WashU weekly Neuroscience publications

Do attentional focus cues affect the type or number of explicit rules? Proof of concepts of the self-invoking trigger or explicit knowledge hypotheses
(2024) Psychology of Sport and Exercise, 70, art. no. 102547, . 

Yamada, M.^a b , Lohse, K.R.^c , Rhea, C.K.^a d , Schmitz, R.J.^a , Raisbeck, L.D.^a

^a The Department of Kinesiology, The University of North Carolina at Greensboro, United States
^b The Department of Kinesiology, Whittier College, Whittier, CA, United States
^c Program in Physical Therapy, Department of Neurology, Washington University School of Medicine in Saint Louis, United States
^d College of Health Science, Old Dominion University, United States

Abstract
Internal focus has been shown to be detrimental to performance by disrupting the motor system, whereas external focus enhances performance by promoting automaticity. One hypothesis, which explains the underlying mechanism of the disruption of the motor system, proposes that internal focus affects the type of thoughts (explicit rules) by invoking self-conscious, evaluative thoughts (McKay et al., 2015). In contrast, another hypothesis proposes that internal focus increases the number of explicit rules, loading working memory (Poolton et al., 2006). To examine the competing hypotheses, neurotypical young adults (22.98 ± 4.46 years old, n = 20 males, n = 40 females) were assigned to one of three groups: external focus (n = 20), internal focus (n = 20), and control (n = 20) groups, and practiced a reciprocal aiming task for two days with retention/transfer tests. Between trials, participant’s thoughts were evaluated by an open-ended questionnaire. The type of explicit rules was analyzed using a chi-square test, and the number of explicit rules was analyzed using a mixed-effect Poisson regression. The results showed that external focus resulted in a greater proportion of explicit rules about the task and a lesser proportion of self-evaluative thoughts. The number of explicit rules did not differ between groups. Our results suggest that external focus may strengthen focus on task-relevant features, while internal focus moves people’s attention away from important features, potentially explaining why the motor system is disrupted by internal focus. © 2023

Author Keywords
Explicit and implicit knowledge;  Fitts law;  Focus of attention;  Goal-directed aiming;  Motor behavior;  Motor learning;  Skill acquisition;  Verbal instructions

Document Type: Article
Publication Stage: Final
Source: Scopus

PPTC7 maintains mitochondrial protein content by suppressing receptor-mediated mitophagy
(2023) Nature Communications, 14 (1), art. no. 6431, . 

Niemi, N.M.^a b , Serrano, L.R.^c , Muehlbauer, L.K.^d , Balnis, C.E.^c , Wei, L.^b , Smith, A.J.^e , Kozul, K.-L.^f , Forny, M.^b , Connor, O.M.^g , Rashan, E.H.^h , Shishkova, E.^c i , Schueler, K.L.^h , Keller, M.P.^h , Attie, A.D.^h , Friedman, J.R.^g , Pagan, J.K.^f j k , Coon, J.J.^a c d i , Pagliarini, D.J.^{a b e h l}

^a Morgridge Institute for Research, Madison, WI 53715, United States
^b Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States
^d Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, United States
^e Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^f School of Biomedical Sciences, Faculty of Medicine, University of Queensland, Brisbane, QLD 4072, Australia
^g Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States
^h Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, United States
ⁱ National Center for Quantitative Biology of Complex Systems, Madison, WI 53706, United States
^j The University of Queensland, Institute for Molecular Bioscience, Brisbane, QLD 4072, Australia
^k The University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia
^l Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7 -/- mouse embryonic fibroblasts (MEFs) display a major increase in mitophagy that is reversed upon deletion of these receptors. Our phosphoproteomics analyses reveal a common set of elevated phosphosites between perinatal tissues, adult liver, and MEFs, including multiple sites on BNIP3 and NIX, and our molecular studies demonstrate that PPTC7 can directly interact with and dephosphorylate these proteins. These data suggest that Pptc7 deletion causes mitochondrial dysfunction via dysregulation of several metabolic pathways and that PPTC7 may directly regulate mitophagy receptor function or stability. Overall, our work reveals a significant role for PPTC7 in the mitophagic response and furthers the growing notion that management of mitochondrial protein phosphorylation is essential for ensuring proper organelle content and function. © 2023, Springer Nature Limited.

Funding details
National Institutes of HealthNIHR01DK101573, R01DK102948, RC2DK125961
Wisconsin Alumni Research FoundationWARF
Washington University in St. LouisWUSTL
University of Wisconsin Carbone Cancer CenterUWCCCP30CA014520
Diabetes Research Center, University of WashingtonDRC, UWP30DK020579, R35GM137894, T32G002760
BRAIN Foundation2020
Australian Research CouncilARCFT180100172
National Health and Medical Research CouncilNHMRCAPP1183915, APP2019993
Mito Foundation2022

Document Type: Article
Publication Stage: Final
Source: Scopus

Generalization of procedural motor sequence learning after a single practice trial
(2023) npj Science of Learning, 8 (1), art. no. 45, . 

Johnson, B.P.^a b , Iturrate, I.^a c , Fakhreddine, R.Y.^a d , Bönstrup, M.^e , Buch, E.R.^a , Robertson, E.M.^f , Cohen, L.G.^a

^a Human Cortical Physiology and Neurorehabilitation Section, NINDS, NIH, Bethesda, United States
^b Washington University in St Louis, St. Louis, United States
^c Amazon EU, Barcelona, Spain
^d UT Austin, Austin, United States
^e University of Leipzig, Leipzig, Germany
^f Center for Cognitive Neuroimaging, University of Glasgow, Scotland, Glasgow, United Kingdom

Abstract
When humans begin learning new motor skills, they typically display early rapid performance improvements. It is not well understood how knowledge acquired during this early skill learning period generalizes to new, related skills. Here, we addressed this question by investigating factors influencing generalization of early learning from a skill A to a different, but related skill B. Early skill generalization was tested over four experiments (N = 2095). Subjects successively learned two related motor sequence skills (skills A and B) over different practice schedules. Skill A and B sequences shared ordinal (i.e., matching keypress locations), transitional (i.e., ordered keypress pairs), parsing rule (i.e., distinct sequence events like repeated keypresses that can be used as a breakpoint for segmenting the sequence into smaller units) structures, or possessed no structure similarities. Results showed generalization for shared parsing rule structure between skills A and B after only a single 10-second practice trial of skill A. Manipulating the initial practice exposure to skill A (1 to 12 trials) and inter-practice rest interval (0–30 s) between skills A and B had no impact on parsing rule structure generalization. Furthermore, this generalization was not explained by stronger sensorimotor mapping between individual keypress actions and their symbolic representations. In contrast, learning from skill A did not generalize to skill B during early learning when the sequences shared only ordinal or transitional structure features. These results document sequence structure that can be very rapidly generalized during initial learning to facilitate generalization of skill. © 2023, Springer Nature Limited.

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDS

Document Type: Article
Publication Stage: Final
Source: Scopus

COVID-19 pandemic stressors are associated with reported increases in frequency of drunkenness among individuals with a history of alcohol use disorder
(2023) Translational Psychiatry, 13 (1), art. no. 311, . 

Meyers, J.L.^a , McCutcheon, V.V.^b , Horne-Osipenko, K.A.^a , Waters, L.R.^a , Barr, P.^a , Chan, G.^c , Chorlian, D.B.^a , Johnson, E.C.^b , Kuo, S.I.-C.^d , Kramer, J.R.^e , Dick, D.M.^d , Kuperman, S.^e , Kamarajan, C.^a , Pandey, G.^a , Singman, D.^a , de Viteri, S.S.-S.^a , Salvatore, J.E.^d , Bierut, L.J.^b , Foroud, T.^f , Goate, A.^f , Hesselbrock, V.^c , Nurnberger, J.^g h , Plaweck, M.H.^g h , Schuckit, M.A.ⁱ , Agrawal, A.^b , Edenberg, H.J.^g , Bucholz, K.K.^b , Porjesz, B.^a

^a Department of Psychiatry and Behavioral Sciences, State University of New York Downstate Medical Center, Brooklyn, NY, United States
^b Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ, United States
^e Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^f Departments of Genetics and Genomic Sciences, Neuroscience, and Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^g Department of Biochemistry and Molecular Biology and Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^h Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
ⁱ Department of Psychiatry, University of California San Diego Medical School, La JollaCA, United States

