MH066031
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study
(2024) JMIR Aging, 7, art. no. e52831, .
Paolillo, E.W.a x , Casaletto, K.B.a , Clark, A.L.a , Taylor, J.C.a , Heuer, H.W.a , Wise, A.B.a , Dhanam, S.a , Sanderson-Cimino, M.a , Saloner, R.a , Kramer, J.H.a , Kornak, J.b , Kremers, W.c , Forsberg, L.d , Appleby, B.e , Bayram, E.f , Bozoki, A.g , Brushaber, D.c , Darby, R.R.h , Day, G.S.i , Dickerson, B.C.j , Domoto-Reilly, K.k , Elahi, F.l m , Fields, J.A.n , Ghoshal, N.o , Graff-Radford, N.i , Hall, M.G.H.a , Honig, L.S.p , Huey, E.D.q , Lapid, M.I.n , Litvan, I.f , Mackenzie, I.R.r , Masdeu, J.C.s , Mendez, M.F.t , Mester, C.c , Miyagawa, T.d , Naasan, G.u , Pascual, B.s , Pressman, P.v , Ramos, E.M.t , Rankin, K.P.a , Rexach, J.t , Rojas, J.C.a , VandeVrede, L.a , Wong, B.w , Wszolek, Z.K.i , Boeve, B.F.d , Rosen, H.J.a , Boxer, A.L.a , Staffaroni, A.M.a , Apostolova, L.y , Barmada, S.z , Bayram, E.aa , Botha, H.ab , Bozoki, A.ac , Cobigo, Y.ad , Day, G.S.ae , Dickson, D.ae , Faber, K.af , Fagan, A.ag , Fong, J.ad , Foroud, T.af , Galasko, D.R.aa , Gavrilova, R.ab , Gendron, T.ae , Geschwind, D.ah , Goldman, J.ai , Graff-Radford, J.ab , Grant, I.M.aj , Grossman, M.ak , Hales, C.M.al , Heuer, H.W.ad , Hsiung, G.-Y.am , Huang, E.ad , Irwin, D.ak , Johnson, N.ab , Jones, D.T.ab , Kantarci, K.ab , Knopman, D.ab , Kolander, T.ab , Kwan, J.an , Lago, A.L.ad , Lavigne, S.B.ao , Lee, S.ad , Léger, G.C.aa , Ljubenkov, P.ad , Lucente, D.ap , Manoochehri, M.ai , Massimo, L.ak , McGinnis, S.ap , McMillan, C.T.ak , Molden, J.aq , Onyike, C.ar , Pantelyat, A.ar , Paulson, H.z , Petrucelli, L.ae , Rademakers, R.as , Ramanan, V.ab , Rao, M.ab , Rascovsky, K.ak , Rhoads, K.W.at , Ritter, A.au , Roberson, E.D.av , Rogalski, E.aj , Savica, R.ab , Seeley, W.ad , Snyder, A.an , Sullivan, A.C.ao , Syrjanen, J.M.ab , Tartaglia, M.C.aw , Tipton, P.W.ae , Vandebergh, M.as , Toga, A.ax , Weintraub, S.aj , Wint, D.au , Wolf, A.ad , Yokoyoma, J.ad , ALLFTD Consortiumay
a Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, United States
b Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
c Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, United States
d Department of Neurology, Mayo Clinic, Rochester, MN, United States
e Department of Neurology, Case Western Reserve University, Cleveland, OH, United States
f Department of Neurosciences, University of California, La Jolla, San Diego, CA, United States
g Department of Neurology, University of North Carolina, Chapel Hill, NC, United States
h Department of Neurology, Vanderbilt University, Nashville, TN, United States
i Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
j Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
k Department of Neurology, University of Washington, Seattle, WA, United States
l Department of Neurology, The Deane Center for Wellness and Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, United States
m James J. Peters Veterans Affairs Medical Center, New York, NY, United States
n Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
o Department of Neurology, Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO, United States
p Department of Neurology, Columbia University, New York, NY, United States
q Department of Psychiatry and Human Behavior, Brown University, Providence, RI, United States
r Department of Pathology, University of British Columbia, Vancouver, BC, Canada
s Stanley H. Appel Department of Neurology, Nantz National Alzheimer Center, Houston Methodist Research Institute, Weill Cornell Medicine, Houston, TX, United States
t Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
u Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
v Department of Neurology, University of Colorado, Aurora, CO, United States
w Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
x Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, 675 Nelson Rising Lane, Suite 19094158, San Francisco, CA 94158, United States
y Indiana University, United States
z University of Michigan, United States
aa UCSD, United States
ab Mayo Clinic, Rochester, United States
ac University of North Carolina, United States
ad UCSF, United States
ae Mayo Clinic, Jacksonville, United States
af Indiana University (NCRAD), United States
ag Washington University, St. Louis, United States
ah UCLA, United States
ai Columbia University, United States
aj Northwestern University, United States
ak University of Pennsylvania, United States
al Emory, United States
am University of British Columbia, Canada
an National Institutes of Health, United States
ao UT Health San Antonio, United States
ap MGH, United States
aq University of Colorado, United States
ar Johns Hopkins University, United States
as University of Antwerp, Belgium
at University of Washington, United States
au Cleveland Clinic, Las Vegas, United States
av University of Alabama, Birmingham, United States
aw University of Toronto, Canada
ax Keck School of Medicine, University of Southern California, United States
Abstract
Background: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. Objective: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. Methods: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer’s Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants’ smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. Results: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). Conclusions: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change. © Emily W Paolillo, Kaitlin B Casaletto, Annie L Clark, Jack C Taylor, Hilary W Heuer, Amy B Wise, Sreya Dhanam, Mark Sanderson-Cimino, Rowan Saloner, Joel H Kramer, John Kornak, Walter Kremers, Leah Forsberg, Brian Appleby, Ece Bayram, Andrea Bozoki, Danielle Brushaber, R Ryan Darby, Gregory S Day, Bradford C Dickerson, Kimiko Domoto-Reilly, Fanny Elahi, Julie A Fields, Nupur Ghoshal, Neill Graff-Radford, Matthew G H Hall, Lawrence S Honig, Edward D Huey, Maria I Lapid, Irene Litvan, Ian R Mackenzie, Joseph C Masdeu, Mario F Mendez, Carly Mester, Toji Miyagawa, Georges Naasan, Belen Pascual, Peter Pressman, Eliana Marisa Ramos, Katherine P Rankin, Jessica Rexach, Julio C Rojas, Lawren VandeVrede, Bonnie Wong, Zbigniew K Wszolek, Bradley F Boeve, Howard J Rosen, Adam L Boxer, Adam M Staffaroni, ALLFTD Consortium.
Author Keywords
clinical trials; cognition; cognitive impairment; digital; mobile phone; monitoring; neurodegenerative; neuropsychology; remote; screening; technology
Funding details
Rainwater Charitable FoundationRCF
John Douglas French Alzheimer’s FoundationJDFAF
Association for Frontotemporal DegenerationAFTD
National Institutes of HealthNIHK23AG59888, AG62677, AG02350, AG019724, NS050915, K23AG064029, AG032289-11, AG016976, K24AG045333, AG021886, AG038791, K23AG073514, K23AG061253, NS092089, AG032306, AG058233, AG077557, AG063911, AG062422, AG045390
Alzheimer’s AssociationAAAARF-23-1145318, AARF-22-974065
Document Type: Article
Publication Stage: Final
Source: Scopus
Anxiety sensitivity among Black youth: A cross-sectional analysis of the direct and indirect effects of community violence exposure, neighborhood risk, parenting practices, and peer effects
(2024) Journal of the National Medical Association, .