Abstract
Some sources report increases in alcohol use have been observed since the start of the COVID-19 pandemic, particularly among women. Cross-sectional studies suggest that specific COVID-19-related stressful experiences (e.g., social disconnection) may be driving such increases in the general population. Few studies have explored these topics among individuals with a history of Alcohol Use Disorders (AUD), an especially vulnerable population. Drawing on recent data collected by the Collaborative Study on the Genetics of Alcoholism (COGA; COVID-19 study N = 1651, 62% women, age range: 30–91) in conjunction with AUD history data collected on the sample since 1990, we investigated associations of COVID-19 related stressors and coping activities with changes in drunkenness frequency since the start of the pandemic. Analyses were conducted for those without a history of AUD (N: 645) and three groups of participants with a history of AUD prior to the start of the pandemic: (1) those experiencing AUD symptoms (N: 606), (2) those in remission who were drinking (N: 231), and (3) those in remission who were abstinent (had not consumed alcohol for 5+ years; N: 169). Gender-stratified models were also examined. Exploratory analyses examined the moderating effects of ‘problematic alcohol use’ polygenic risk scores (PRS) and neural connectivity (i.e., posterior interhemispheric alpha EEG coherence) on associations between COVID-19 stressors and coping activities with changes in the frequency of drunkenness. Increases in drunkenness frequency since the start of the pandemic were higher among those with a lifetime AUD diagnosis experiencing symptoms prior to the start of the pandemic (14% reported increased drunkenness) when compared to those without a history of AUD (5% reported increased drunkenness). Among individuals in remission from AUD prior to the start of the pandemic, rates of increased drunkenness were 10% for those who were drinking pre-pandemic and 4% for those who had previously been abstinent. Across all groups, women reported nominally greater increases in drunkenness frequency when compared with men, although only women experiencing pre-pandemic AUD symptoms reported significantly greater rates of increased drunkenness since the start of the pandemic compared to men in this group (17% of women vs. 5% of men). Among those without a prior history of AUD, associations between COVID-19 risk and protective factors with increases in drunkenness frequency were not observed. Among all groups with a history of AUD (including those with AUD symptoms and those remitted from AUD), perceived stress was associated with increases in drunkenness. Among the remitted-abstinent group, essential worker status was associated with increases in drunkenness. Gender differences in these associations were observed: among women in the remitted-abstinent group, essential worker status, perceived stress, media consumption, and decreased social interactions were associated with increases in drunkenness. Among men in the remitted-drinking group, perceived stress was associated with increases in drunkenness, and increased relationship quality was associated with decreases in drunkenness. Exploratory analyses indicated that associations between family illness or death with increases in drunkenness and increased relationship quality with decreases in drunkenness were more pronounced among the remitted-drinking participants with higher PRS. Associations between family illness or death, media consumption, and economic hardships with increases in drunkenness and healthy coping with decreases in drunkenness were more pronounced among the remitted-abstinent group with lower interhemispheric alpha EEG connectivity. Our results demonstrated that only individuals with pre-pandemic AUD symptoms reported greater increases in drunkenness frequency since the start of the COVID-19 pandemic compared to those without a lifetime history of AUD. This increase was more pronounced among women than men in this group. However, COVID-19-related stressors and coping activities were associated with changes in the frequency of drunkenness among all groups of participants with a prior history of AUD, including those experiencing AUD symptoms, as well as abstinent and non-abstinent participants in remission. Perceived stress, essential worker status, media consumption, social connections (especially for women), and relationship quality (especially for men) are specific areas of focus for designing intervention and prevention strategies aimed at reducing pandemic-related alcohol misuse among this particularly vulnerable group. Interestingly, these associations were not observed for individuals without a prior history of AUD, supporting prior literature that demonstrates that widespread stressors (e.g., pandemics, terrorist attacks) disproportionately impact the mental health and alcohol use of those with a prior history of problems. © 2023, Springer Nature Limited.

Funding details
National Institutes of HealthNIHU10AA008401
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA
Indiana UniversityIU
Washington University in St. LouisWUSTL
Icahn School of Medicine at Mount SinaiISMMS
University of Connecticut
University of California, San DiegoUCSD
Rutgers, The State University of New JerseyRU
Howard University
Roy J. and Lucille A. Carver College of Medicine, University of IowaCCOM

Document Type: Article
Publication Stage: Final
Source: Scopus

Deep representation learning identifies associations between physical activity and sleep patterns during pregnancy and prematurity
(2023) npj Digital Medicine, 6 (1), art. no. 171, . 

Ravindra, N.G.^a b c , Espinosa, C.^a b c , Berson, E.^a c d , Phongpreecha, T.^a c d , Zhao, P.^e f , Becker, M.^a b c , Chang, A.L.^a b c , Shome, S.^a b c , Marić, I.^a b c , De Francesco, D.^a b c , Mataraso, S.^a b c , Saarunya, G.^a b c , Thuraiappah, M.^a b c , Xue, L.^a b c , Gaudillière, B.^a , Angst, M.S.^a , Shaw, G.M.^b , Herzog, E.D.^e , Stevenson, D.K.^b , England, S.K.^f , Aghaeepour, N.^a b c

^a Department of Anesthesiology, Perioperative and Pain Medicine, Stanford School of Medicine, Stanford, CA, United States
^b Department of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
^c Department of Biomedical Data Science, Stanford University, Stanford, CA, United States
^d Department of Pathology, Stanford School of Medicine, Stanford, CA, United States
^e Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Preterm birth (PTB) is the leading cause of infant mortality globally. Research has focused on developing predictive models for PTB without prioritizing cost-effective interventions. Physical activity and sleep present unique opportunities for interventions in low- and middle-income populations (LMICs). However, objective measurement of physical activity and sleep remains challenging and self-reported metrics suffer from low-resolution and accuracy. In this study, we use physical activity data collected using a wearable device comprising over 181,944 h of data across N = 1083 patients. Using a new state-of-the art deep learning time-series classification architecture, we develop a ‘clock’ of healthy dynamics during pregnancy by using gestational age (GA) as a surrogate for progression of pregnancy. We also develop novel interpretability algorithms that integrate unsupervised clustering, model error analysis, feature attribution, and automated actigraphy analysis, allowing for model interpretation with respect to sleep, activity, and clinical variables. Our model performs significantly better than 7 other machine learning and AI methods for modeling the progression of pregnancy. We found that deviations from a normal ‘clock’ of physical activity and sleep changes during pregnancy are strongly associated with pregnancy outcomes. When our model underestimates GA, there are 0.52 fewer preterm births than expected (P = 1.01e − 67, permutation test) and when our model overestimates GA, there are 1.44 times (P = 2.82e − 39, permutation test) more preterm births than expected. Model error is negatively correlated with interdaily stability (P = 0.043, Spearman’s), indicating that our model assigns a more advanced GA when an individual’s daily rhythms are less precise. Supporting this, our model attributes higher importance to sleep periods in predicting higher-than-actual GA, relative to lower-than-actual GA (P = 1.01e − 21, Mann-Whitney U). Combining prediction and interpretability allows us to signal when activity behaviors alter the likelihood of preterm birth and advocates for the development of clinical decision support through passive monitoring and exercise habit and sleep recommendations, which can be easily implemented in LMICs. © 2023, Springer Nature Limited.

Funding details
National Institutes of HealthNIH19PABHI34580007, 1R01HL139844, P01HD106414, P30AG066515, R01AG058417, R01HD105256, R35GM138353, R61NS114926
Burroughs Wellcome FundBWF1019816
Bill and Melinda Gates FoundationBMGFINV-001734, INV-003225, OPP1113682
March of Dimes FoundationMDF
American Heart AssociationAHA19PAB / HI34580007
Robertson Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

A cross-sectional study: Association between tobacco/alcohol usage and mental health with disabilities
(2023) Mental Health and Prevention, 32, art. no. 200302, . 

Huang, Y.^a b , Loux, T.^a

^a Department of Epidemiology and Biostatistics, Saint Louis University College for Public Health and Social Justice, Salus Center, 3545 Lafayette Ave, St. Louis, MO 63110, United States
^b Department of Radiation Oncology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States

Abstract
Tobacco and alcohol use are significant public health issues that have been linked to numerous negative mental health outcomes. Numerous studies have established the significant association between tobacco/alcohol usage and mental issues. Smoking tobacco has been linked to a higher risk of developing anxiety disorders and depression. Nicotine, the addictive substance in tobacco, can temporarily alleviate stress and anxiety, but its long-term use can lead to increased anxiety and depression symptoms. Alcohol consumption is also a known factor for both depression and anxiety disorders. Its abuse can disrupt the brain’s chemistry, leading to mood swings, increased anxiety and depressive symptoms. However, there has been relatively less focus on understanding how disability status influence the association between tobacco/alcohol usage and mental health. For individuals with disabilities, these risks are often compounded by a range of factors, such as social isolation, poverty, and limited access to healthcare. In this paper, 27,170 participants with/without disability were used to examine the association between tobacco and alcohol usage and mental health outcomes. Objective: This cross-sectional study aims to investigate the relationship between tobacco and alcohol use and mental health outcomes among individuals with and without disabilities, using data from the 2020 National Survey on Drug Use and Health (NSDUH). Methods: In this study, we conducted bivariate analysis to compare baseline covariates between respondents reporting serious mental issues and those not. To mitigate nonresponse bias, we applied multiple imputation by chained equations before modeling. Linear regression models were subsequently employed to explore the association between tobacco/alcohol usage and K6 scores, considering differences by disability status. The research design was cross-sectional, involving a substantial cohort of 27,170 participants. Results: Our findings indicate that both tobacco and alcohol use, along with disability, are associated with higher K6 scores, indicative of poorer mental health. Specifically, the interaction between disability and tobacco usage contributes to additional points on the K6 score. However, when excluding tobacco consumption, the interaction term between alcohol use and disability status was not found to be statistically significant. Conclusions: Based on nationally representative survey data, our study reveals that individuals using tobacco and alcohol are more likely to report symptoms of serious mental health issues compared to non-users. Furthermore, we highlight the interaction effect between disability and tobacco consumption, which amplifies the risk of poor mental health among this vulnerable population. © 2023 Elsevier GmbH

Author Keywords
Disability;  Mental health;  Tobacco/Alcohol consumption

Document Type: Article
Publication Stage: Final
Source: Scopus

Severity of posttraumatic stress disorder, type 2 diabetes outcomes and all-cause mortality: A retrospective cohort study
(2023) Journal of Psychosomatic Research, 175, art. no. 111510, . 

Salas, J.^a b , Wang, W.^a , Schnurr, P.P.^c , Cohen, B.E.^d , Freedland, K.E.^e , Jaffe, A.S.^f , Lustman, P.J.^e , Friedman, M.^c , Scherrer, J.F.^a b g

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO, United States
^b The Advanced HEAlth Data (AHEAD) Research Institute, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO, United States
^c National Center for PTSD, White River Junction, VT, and Department of Psychiatry, Geisel School of Medicine at Dartmouth, Hanover, NH, United States
^d Department of Medicine, University of California San Francisco School of Medicine and San Francisco VAMC, San Francisco, CA, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Cardiovascular Medicine and Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
^g Department of Psychiatry and Behavioral Neuroscience, School of Medicine, Saint Louis University, St. Louis, MO, United States

Abstract
Background: Some evidence suggests patients with comorbid PTSD and type 2 diabetes (T2D) have worse T2D outcomes than those with T2D alone. However, there is no evidence regarding PTSD severity and risk for starting insulin, hyperglycemia, microvascular complications, and all-cause mortality. Methods: In this retrospective cohort study, Veterans Health Affairs (VHA) medical record data from fiscal year (FY) 2012 to FY2022 were used to identify eligible patients (n = 23,161) who had a PTSD diagnosis, ≥1 PTSD Checklist score, controlled T2D (HbA1c ≤ 7.5) without microvascular complications at baseline. PTSD Checklist for DSM-5 (PCL-5) scores defined mild, moderate, and severe PTSD. Competing risk and survival models estimated the association between PTSD severity and T2D outcomes before and after controlling for confounding. Results: Most (70%) patients were ≥ 50 years of age, 88% were male, 64.2% were of white race and 17.1% had mild, 67.4% moderate and 15.5% severe PTSD. After control for confounding, as compared to mild PTSD, moderate (HR = 1.05; 95% CI:1.01–1.11) and severe PTSD (HR = 1.15; 95%CI:1.07–1.23) were significantly associated with increased risk for microvascular complication. Hyperarousal was associated with a 42% lower risk of starting insulin. Negative mood was associated with a 16% increased risk for any microvascular complication. Severe PTSD was associated with a lower risk for all-cause mortality (HR = 0.76; 95%CI:0.63–0.91). Conclusions: Patients with comorbid PTSD and T2D have an increased risk for microvascular complications. However, they have lower mortality risk perhaps due to more health care use and earlier chronic disease detection. PTSD screening among patients with T2D may be warranted. © 2023 Elsevier Inc.

Author Keywords
Epidemiology;  Insulin;  Microvascular;  PTSD;  Type 2 diabetes;  Veterans

Funding details
98-004, SDR 02-237
U.S. Department of Veterans AffairsVA
Health Services Research and DevelopmentHSR&D

Document Type: Article
Publication Stage: Final
Source: Scopus

A novel immune modulator IM33 mediates a glia-gut-neuronal axis that controls lifespan
(2023) Neuron, 111 (20), pp. 3244-3254.e8. 

Xu, W.^a b , Rustenhoven, J.^a b c d , Nelson, C.A.^b , Dykstra, T.^a b , Ferreiro, A.^e f , Papadopoulos, Z.^a b g , Burnham, C.-A.D.^b , Dantas, G.^b e f h , Fremont, D.H.^b h i j , Kipnis, J.^a b g

^a Brain Immunology and Glia (BIG) Center, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^b Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^c Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand
^d Centre for Brain Research, The University of Auckland, Auckland, New Zealand
^e The Edison Family Center for Genome Sciences and Systems Biology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^g Neuroscience Graduate Program, School of Medicine, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
^h Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
ⁱ The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Biochemistry & Molecular Biophysics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Aging is a complex process involving various systems and behavioral changes. Altered immune regulation, dysbiosis, oxidative stress, and sleep decline are common features of aging, but their interconnection is poorly understood. Using Drosophila, we discover that IM33, a novel immune modulator, and its mammalian homolog, secretory leukocyte protease inhibitor (SLPI), are upregulated in old flies and old mice, respectively. Knockdown of IM33 in glia elevates the gut reactive oxygen species (ROS) level and alters gut microbiota composition, including increased Lactiplantibacillus plantarum abundance, leading to a shortened lifespan. Additionally, dysbiosis induces sleep fragmentation through the activation of insulin-producing cells in the brain, which is mediated by the binding of Lactiplantibacillus plantarum-produced DAP-type peptidoglycan to the peptidoglycan recognition protein LE (PGRP-LE) receptor. Therefore, IM33 plays a role in the glia-microbiota-neuronal axis, connecting neuroinflammation, dysbiosis, and sleep decline during aging. Identifying molecular mediators of these processes could lead to the development of innovative strategies for extending lifespan. © 2023 Elsevier Inc.

Author Keywords
brain-gut axis;  Drosophila;  glia-gut axis;  IM33;  longevity;  neuroimmunology

Funding details
R01-AT009741
National Institutes of HealthNIHP40OD018537
Washington University in St. LouisWUSTL
University of VirginiaUV
National Center for Complementary and Integrative HealthNCCIHDP1AT010416

Document Type: Article
Publication Stage: Final
Source: Scopus

Time- and region-dependent blood-brain barrier impairment in a rat model of organophosphate-induced status epilepticus
(2023) Neurobiology of Disease, 187, art. no. 106316, . 

Bernardino, P.N.^a , Hobson, B.A.^b , Huddleston, S.L.^b , Andrew, P.M.^a , MacMahon, J.A.^a , Saito, N.H.^c , Porter, V.A.^d , Bruun, D.A.^a , Harvey, D.J.^c , Garbow, J.R.^e , Gelli, A.^f , Chaudhari, A.J.^b g , Lein, P.J.^a

^a Department of Molecular Biosciences, University of California, Davis, School of Veterinary Medicine, Davis, CA 95616, United States
^b Center for Molecular and Genomic Imaging, University of California, Davis, Davis, CA 95616, United States
^c Department of Public Health Sciences, University of California, Davis, School of Medicine, Davis, CA 95616, United States
^d Department of Biomedical Engineering, University of California, Davis, College of Engineering, Davis, CA 95616, United States
^e Biomedical Magnetic Resonance Center, Mallinckrodt Institute of Radiology, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
^f Department of Pharmacology, University of California, Davis, School of Medicine, Davis, CA 95616, United States
^g Department of Radiology, University of California, Davis, School of Medicine, Sacramento, CA 95817, United States

Abstract
Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication. © 2023 The Authors

Author Keywords
Albumin;  Blood-brain barrier impairment;  Diisopropylfluorophosphate;  Epilepsy;  MRI;  Organophosphate;  Spontaneous recurrent seizures

Funding details
National Institute of Neurological Disorders and StrokeNINDSNS079202, NS127758
School of Veterinary Medicine, University of California, Davis
Politeknik Negeri BaliPNB

Document Type: Article
Publication Stage: Final
Source: Scopus

Intracranial stimulation and EEG feature analysis reveal affective salience network specialization
(2023) Brain: A Journal of Neurology, 146 (10), pp. 4366-4377. 