Foell, A.a , Pitzer, K.A.b , Nebbitt, V.c , Lombe, M.d , Yu, M.e , Villodas, M.L.f , Enelamah, N.g , Lateef, H.b
a Jane Addams College of Social Work, University of Illinois Chicago, 1040 West Harrison Street, Chicago, IL 60607, United States
b Brown School, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
c School of Social Work, Morgan State University, 1700 E. Cold Spring Lane, Baltimore, MD 21251, United States
d School of Social Work, Boston University, 264 Bay State Road, Boston, MA 02215, United States
e School of Social Work, Department of Public Health, University of Missouri, 720 Clark Hall, Columbia, MO 65211, United States
f Department of Social Work, George Mason University, 4400 University Drive, Fairfax, VA 22030, United States
g Department of Social Work, University of New Hampshire, 55 College Road, Durham, NH 03824, United States
Abstract
Youth exposed to community violence and neighborhood stressors report devastating mental health consequences. Black youth are at greater risk and experience community violence at rates higher than other youth populations. An underexplored mental health consequence is anxiety sensitivity, the fear of experiencing anxiety-related symptoms, which contributes to maladaptive coping strategies and the development and severity of other mental health problems. This study utilized structural equation modeling (SEM) to examine socio-ecological risk and protective factors associated with community violence exposure and anxiety sensitivity among low-income Black youth. Survey data are from a sample of 320 Black youth residing in public and subsidized housing in a Northeastern city in the United States. Results indicated that neighborhood risk, parenting behaviors, and exposure to delinquent peers were indirectly associated with anxiety sensitivity, which occurred through community violence exposure. Additionally, neighborhood risks had direct effects on anxiety sensitivity. Results point to the need to incorporate social and environmental factors in interventions addressing anxiety sensitivity among Black youth in urban communities. © 2024 The Authors
Author Keywords
Anxiety sensitivity; Black youth; Community violence exposure; Youth development
Funding details
National Institutes of HealthNIH
2010-0297, 2010-2013
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Using Multimodal Assessments to Reevaluate Depression Designations for Spine Surgery Candidates
(2024) Journal of Bone and Joint Surgery, .
Benedict, B.a , Frumkin, M.b , Botterbush, K.a , Javeed, S.a , Zhang, J.K.a c , Yakdan, S.a , Neuman, B.J.d , Steinmetz, M.P.e , Ghogawala, Z.f , Kelly, M.P.g , Goodin, B.R.h , Piccirillo, J.F.i , Ray, W.Z.a , Rodebaugh, T.L.j , Greenberg, J.K.a
a Department of Neurological Surgery, Washington University, St. Louis, MO, United States
b Department of Psychology and Brain Sciences, Washington University, St. Louis, MO, United States
c Department of Neurological Surgery, University of Utah, Salt Lake City, UT, United States
d Department of Orthopedic Surgery, Washington University, St. Louis, MO, United States
e Department of Neurosurgery, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, United States
f Department of Neurosurgery, Lahey Hospital and Medical Center, Burlington, MA, United States
g Department of Orthopedic Surgery, Rady Children’s Hospital, San Diego, CA, United States
h Department of Anesthesiology, Washington University, St. Louis, MO, United States
i Department of Otolaryngology, Washington University, St. Louis, MO, United States
j Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, United States
Abstract
Background: Depression is common in spine surgery candidates and may influence postoperative outcomes. Ecological momentary assessments (EMAs) can overcome limitations of existing depression screening methods (e.g., recall bias, inaccuracy of historical diagnoses) by longitudinally monitoring depression symptoms in daily life. In this study, we compared EMA-based depression assessment with retrospective self-report (a 9-item Patient Health Questionnaire [PHQ-9]) and chart-based depression diagnosis in lumbar spine surgery candidates. We further examined the associations of each depression assessment method with surgical outcomes. Methods: Adult patients undergoing lumbar spine surgery (n = 122) completed EMAs quantifying depressive symptoms up to 5 times daily for 3 weeks preoperatively. Correlations (rank-biserial or Spearman) among EMA means, a chart-based depression history, and 1-time preoperative depression surveys (PHQ-9 and Psychache Scale) were analyzed. Confirmatory factor analysis was used to categorize PHQ-9 questions as somatic or non-somatic; subscores were compared with a propensity score-matched general population cohort. The associations of each screening modality with 6-month surgical outcomes (pain, disability, physical function, pain interference) were analyzed with multivariable regression. Results: The association between EMA Depression scores and a depression history was weak (rrb = 0.34 [95% confidence interval (CI), 0.14 to 0.52]). Moderate correlations with EMA-measured depression symptoms were observed for the