Metzger, B.A.^a , Kalva, P.^b , Mocchi, M.M.^b , Cui, B.^b , Adkinson, J.A.^b , Wang, Z.^c , Mathura, R.^b , Kanja, K.^b , Gavvala, J.^d , Krishnan, V.^d , Lin, L.^d , Maheshwari, A.^d , Shofty, B.^e , Magnotti, J.F.^c , Willie, J.T.^f , Sheth, S.A.^b , Bijanki, K.R.^b

^a Department of Psychology, Swarthmore College, PA 19081, Swarthmore, United States
^b Department of Neurosurgery, Baylor College of Medicine, Houston, TX 77030, United States
^c Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^d Department of Neurology, Baylor College of Medicine, Houston, TX 77030, United States
^e Department of Neurosurgery, University of Utah Health, Salt Lake City, UT 84132, United States
^f Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States

Abstract
Emotion is represented in limbic and prefrontal brain areas, herein termed the affective salience network (ASN). Within the ASN, there are substantial unknowns about how valence and emotional intensity are processed-specifically, which nodes are associated with affective bias (a phenomenon in which participants interpret emotions in a manner consistent with their own mood). A recently developed feature detection approach (‘specparam’) was used to select dominant spectral features from human intracranial electrophysiological data, revealing affective specialization within specific nodes of the ASN. Spectral analysis of dominant features at the channel level suggests that dorsal anterior cingulate (dACC), anterior insula and ventral-medial prefrontal cortex (vmPFC) are sensitive to valence and intensity, while the amygdala is primarily sensitive to intensity. Akaike information criterion model comparisons corroborated the spectral analysis findings, suggesting all four nodes are more sensitive to intensity compared to valence. The data also revealed that activity in dACC and vmPFC were predictive of the extent of affective bias in the ratings of facial expressions-a proxy measure of instantaneous mood. To examine causality of the dACC in affective experience, 130 Hz continuous stimulation was applied to dACC while patients viewed and rated emotional faces. Faces were rated significantly happier during stimulation, even after accounting for differences in baseline ratings. Together the data suggest a causal role for dACC during the processing of external affective stimuli. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
affective salience network;  anterior cingulate;  brain stimulation;  emotion;  intracranial EEG

Document Type: Article
Publication Stage: Final
Source: Scopus

Biallelic variants in COQ7 cause distal hereditary motor neuropathy with upper motor neuron signs
(2023) Brain: A Journal of Neurology, 146 (10), pp. 4191-4199. 

Rebelo, A.P.^a , Tomaselli, P.J.^b , Medina, J.^a , Wang, Y.^c , Dohrn, M.F.^a d , Nyvltova, E.^e , Danzi, M.C.^a , Garrett, M.^f , Smith, S.E.^f , Pestronk, A.^f , Li, C.^f , Ruiz, A.^a , Jacobs, E.^a , Feely, S.M.E.^g , França, M.C.^b , Gomes, M.V.^b , Santos, D.F.^h , Kumar, S.ⁱ , Lombard, D.B.ⁱ , Saporta, M.^a , Hekimi, S.^c , Barrientos, A.^e , Weihl, C.^f , Shy, M.E.^g , Marques, W.^b , Zuchner, S.^a

^a Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL 33136, United States
^b Department of Neurology, University of São Paulo, Ribeirão Preto, 14048-900, Brazil
^c Department of Biology, McGill University, Montreal, QC H3A 1A1, Canada
^d Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, 52074, Germany
^e Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, United States
^f Department of Neurology, Washington University, St. Louis, United States
^g Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States
^h Department of Neurology, Federal University of Uberlândia, Uberlândia, MG 38405-320, Brazil
ⁱ Department of Pathology & Laboratory Medicine, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, United States

Abstract
COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary CoQ10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder. We identified COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy with upper neuron involvement, expending the clinical phenotype associated with defects in this gene. A recurrent p.Met1? change was identified in five families from Brazil with evidence of a founder effect. Fibroblasts isolated from patients revealed a substantial depletion of COQ7 protein levels, indicating protein instability leading to loss of enzyme function. High-performance liquid chromatography assay showed that fibroblasts from patients had reduced levels of CoQ10, and abnormal accumulation of the biosynthetic precursor DMQ10. Accordingly, fibroblasts from patients displayed significantly decreased oxygen consumption rates in patients, suggesting mitochondrial respiration deficiency. Induced pluripotent stem cell-derived motor neurons from patient fibroblasts showed significantly increased levels of extracellular neurofilament light protein, indicating axonal degeneration. Our findings indicate a molecular pathway involving CoQ10 biosynthesis deficiency and mitochondrial dysfunction in patients with distal hereditary motor neuropathy. Further studies will be important to evaluate the potential benefits of CoQ10 supplementation in the clinical outcome of the disease. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
charcot-Marie-Tooth disease;  coQ10;  hereditary motor neuropathy;  mitochondria;  motor neuron

Document Type: Article
Publication Stage: Final
Source: Scopus

Peripheral CCL2-CCR2 signalling contributes to chronic headache-related sensitization
(2023) Brain: A Journal of Neurology, 146 (10), pp. 4274-4291. 

Ryu, S., Liu, X., Guo, T., Guo, Z., Zhang, J., Cao, Y.-Q.

Department of Anesthesiology and Washington University Pain Center, Washington University School of Medicine, Campus Box MSC 8054-86-05, St. Louis, MO 63110, United States

Abstract
Migraine, especially chronic migraine, is highly debilitating and still lacks effective treatment. The persistent headache arises from activation and sensitization of primary afferent neurons in the trigeminovascular pathway, but the underlying mechanisms remain incompletely understood. Animal studies indicate that signalling through chemokine C-C motif ligand 2 (CCL2) and C-C motif chemokine receptor 2 (CCR2) mediates the development of chronic pain after tissue or nerve injury. Some migraine patients had elevated CCL2 levels in CSF or cranial periosteum. However, whether the CCL2-CCR2 signalling pathway contributes to chronic migraine is not clear. Here, we modelled chronic headache with repeated administration of nitroglycerin (NTG, a reliable migraine trigger in migraineurs) and found that both Ccl2 and Ccr2 mRNA were upregulated in dura and trigeminal ganglion (TG) tissues that are implicated in migraine pathophysiology. In Ccl2 and Ccr2 global knockout mice, repeated NTG administration did not evoke acute or persistent facial skin hypersensitivity as in wild-type mice. Intraperitoneal injection of CCL2 neutralizing antibodies inhibited chronic headache-related behaviours induced by repeated NTG administration and repetitive restraint stress, suggesting that the peripheral CCL2-CCR2 signalling mediates headache chronification. We found that CCL2 was mainly expressed in TG neurons and cells associated with dura blood vessels, whereas CCR2 was expressed in subsets of macrophages and T cells in TG and dura but not in TG neurons under both control and disease states. Deletion of Ccr2 gene in primary afferent neurons did not alter NTG-induced sensitization, but eliminating CCR2 expression in either T cells or myeloid cells abolished NTG-induced behaviours, indicating that both CCL2-CCR2 signalling in T cells and macrophages are required to establish chronic headache-related sensitization. At cellular level, repeated NTG administration increased the number of TG neurons that responded to calcitonin-gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) as well as the production of CGRP in wild-type but not Ccr2 global knockout mice. Lastly, co-administration of CCL2 and CGRP neutralizing antibodies was more effective in reversing NTG-induced behaviours than individual antibodies. Taken together, these results suggest that migraine triggers activate CCL2-CCR2 signalling in macrophages and T cells. This consequently enhances both CGRP and PACAP signalling in TG neurons, ultimately leading to persistent neuronal sensitization underlying chronic headache. Our work not only identifies the peripheral CCL2 and CCR2 as potential targets for chronic migraine therapy, but also provides proof-of-concept that inhibition of both peripheral CGRP and CCL2-CCR2 signalling is more effective than targeting either pathway alone. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
CCL2;  CCR2;  headache;  migraine;  neuroimmune interaction;  peripheral sensitization

Document Type: Article
Publication Stage: Final
Source: Scopus

Was COVID-19 Associated With Worsening Inequities in Stroke Treatment and Outcomes?
(2023) Journal of the American Heart Association, 12 (19), p. e031221. 

Glance, L.G.^a b c , Benesch, C.G.^d , Joynt Maddox, K.E.^e f , Bender, M.T.^g , Shang, J.^h , Stone, P.W.^h , Lustik, S.J.^a , Nadler, J.W.^a , Galton, C.^a , Dick, A.W.^c

^a Department of Anesthesiology and Perioperative Medicine University of Rochester School of Medicine Rochester NY
^b Department of Public Health Sciences University of Rochester School of Medicine Rochester NY
^c RAND Health, RAND Boston MA
^d Department of Neurology University of Rochester School of Medicine Rochester NY
^e Department of Medicine Washington University in St. Louis St. Louis MO
^f Center for Health Economics and Policy at the Institute for Public Health Washington University in St. Louis St. Louis MO
^g Department of Neurosurgery University of Rochester School of Medicine Rochester NY
^h Columbia School of Nursing, Center for Health Policy New York NY

Abstract
Background COVID-19 stressed hospitals and may have disproportionately affected the stroke outcomes and treatment of Black and Hispanic individuals. Methods and Results This retrospective study used 100% Medicare Provider Analysis and Review file data from between 2016 and 2020. We used interrupted time series analyses to examine whether the COVID-19 pandemic exacerbated disparities in stroke outcomes and reperfusion therapy. Among 1 142 560 hospitalizations for acute ischemic strokes, 90 912 (8.0%) were Hispanic individuals; 162 752 (14.2%) were non-Hispanic Black individuals; and 888 896 (77.8%) were non-Hispanic White individuals. The adjusted odds of mortality increased by 51% (adjusted odds ratio [aOR], 1.51 [95% CI, 1.34-1.69]; P<0.001), whereas the rates of nonhome discharges decreased by 11% (aOR, 0.89 [95% CI, 0.82-0.96]; P=0.003) for patients hospitalized during weeks when the hospital’s proportion of patients with COVID-19 was >30%. The overall rates of motor deficits (P=0.25) did not increase, and the rates of reperfusion therapy did not decrease as the weekly COVID-19 burden increased. Black patients had lower 30-day mortality (aOR, 0.70 [95% CI, 0.69-0.72]; P<0.001) but higher rates of motor deficits (aOR, 1.14 [95% CI, 1.12-1.16]; P<0.001) than White individuals. Hispanic patients had lower 30-day mortality and similar rates of motor deficits compared with White individuals. There was no differential increase in adverse outcomes or reduction in reperfusion therapy among Black and Hispanic individuals compared with White individuals as the weekly COVID-19 burden increased. Conclusions This national study of Medicare patients found no evidence that the hospital COVID-19 burden exacerbated disparities in treatment and outcomes for Black and Hispanic individuals admitted with an acute ischemic stroke.

Author Keywords
COVID‐19;  disparities;  equity;  stroke

Document Type: Article
Publication Stage: Final
Source: Scopus

Feeling uncertain despite knowing the risk: Patients with OCD (but not controls) experience known and unknown probabilistic decisions as similarly distressing and uncertain
(2023) Journal of Obsessive-Compulsive and Related Disorders, 39, art. no. 100842, . 

Jacoby, R.J.^a , Szkutak, A.^b , Shin, J.^c , Lerner, J.^d , Wilhelm, S.^a

^a Massachusetts General Hospital/Harvard Medical School, 185 Cambridge Street, Suite 2000, Boston, MA 02114, United States
^b Teachers College, Columbia University, 422F Thompson Hall, 525 W 120th Street, New York, NY 10027, United States
^c Washington University in St. Louis, CB 1125, One Brookings Drive, St. Louis, MO 63130-4899, United States
^d Harvard Kennedy School, 79 John F. Kennedy Street, Cambridge, MA 02138, United States

Abstract
Patients with obsessive compulsive disorder (OCD) present as risk-averse and avoidant of feared stimuli, yet the literature examining risk aversion in OCD is conflicting. One possible explanation is that patients may exhibit aversion only on ambiguous tasks where the likelihood of possible outcomes is unknown. To test this idea, the current study assigned 30 patients with OCD versus 30 non-psychiatric controls (NPC) to conditions of known versus unknown risk (i.e., probabilities) on the Beads Task. Importantly, the task involved real financial stakes. We also examined self-reported intolerance of uncertainty (IU) as a mechanism. Results revealed a significant risk information × group interaction for certainty about the decision. Specifically, while NPCs felt significantly less certain on the unknown risk (versus known risk) task, the OCD group felt uncertain regardless of risk information. Results also revealed a significant main effect of group for distress after deciding, such that the OCD group was more distressed across all task versions compared to NPCs. Elevated trait IU was associated with higher task-related distress. Results indicate that even when patients with OCD are given information about likelihoods, they still feel uncertain and experience distress. Findings have clinical implications for addressing risk aversion and ambiguity/uncertainty in treatment. © 2023 Elsevier Inc.

Author Keywords
Behavioral assessment;  Decision making;  Obsessive compulsive disorder;  Uncertainty

Funding details
K23 MH120351
National Science FoundationNSF1R01CA224545-01A1, SES1559511
National Institutes of HealthNIH
National Institute of Mental HealthNIMHK23MH120351
Centers for Disease Control and PreventionCDC
WILEY
International OCD FoundationIOCDF
Harvard University
Tourette Association of AmericaTAA
Department of Psychology, Harvard University

Document Type: Article
Publication Stage: Final
Source: Scopus

Genetics of vegetarianism: A genome-wide association study
(2023) PLoS ONE, 18 (10 October), art. no. e0291305, . 

Yaseen, N.R.^a , Barnes, C.L.K.^b , Sun, L.^c , Takeda, A.^d , Rice, J.P.^c

^a Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^b Fios Genomics, Edinburgh, United Kingdom
^c Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Retired, St. Louis, MO, United States

Abstract
A substantial body of evidence points to the heritability of dietary preferences. While vegetarianism has been practiced for millennia in various societies, its practitioners remain a small minority of people worldwide, and the role of genetics in choosing a vegetarian diet is not well understood. Dietary choices involve an interplay between the physiologic effects of dietary items, their metabolism, and taste perception, all of which are strongly influenced by genetics. In this study, we used a genome-wide association study (GWAS) to identify loci associated with strict vegetarianism in UK Biobank participants. Comparing 5,324 strict vegetarians to 329,455 controls, we identified one SNP on chromosome 18 that is associated with vegetarianism at the genome-wide significant level (rs72884519, β = -0.11, P = 4.997 x 10−8), and an additional 201 suggestively significant variants. Four genes are associated with rs72884519: TMEM241, RIOK3, NPC1, and RMC1. Using the Functional Mapping and Annotation (FUMA) platform and the Multi-marker Analysis of GenoMic Annotation (MAGMA) tool, we identified 34 genes with a possible role in vegetarianism, 3 of which are GWAS-significant based on gene-level analysis: RIOK3, RMC1, and NPC1. Several of the genes associated with vegetarianism, including TMEM241, NPC1, and RMC1, have important functions in lipid metabolism and brain function, raising the possibility that differences in lipid metabolism and their effects on the brain may underlie the ability to subsist on a vegetarian diet. These results support a role for genetics in choosing a vegetarian diet and open the door to future studies aimed at further elucidating the physiologic pathways involved in vegetarianism. Copyright: © 2023 Yaseen et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

Incorporating physics to overcome data scarcity in predictive modeling of protein function: A case study of BK channels
(2023) PLoS Computational Biology, 19 (9), art. no. e1011460, . 

Nordquist, E.^a , Zhang, G.^b , Barethiya, S.^a , Ji, N.^c , White, K.M.^b , Han, L.^b , Jia, Z.^a , Shi, J.^b , Cui, J.^b , Chen, J.^a

^a Department of Chemistry, University of Massachusetts Amherst, Amherst, MA, United States
^b Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Biology, Boston College, Chestnut Hill, MA, United States

Abstract
Machine learning has played transformative roles in numerous chemical and biophysical problems such as protein folding where large amount of data exists. Nonetheless, many important problems remain challenging for data-driven machine learning approaches due to the limitation of data scarcity. One approach to overcome data scarcity is to incorporate physical principles such as through molecular modeling and simulation. Here, we focus on the big potassium (BK) channels that play important roles in cardiovascular and neural systems. Many mutants of BK channel are associated with various neurological and cardiovascular diseases, but the molecular effects are unknown. The voltage gating properties of BK channels have been characterized for 473 site-specific mutations experimentally over the last three decades; yet, these functional data by themselves remain far too sparse to derive a predictive model of BK channel voltage gating. Using physics-based modeling, we quantify the energetic effects of all single mutations on both open and closed states of the channel. Together with dynamic properties derived from atomistic simulations, these physical descriptors allow the training of random forest models that could reproduce unseen experimentally measured shifts in gating voltage, ΔV1/2, with a RMSE ~ 32 mV and correlation coefficient of R ~ 0.7. Importantly, the model appears capable of uncovering nontrivial physical principles underlying the gating of the channel, including a central role of hydrophobic gating. The model was further evaluated using four novel mutations of L235 and V236 on the S5 helix, mutations of which are predicted to have opposing effects on V1/2 and suggest a key role of S5 in mediating voltage sensor-pore coupling. The measured ΔV1/2 agree quantitatively with prediction for all four mutations, with a high correlation of R = 0.92 and RMSE = 18 mV. Therefore, the model can capture nontrivial voltage gating properties in regions where few mutations are known. The success of predictive modeling of BK voltage gating demonstrates the potential of combining physics and statistical learning for overcoming data scarcity in nontrivial protein function prediction. Copyright: © 2023 Nordquist et al.

Funding details
T32 GM008515, T32 GM139789
National Institutes of HealthNIHR01 HL070393, R01 HL142301, R35 GM144045, RO1 NS060706

Document Type: Article
Publication Stage: Final
Source: Scopus

Toward peripheral nerve mechanical characterization using Brillouin imaging spectroscopy
(2023) Neurophotonics, 10 (3), art. no. 035007, . Cited 1 time.