PHQ-9 (rs = 0.51 [95% CI, 0.37 to 0.63]) and the Psychache Scale (rs = 0.68 [95% CI, 0.57 to 0.76]). Compared with the matched general population cohort, spine surgery candidates endorsed similar non-somatic symptoms but significantly greater somatic symptoms on the PHQ-9. EMA Depression scores had a stronger association with 6-month surgical outcomes than the other depression screening modalities did. Conclusions: A history of depression in the medical record is not a reliable indication of preoperative depression symptom severity. Cross-sectional depression assessments such as PHQ-9 have stronger associations with daily depression symptoms but may conflate somatic depression symptoms with spine-related disability. As an alternative to these methods, mobile health technology and EMAs provide an opportunity to collect real-time, longitudinal data on depression symptom severity, potentially improving prognostic accuracy. Copyright © 2024 by The Journal of Bone and Joint Surgery.
Funding details
Scoliosis Research SocietySRS
Foundation for Barnes-Jewish HospitalFBJH
Cervical Spine Research SocietyCSRS
National Institute of Mental HealthNIMH1F31MH124291-01A
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Examining the Most Important Risk Factors for Predicting Youth Persistent and Distressing Psychotic-Like Experiences
(2024) Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, .
Karcher, N.R.a , Sotiras, A.b c , Niendam, T.A.d , Walker, E.F.e , Jackson, J.J.f , Barch, D.M.a f
a Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States
b Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States
c Institute for Informatics, Data Science & Biostatistics, Washington University School of Medicine, St. Louis, Missouri, United States
d Department of Psychiatry and Behavioral Sciences, University of California Davis, Davis, California, United States
e Department of Psychology, Emory University, Georgia, Atlanta, United States
f Department of Psychological and Brain Sciences, Washington University in St Louis, St. Louis, Missouri, United States
Abstract
Background: Persistence and distress distinguish more clinically significant psychotic-like experiences (PLEs) from those that are less likely to be associated with impairment and/or need for care. Identifying risk factors that identify clinically relevant PLEs early in development is important for improving our understanding of the etiopathogenesis of these experiences. Machine learning analyses were used to examine the most important baseline factors distinguishing persistent distressing PLEs. Methods: Using Adolescent Brain Cognitive Development (ABCD) Study data on PLEs from 3 time points (ages 9–13 years), we created the following groups: individuals with persistent distressing PLEs (n = 305), individuals with transient distressing PLEs (n = 374), and individuals with low-level PLEs demographically matched to either the persistent distressing PLEs group (n = 305) or the transient distressing PLEs group (n = 374). Random forest classification models were trained to distinguish persistent distressing PLEs from low-level PLEs, transient distressing PLEs from low-level PLEs, and persistent distressing PLEs from transient distressing PLEs. Models were trained using identified baseline predictors as input features (i.e., cognitive, neural [cortical thickness, resting-state functional connectivity], developmental milestone delays, internalizing symptoms, adverse childhood experiences). Results: The model distinguishing persistent distressing PLEs from low-level PLEs showed the highest accuracy (test sample accuracy = 69.33%; 95% CI, 61.29%–76.59%). The most important predictors included internalizing symptoms, adverse childhood experiences, and cognitive functioning. Models for distinguishing persistent PLEs from transient distressing PLEs generally performed poorly. Conclusions: Model performance metrics indicated that while most important factors overlapped across models (e.g., internalizing symptoms), adverse childhood experiences were especially important for predicting persistent distressing PLEs. Machine learning analyses proved useful for distinguishing the most clinically relevant group from the least clinically relevant group but showed limited ability to distinguish among clinically relevant groups that differed in PLE persistence. © 2024 Society of Biological Psychiatry
Author Keywords
ABCD Study; Adverse childhood experiences; Distress; Machine learning; Persistence; Psychotic-like experiences
Funding details
National Institute of Neurological Disorders and StrokeNINDS
BrightFocus FoundationBFF
National Institutes of HealthNIHU01DA041134, U24DA041147, U01DA041025, U01DA041156, U01DA041028, U01DA041022, U01DA041174, U01DA041093, U24DA041123, U01DA041048, U01DA041148, U01DA041089, U01DA041106, U01DA041117
National Institute of Mental HealthNIMHK23MH121792-01
National Institute on Drug AbuseNIDAU01DA041120
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Amplitude Parameters Are Predictive of Hearing Preservation in a Randomized Controlled Trial of Intracochlear Electrocochleography During Cochlear Implant Surgery
(2024) Otology and Neurotology, .