Cheburkanov, V.^a , Du, J.^b c , Brogan, D.M.^d , Berezin, M.Y.^b c , Yakovlev, V.V.^a

^a Texas A&M University, Department of Biomedical Engineering, College Station, TX, United States
^b Washington University School of Medicine, Department of Radiology, St. Louis, MO, United States
^c Washington University, Institute of Materials Science and Engineering, St. Louis, MO, United States
^d Washington University School of Medicine, Department of Orthopedic Surgery, St. Louis, MO, United States

Abstract
Significance: Peripheral nerves are viscoelastic tissues with unique elastic characteristics. Imaging of peripheral nerve elasticity is important in medicine, particularly in the context of nerve injury and repair. Elasticity imaging techniques provide information about the mechanical properties of peripheral nerves, which can be useful in identifying areas of nerve damage or compression, as well as assessing the success of nerve repair procedures. Aim: We aim to assess the feasibility of Brillouin microspectroscopy for peripheral nerve imaging of elasticity, with the ultimate goal of developing a new diagnostic tool for peripheral nerve injury in vivo. Approach: Viscoelastic properties of the peripheral nerve were evaluated with Brillouin imaging spectroscopy. Results: An external stress exerted on the fixed nerve resulted in a Brillouin shift. Quantification of the shift enabled correlation of the Brillouin parameters with nerve elastic properties. Conclusions: Brillouin microscopy provides sufficient sensitivity to assess viscoelastic properties of peripheral nerves. © The Authors.

Author Keywords
brillouin;  confocal imaging;  ex vivo;  nerve

Funding details
National Science FoundationNSFCMMI-1826078
National Institutes of HealthNIHR01GM127696, R21CA269099, R21GM142107
U.S. Food and Drug AdministrationFDA80ARC023CA002, R01 CA208623
National Aeronautics and Space AdministrationNASA
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0366, FA9550-20-1-0367
Army Research LaboratoryARLW911NF-17-2-0144
Biomedical Advanced Research and Development AuthorityBARDA

Document Type: Article
Publication Stage: Final
Source: Scopus

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable
(2023) Neurorehabilitation and Neural Repair, . 

Hayward, K.S.^a , Dalton, E.J.^a , Barth, J.^b , Brady, M.^c , Cherney, L.R.^d , Churilov, L.^a , Clarkson, A.N.^e , Dawson, J.^f , Dukelow, S.P.^g , Feys, P.^h , Hackett, M.ⁱ , Zeiler, S.R.^j , Lang, C.E.^k

^a The University of Melbourne, Melbourne, VIC, Australia
^b Providence VA Medical Center, Providence, RI, United States
^c Glasgow Caledonian University, Glasgow, United Kingdom
^d Shirley Ryan AbilityLab, Chicago, IL, United States
^e University of Otago, Dunedin, New Zealand
^f University of Glasgow, Glasgow, United Kingdom
^g University of Calgary, Calgary, AB, Canada
^h Reval University of Hasselt, Hasselt, Belgium
ⁱ University of New South Wales, Sydney, NSW, Australia
^j Johns Hopkins University, Baltimore, MD, United States
^k Washington University School of Medicine, St. Louis, MO, United States

Abstract
Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. “Identifying appropriate type of control” was ranked easy to address and very important, “variability in usual care” was ranked hard to address and of low importance, and “understanding the content of the control and how it differs from the experimental intervention” was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders. © The Author(s) 2023.

Author Keywords
Clinical trial;  consensus;  control;  preclinical;  recovery;  rehabilitation;  stroke

Funding details
GNT2015705
Ipsen

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

Longitudinal predictors of health-related quality of life in isolated dystonia
(2023) Journal of Neurology, . 

Junker, J.^a b , Hall, J.^c , Berman, B.D.^d , Vidailhet, M.^e f , Roze, E.^e , Bäumer, T.^g , Malaty, I.A.^h , Shukla, A.W.^h , Jankovic, J.ⁱ , Reich, S.G.^j , Espay, A.J.^k , Duque, K.R.^k , Patel, N.^l , Perlmutter, J.S.^m , Jinnah, H.A.ⁿ , Brandt, V.^o , Brüggemann, N.^a b

^a Department of Neurology, University of Luebeck, Ratzeburger Allee 160, SH, Lübeck, 23538, Germany
^b Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
^c Southampton Education School, University of Southampton, Southampton, United Kingdom
^d Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
^e Departement de Neurologie, AP-HP, Hopital de La Pitie-Salpetriere, Paris, France
^f Institut du Cerveau_ Paris Brain Institute-ICM, INSERM 1127, CNRS 7225, Sorbonne Université, Paris, France
^g Institute of Systems Motor Science, University of Luebeck, Luebeck, Germany
^h Department of Neurology, Fixel Institute for Neurologic Disorders, University of Florida, Gainesville, FL, United States
ⁱ Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States
^j Department of Neurology, School of Medicine, University of Maryland, Baltimore, MD, United States
^k Department of Neurology, University of Cincinnati, Cincinnati, OH, United States
^l RUSH Parkinson’s Disease and Movement Disorders Center, Department of Neurological Science, RUSH University Medical Center Chicago, Chicago, IL, United States
^m Departments of Neurology, Radiology and Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
ⁿ Department of Neurology and Human Genetics, Emory University, Atlanta, GA, United States
^o School of Psychology, Centre for Innovation in Mental Health, University of Southampton, Southampton, United Kingdom

Abstract
Objective: To determine longitudinal predictors of health-related quality of life (HR-QoL) in an international multicenter cohort of patients with isolated dystonia. Methods: Out of 603 dystonia patients prospectively enrolled in the Natural History Dystonia Coalition study, 155 were assessed three times within 2 years for HR-QoL, symptoms of depression, generalized anxiety disorder (GAD), and social anxiety disorder (SAD), as well as dystonia severity and dystonic tremor. In addition, the impact of botulinum neurotoxin (BoNT) injections on HR-QoL was evaluated after 1 year. Results: Depressive symptoms at baseline predicted lower HR-QoL on all subscales after 2 years (all p ≤ 0.001). Higher GAD scores at baseline predicted lower HR-QoL related to general health, pain and emotional well-being, whereas higher SAD scores predicted higher pain-related QoL after 2 years (all p ≤ 0.006). Dystonia severity at baseline predicted social functioning (p = 0.002). Neither dystonic tremor, age, or sex predicted HR-QoL at 2 years. Two latent categories were revealed across the three-time points: Category 1 with higher total HR-QoL scores (mean HR-QoL = 74.4% ± 16.1), susceptible to symptoms of depression and SAD, and Category 2 with lower total HR-QoL scores (mean HR-QoL = 45.5% ± 17.6), susceptible to symptoms of GAD. HR-QoL improved over the course of 1 year irrespective of the use of BoNT. Conclusion: The longitudinal impact of psychiatric symptoms on HR-QoL emphasizes the importance of incorporating mental health treatment, in particular also the therapy of anxiety disorders, into treatment regimens for dystonia. © 2023, The Author(s).

Author Keywords
Anxiety;  BoNT;  Depression;  Dystonia;  Quality of life

Funding details
U54 TR001456
National Institute of Neurological Disorders and StrokeNINDSU54 NS065701, U54 NS116025
Dystonia CoalitionDC
Rare Diseases Clinical Research NetworkRDCRN

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

Geroscience-Centric Perspective for Geriatric Psychiatry: Integrating Aging Biology With Geriatric Mental Health Research
(2023) American Journal of Geriatric Psychiatry, . 

Diniz, B.S.^a , Seitz-Holland, J.^b c , Sehgal, R.^d , Kasamoto, J.^d , Higgins-Chen, A.T.^e f , Lenze, E.^g

^a UConn Center on Aging & Department of Psychiatry (BSD), School of Medicine, University of Connecticut Health Center, Farmington, CT, United States
^b Department of Psychiatry (JSH), Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^c Department of Psychiatry (JSH), Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^d Program in Computational Biology and Bioinformatics (RS, JK), Yale University, New Haven, CT, United States
^e Department of Psychiatry (ATHC), Yale University School of Medicine, New Haven, CT, United States
^f Department of Pathology (ATHC), Yale University School of Medicine, New Haven, CT, United States
^g Department of Psychiatry (EL), School of Medicine, Washington University at St. Louis, St. Louis, MO, United States

Abstract
The geroscience hypothesis asserts that physiological aging is caused by a small number of biological pathways. Despite the explosion of geroscience research over the past couple of decades, the research on how serious mental illnesses (SMI) affects the biological aging processes is still in its infancy. In this review, we aim to provide a critical appraisal of the emerging literature focusing on how we measure biological aging systematically, and in the brain and how SMIs affect biological aging measures in older adults. We will also review recent developments in the field of cellular senescence and potential targets for interventions for SMIs in older adults, based on the geroscience hypothesis. © 2023 American Association for Geriatric Psychiatry

Author Keywords
Aging;  geroscience;  late-life depression;  serious mental illnesses

Funding details
National Institutes of HealthNIHR01MH115953
Brain and Behavior Research FoundationBBRF
Merck
Patient-Centered Outcomes Research InstitutePCORI
University of WashingtonUWR01AG057912, R01AG068937, UL1TR002345
Janssen Pharmaceuticals

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

Age-Related Alterations in Gray Matter Microstructure in Older People With Remitted Major Depression at Risk for Dementia
(2023) Biological Psychiatry Global Open Science, . 