Harris, M.S.a , Koka, K.b , Thompson-Harvey, A.a , Harvey, E.a , Riggs, W.J.c , Saleh, S.d , Holder, J.T.e , Dwyer, R.T.b , Prentiss, S.M.f , Lefler, S.M.g , Kozlowski, K.a , Hiss, M.M.c , Ortmann, A.J.g , Nelson-Bakkum, E.R.b , Büchner, A.h , Salcher, R.h , Harvey, S.A.a , Hoffer, M.E.f , Bohorquez, J.E.i , Alzhrani, F.d , Alshihri, R.d , Almuhawas, F.d , Danner, C.J.j , Friedland, D.R.a , Seidman, M.D.k , Lenarz, T.h , Telischi, F.F.f , Labadie, R.F.l , Buchman, C.A.g , Adunka, O.F.c
a Department of Otolaryngology & Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, United States
b Advanced Bionics, LLC, Valencia, CA, United States
c Department of Otolaryngology-Head & Neck Surgery, The Ohio State University, Wexner Medical Center, Columbus, OH, United States
d King Saud University, College of Medicine, King Abdullah Ear Specialist Center (KAESC), Riyadh, Saudi Arabia
e Department of Hearing and Speech Sciences, Vanderbilt Bill Wilkerson Center, Vanderbilt University Medical Center, Nashville, TN, United States
f Department of Otolaryngology-Head & Neck Surgery, Miller School of Medicine, University of Miami, Miami, FL, United States
g Department of Otolaryngology-Head & Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
h Medizinische Hochschule Hannover, Hannover, Germany
i Department of Biomedical Engineering, University of Miami, Miami, FL, United States
j Tampa Bay General Hospital, Tampa Bay, FL, United States
k AdventHealth, University of Central Florida, Orlando, FL, United States
l Department of Otolaryngology-Head & Neck Surgery, Medical University of South Carolina, Charleston, SC, United States
Abstract
Objective To prospectively evaluate the association between hearing preservation after cochlear implantation (CI) and intracochlear electrocochleography (ECochG) amplitude parameters. Study Design Multi-institutional, prospective randomized clinical trial. Setting Ten high-volume, tertiary care CI centers. Patients Adults (n = 87) with sensorineural hearing loss meeting CI criteria (2018-2021) with audiometric thresholds of ≤80 dB HL at 500 Hz. Methods Participants were randomized to CI surgery with or without audible ECochG monitoring. Electrode arrays were inserted to the full-depth marker. Hearing preservation was determined by comparing pre-CI, unaided low-frequency (125-, 250-, and 500-Hz) pure-tone average (LF-PTA) to LF-PTA at CI activation. Three ECochG amplitude parameters were analyzed: 1) insertion track patterns, 2) magnitude of ECochG amplitude change, and 3) total number of ECochG amplitude drops. Results The Type CC insertion track pattern, representing corrected drops in ECochG amplitude, was seen in 76% of cases with ECochG “on,”compared with 24% of cases with ECochG “off”(p = 0.003). The magnitude of ECochG signal drop was significantly correlated with the amount of LF-PTA change pre-CI and post-CI (p < 0.05). The mean number of amplitude drops during electrode insertion was significantly correlated with change in LF-PTA at activation and 3 months post-CI (p ≤ 0.01). Conclusions ECochG amplitude parameters during CI surgery have important prognostic utility. Higher incidence of Type CC in ECochG “on”suggests that monitoring may be useful for surgeons in order to recover the ECochG signal and preventing potentially traumatic electrode-cochlear interactions. © 2024, Otology & Neurotology, Inc.
Author Keywords
Clinical trial; Cochlear implantation; ECochG; Electrocochleography; Hearing preservation
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Epidural methadone and morphine pharmacokinetics and clinical effects in healthy volunteers: A randomized, crossover-design trial
(2024) British Journal of Clinical Pharmacology, .
Hincker, A.a b , Reschke, M.c , Ginosar, Y.d , Kagan, L.e , Kharasch, E.D.f , Siemiątkowska, A.e g , Park, C.e , Bakos, K.h , Ben-Abdallah, A.a , Haroutounian, S.a i
a Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, United States
b Division of Obstetric Anesthesiology, Mercy Hospital Saint Louis, Saint Louis, MO, United States
c Department of Anesthesiology, Banner University Medical Center, Phoenix, AZ, United States
d Department of Anesthesiology, Critical Care and Pain Medicine, Hadassah Ein Karem Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Israel
e Department of Pharmaceutics and Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, United States
f Department of Anesthesiology, Duke University School of Medicine; Bermaride LLC, Durham, NC, United States
g Department of Physical Pharmacy and Pharmacokinetics, Poznan University of Medical Sciences, Collegium Pharmaceuticum, 3 Rokietnicka Street, Poznan, 60-806, Poland
h Investigational Drug Service, Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO, United States
i Washington University Pain Center, Washington University School of Medicine, St Louis, MO, United States
Abstract
Aims: Epidural opioids can provide effective analgesia for acute postoperative pain. Due to its unique physicochemical properties and long systemic elimination half-life, epidural methadone may provide lasting analgesia with minimal adverse effects; however, human studies are lacking. The aim of the study was to test the hypothesis that epidural methadone would exhibit greater segmental analgesia (analgesia at the dermatome of injection vs. distant dermatomes) than epidural morphine. Methods: In a prospective, randomized, double-blinded, crossover study, thirteen healthy volunteers received a 4-mg epidural bolus of methadone or morphine at L3–L4 and underwent repeated assessment of dermatomal heat pain tolerance and pressure pain threshold at lumbar (L3) and trigeminal (V2) dermatomes, pupil diameter, respiratory parameters and venous opioid concentration for 24 h. The primary outcome was selective (lumbar vs. trigeminal) segmental analgesia for heat pain, as a marker of a spinal analgesic mechanism. Results: The degree of segmental analgesia to heat pain tolerance was not different between morphine and methadone (P =.09), although morphine (P =.0009) but not methadone (P =.81) produced significant analgesia to heat pain at the lumbar vs. trigeminal dermatome over 0–12 h. Morphine overall provided longer lasting analgesia to heat pain vs. methadone (24 vs. 2 h, respectively). Morphine elicited greater systemic effects, including miosis (P =.009) and opioid-related adverse effects (P =.002). Conclusions: These results suggest that, with equal epidural doses, both methadone and morphine produced analgesia and methadone did not produce greater segmental effects than morphine. Epidural methadone provided a more favourable adverse effect profile. © 2024 British Pharmacological Society.
Author Keywords
opioids; pain; pharmacodynamics; pharmacokinetics
Funding details
Washington University in St. LouisWUSTL
National Institutes of HealthNIH
Society for Obstetric Anesthesia and PerinatologySOAP
R01DA042985
National Institute of General Medical SciencesNIGMS1R01GM124046‐01A1
Document Type: Article
Publication Stage: Article in Press
Source: Scopus