Anderson, J.A.E.^a b c , Rashidi-Ranjbar, N.^b d , Nazeri, A.^e , Chad, J.A.^f g , Zhukovsky, P.^b , Mulsant, B.H.^b h , Herrmann, N.^h i , Mah, L.^g h , Flint, A.J.^h j , Fischer, C.E.^d h , Pollock, B.G.^b h , Rajji, T.K.^b h k , Voineskos, A.N.^b d h , PACt-MD Study Group^l

^a Department of Cognitive Science, Carleton University, Ottawa, ON, Canada
^b Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
^c Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
^d Keenan Research Centre for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada
^e Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri (AN), United States
^f Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
^g Baycrest Health Sciences, Toronto, ON, Canada
^h Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
ⁱ Sunnybrook Health Sciences Centre, Department of Psychiatry, University of Toronto, Toronto, ON, Canada
^j Centre for Mental Health, University Health Network, Toronto, ON, Canada
^k Toronto Dementia Research Alliance, University of Toronto, Toronto, ON, Canada

Abstract
Background: Major depressive disorder (MDD) in late life is a risk factor for mild cognitive impairment (MCI) and Alzheimer’s disease. However, studies of gray matter changes have produced varied estimates of which structures are implicated in MDD and dementia. Changes in gray matter volume and cortical thickness are macrostructural measures for the microstructural processes of free water accumulation and dendritic spine loss. Methods: We conducted multishell diffusion imaging to assess gray matter microstructure in 244 older adults with remitted MDD (n = 44), MCI (n = 115), remitted MDD+MCI (n = 61), or without psychiatric disorders or cognitive impairment (healthy control participants; n = 24). We estimated measures related to neurite density, orientation dispersion, and free water (isotropic volume fraction) using a biophysically plausible model (neurite orientation dispersion and density imaging). Results: Results showed that increasing age was correlated with an increase in isotropic volume fraction and a decrease in orientation dispersion index, which is consistent with neuropathology dendritic loss. In addition, this relationship between age and increased isotropic volume fraction was more disrupted in the MCI group than in the remitted MDD or healthy control groups. However, the association between age and orientation dispersion index was similar for all 3 groups. Conclusions: The findings suggest that the neurite orientation dispersion and density imaging measures could be used to identify biological risk factors for Alzheimer’s disease, signifying both conventional neurodegeneration observed with MCI and dendritic loss seen in MDD. © 2023 The Authors

Author Keywords
Corticolimbic circuit;  Dementia;  Diffusion-weighted imaging;  Fractional anisotropy;  Frontal-executive circuit;  Geriatric;  Gray matter;  Major depressive disorder;  Mild cognitive impairment;  MRI;  Structural covariance;  T1-weighted image

Funding details
CRC-2020-00174
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
National Institute on AgingNIA
Brain and Behavior Research FoundationBBRF29306
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
American Geriatrics SocietyAGS16/490,680, 3,054,093
Eli Lilly and Company
Pfizer
Patient-Centered Outcomes Research InstitutePCORI
BrightFocus FoundationBFF
F. Hoffmann-La Roche
University of California, San DiegoUCSD
University of Pittsburgh
Genome CanadaGC
Ontario Brain InstituteOBI
Fondation Brain Canada
Centre for Addiction and Mental HealthCAMH
Weston Brain InstituteWBI
Centre for Addiction and Mental Health FoundationCAMH
St. Michael’s Hospital Foundation
St. Michael’s Hospital Foundation
Consortium canadien en neurodégénérescence associée au vieillissementCCNA
Health Canada
Canadian Institutes of Health ResearchIRSC
Alzheimer Society
Canada Foundation for InnovationCFI
Ontario Ministry of Health and Long-Term CareMOHLTC
W. Garfield Weston Foundation
Ontario Ministry of Research, Innovation and ScienceMRIS
University of TorontoU of T
Centre for Aging + Brain Health InnovationCABHI

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

Towards Outcome-Driven Patient Subgroups: A Machine Learning Analysis Across Six Depression Treatment Studies
(2023) American Journal of Geriatric Psychiatry, . 

Benrimoh, D.^a b c , Kleinerman, A.^d , Furukawa, T.A.^e , III, C.F.R.^f g , Lenze, E.J.^h , Karp, J.ⁱ , Mulsant, B.^j , Armstrong, C.^c , Mehltretter, J.^c , Fratila, R.^c , Perlman, K.^a c , Israel, S.^c , Popescu, C.^c , Golden, G.^c , Qassim, S.^c , Anacleto, A.^c , Tanguay-Sela, M.^c , Kapelner, A.^k , Rosenfeld, A.^d , Turecki, G.^a

^a Department of Psychiatry (DB, KP, GT), McGill University, Montreal, Canada
^b Department of Psychiatry (DB), Stanford University, Stanford, CA, United States
^c Aifred Health (DB, CA, JM, RF, KP, SI, CP, GG, SQ, AA, MTS), Montreal, Canada
^d Bar-Ilan University (AK, AR), Ramat Gan, Israel
^e Department of Health Promotion and Human Behavior (TAF), Kyoto University Graduate School of Medicine/School of Public Health, Japan
^f Department of Psychiatry (CFR), University of Pittsburgh School of Medicine, United States
^g Department of Psychiatry (CFR), Tufts University School of Medicine, United States
^h Department of Psychiatry (EJL), Washington University School of Medicine, St. Louis, MS, United States
ⁱ Department of Psychiatry (JK), University of Arizona, United States
^j Department of Psychiatry (BM), University of Toronto, Canada
^k Department of Mathematics (AK), Queens College, CUNY, United States

Abstract
Background: Major depressive disorder (MDD) is a heterogeneous condition; multiple underlying neurobiological and behavioral substrates are associated with treatment response variability. Understanding the sources of this variability and predicting outcomes has been elusive. Machine learning (ML) shows promise in predicting treatment response in MDD, but its application is limited by challenges to the clinical interpretability of ML models, and clinicians often lack confidence in model results. In order to improve the interpretability of ML models in clinical practice, our goal was to demonstrate the derivation of treatment-relevant patient profiles comprised of clinical and demographic information using a novel ML approach. Methods: We analyzed data from six clinical trials of pharmacological treatment for depression (total n = 5438) using the Differential Prototypes Neural Network (DPNN), a ML model that derives patient prototypes which can be used to derive treatment-relevant patient clusters while learning to generate probabilities for differential treatment response. A model classifying remission and outputting individual remission probabilities for five first-line monotherapies and three combination treatments was trained using clinical and demographic data. Prototypes were evaluated for interpretability by assessing differences in feature distributions (e.g. age, sex, symptom severity) and treatment-specific outcomes. Results: A 3-prototype model achieved an area under the receiver operating curve of 0.66 and an expected absolute improvement in remission rate for those receiving the best predicted treatment of 6.5% (relative improvement of 15.6%) compared to the population remission rate. We identified three treatment-relevant patient clusters. Cluster A patients tended to be younger, to have increased levels of fatigue, and more severe symptoms. Cluster B patients tended to be older, female, have less severe symptoms, and the highest remission rates. Cluster C patients had more severe symptoms, lower remission rates, more psychomotor agitation, more intense suicidal ideation, and more somatic genital symptoms. Conclusion: It is possible to produce novel treatment-relevant patient profiles using ML models; doing so may improve interpretability of ML models and the quality of precision medicine treatments for MDD. © 2023

Author Keywords
artificial intelligence;  machine learning;  major depression;  subgroups

Funding details
2153, 2158
2199
2148
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
American Association for Geriatric PsychiatryAAGP
University of Pittsburgh
University of MarylandUMD
University of South FloridaUSF
National Research Council CanadaNRC
Shionogi2020-548587, 2022-082495
Kyoto University

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

Unicorn, Hare, or Tortoise? Using Machine Learning to Predict Working Memory Training Performance
(2023) Journal of Cognition, 6 (1), art. no. 53, . 

Feng, Y.^a , Pahor, A.^b c d , Seitz, A.R.^b c , Barbour, D.L.^e , Jaeggi, S.M.^a b

^a University of California, Irvine, School of Education, School of Social Sciences, Department of Cognitive Sciences, Irvine, CA, United States
^b Northeastern University, Department of Psychology, Boston, MA, United States
^c University of California, Riverside, Department of Psychology, Riverside, CA, United States
^d University of Maribor, Department of Psychology, Maribor, Slovenia
^e Washington University in St. Louis, Department of Biomedical Engineering, St. Louis, MO, United States

Abstract
People differ considerably in the extent to which they benefit from working memory (WM) training. Although there is increasing research focusing on individual differences associated with WM training outcomes, we still lack an understanding of which specific individual differences, and in what combination, contribute to inter-individual variations in training trajectories. In the current study, 568 undergraduates completed one of several N-back intervention variants over the course of two weeks. Participants’ training trajectories were clustered into three distinct training patterns (high performers, intermediate performers, and low performers). We applied machine-learning algorithms to train a binary tree model to predict individuals’ training patterns relying on several individual difference variables that have been identified as relevant in previous literature. These individual difference variables included pre-existing cognitive abilities, personality characteristics, motivational factors, video game experience, health status, bilingualism, and socioeconomic status. We found that our classification model showed good predictive power in distinguishing between high performers and relatively lower performers. Furthermore, we found that openness and pre-existing WM capacity to be the two most important factors in distinguishing between high and low performers. However, among low performers, openness and video game background were the most significant predictors of their learning persistence. In conclusion, it is possible to predict individual training performance using participant characteristics before training, which could inform the development of personalized interventions. © 2023 The Author(s).

Author Keywords
Individual differences;  Machine learning;  Working memory

Funding details
National Institute of Mental HealthNIMH1R01MH111742
National Institute on AgingNIA1K02AG054665

Document Type: Article
Publication Stage: Final
Source: Scopus

Control intervention design for preclinical and clinical trials: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable
(2023) International Journal of Stroke, . Cited 2 times.

Hayward, K.S.^a , Dalton, E.J.^a , Barth, J.^b , Brady, M.^c , Cherney, L.R.^d , Churilov, L.^a , Clarkson, A.N.^e , Dawson, J.^f , Dukelow, S.P.^g , Feys, P.^h , Hackett, M.ⁱ , Zeiler, S.R.^j , Lang, C.E.^k

^a The University of Melbourne, Melbourne, VIC, Australia
^b Providence VA Medical Center, Providence, RI, United States
^c Glasgow Caledonian University, Glasgow, United Kingdom
^d Shirley Ryan AbilityLab, Chicago, IL, United States
^e University of Otago, Dunedin, New Zealand
^f University of Glasgow, Glasgow, United Kingdom
^g University of Calgary, Calgary, AB, Canada
^h Reval University of Hasselt, Hasselt, Belgium
ⁱ University of New South Wales, Sydney, NSW, Australia
^j Johns Hopkins University, Baltimore, MD, United States
^k Washington University School of Medicine, St. Louis, MO, United States

Abstract
Control comparator selection is a critical trial design issue. Preclinical and clinical investigators who are doing trials of stroke recovery and rehabilitation interventions must carefully consider the appropriateness and relevance of their chosen control comparator as the benefit of an experimental intervention is established relative to a comparator. Establishing a strong rationale for a selected comparator improves the integrity of the trial and validity of its findings. This Stroke Recovery and Rehabilitation Roundtable (SRRR) taskforce used a graph theory voting system to rank the importance and ease of addressing challenges during control comparator design. “Identifying appropriate type of control” was ranked easy to address and very important, “variability in usual care” was ranked hard to address and of low importance, and “understanding the content of the control and how it differs from the experimental intervention” was ranked very important but not easy to address. The CONtrol DeSIGN (CONSIGN) decision support tool was developed to address the identified challenges and enhance comparator selection, description, and reporting. CONSIGN is a web-based tool inclusive of seven steps that guide the user through control comparator design. The tool was refined through multiple rounds of pilot testing that included more than 130 people working in neurorehabilitation research. Four hypothetical exemplar trials, which span preclinical, mood, aphasia, and motor recovery, demonstrate how the tool can be applied in practice. Six consensus recommendations are defined that span research domains, professional disciplines, and international borders. © 2023 World Stroke Organization.

Author Keywords
Clinical trial;  consensus;  control;  preclinical;  recovery;  rehabilitation;  stroke

Funding details
GNT2015705
Ipsen

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

Sellar xanthogranuloma as a diagnostic challenge: a report on five cases
(2023) Frontiers in Neuroscience, 17, art. no. 1227144, . 

Fernández, S.C.^a , Bernhardt, M.C.^b , Grondona, E.^a c , Venier, A.C.^a c , Bertolino, M.L.^d , Pautasso, M.J.^d , Mezzano, E.^e , Damilano, R.A.^f , Sala, C.S.^f , Herrera, E.J.^g , Pesaola, F.N.^h , Maldonado, C.A.^a c , Quintar, A.A.^a c , De Paul, A.L.^a c

^a Centro de Microscopía Electrónica, Facultad de Ciencias Médicas, Universidad Nacional de Córdoba, Córdoba, Argentina
^b Servicio de Patología, Clínica Universitaria Reina Fabiola, Córdoba, Argentina
^c Instituto de Investigación en Ciencias de la Salud (INICSA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Córdoba, Argentina
^d Servicio de Neurocirugía, Clínica Universitaria Reina Fabiola, Córdoba, Argentina
^e Servicio de Endocrinología, Clínica Universitaria Reina Fabiola, Córdoba, Argentina
^f Servicio de Endocrinología, Sanatorio Allende, Córdoba, Argentina
^g Servicio de Neurocirugía, Sanatorio Allende, Córdoba, Argentina
^h Department of Pediatrics, School of Medicine, Genetics and Genomic Medicine, Washington University in St. Louis, Saint Louis, MO, United States

Abstract
Xanthogranulomas are considered rare tumors, with their sellar and non-sellar frequency ranging from 1.6 to 7% among intracranial lesions, and described as a separate entity by the World Health Organization in 2000. The diagnosis of sellar xanthogranulomas is challenging, given their uncertain origin and clinical course. In addition, the limited reporting of sellar xanthogranuloma cases and the absence of characteristic images make these entities difficult to distinguish from other cystic lesions of the sellar region, such as adamantinomatous craniopharyngiomas, Rathke’s cleft cysts, pituitary tumors, arachnoid cysts, epidermoid cysts, and dermoid cysts. Here, we describe the clinical presentation, radiological findings, immunohistochemical/histopathological analysis, and the ultrastructural examination by transmission electron microscopy of five sellar xanthogranulomas cases reported in two care centers in Cordoba, Argentina. Two males and three females between 37 and 73 years of age (average 51.8 years) presented with persistent headaches, generalized endocrine defects, and visual problems. MRI revealed cystic formations in the sellar region, which usually projected into adjacent tissues such as the suprasellar region or cavernous sinuses, and compressed other structures such as the optic chiasm, pituitary gland, and cranial nerves. All patients underwent surgical intervention to remove the tumor tissue. The histopathological analysis of the samples showed cellular tissue with a xanthogranulomatous appearance, inflammatory cellular infiltrate (mainly lymphocytes and macrophages), fibroblasts, abundant collagen fibers, and hemorrhages. An ultrastructural analysis helped to identify cellular infiltrates and granules resulting from tumor cell activity. The data support the hypothesis that sellar xanthogranulomas could occur as an inflammatory reaction secondary to the rupture and hemorrhage of a previous cystic process, thereby generating an expansion of the tumor body toward adjacent tissues. The information obtained from these cases contributes to the current knowledge about this disease’s origin and clinical and histological evolution. However, the scarcity of patients and the observed phenotypic heterogeneity make its diagnosis still challenging. Undoubtedly, more investigations are needed to provide additional information in order to be able to achieve a more accurate diagnosis and effective treatment of this rare disease. Copyright © 2023 Fernández, Bernhardt, Grondona, Venier, Bertolino, Pautasso, Mezzano, Damilano, Sala, Herrera, Pesaola, Maldonado, Quintar and De Paul.

Author Keywords
chronic inflammation;  electron microscopy;  MRI;  pituitary adenoma;  Rathke’s cleft cyst;  sellar region;  xanthogranuloma

Funding details
Secretaria de Ciencia y Tecnología – Universidad Nacional de CórdobaSECyT, UNC
Universidad Nacional de ColombiaUNAL33620180100675CB
Consejo Nacional de Investigaciones Científicas y TécnicasCONICET11220200102210, PIP 2020-2023
Agencia Nacional de Promoción Científica y TecnológicaANPCyT
Ministerio de Ciencia y TecnologíaMICYTFONCYT-PICT 0950-2020-2024

Document Type: Article
Publication Stage: Final
Source: Scopus

Door-To-Door Video-Enhanced Prevalence Study of Tourette Disorder Among African Americans
(2023) Evidence-Based Practice in Child and Adolescent Mental Health, . 

Striley, C.^a , Black, K.J.^b , Chichetto, N.E.^a , Vagelakos, L.^c

^a Department of Epidemiology, University of Florida, Gainesville, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c Orlando Health, Florida, FL, United States

Abstract
Tourette syndrome (TS) affects about 0.5% of the population worldwide, but only sparse and conflicting data exist on TS prevalence among minority samples. Here we used VISITTS (a survey preceded by a short video showing tic phenomenology) and community outreach to provide estimates of tic disorder prevalence in African Americans. Community health workers (CHWs) left flyers at households in a predominantly minority neighborhood and approached people at a community health fair. Of 606 such contacts, 222 individuals agreed to discuss the study. Of these, 70% enrolled, of whom 82% identified as Black and 64% female. The VISITTS was well received. Lifetime prevalence of TS or another chronic tic disorder (TS/CTD) was 3.2%, and 31% endorsed any lifetime simple tic. The number of enrolled Black participants is remarkable compared to earlier TS studies, allowing one of the first prevalence estimates in this population (TS 2.3%, TS/CTD 3.9%). Tic disorders were endorsed only by Black respondents, though the small White sample precluded statistical comparison. Women had higher rates than men of TS (M:F = 0:1) and of any lifetime simple tic (M:F = 0.85), differing significantly from the expected 4:1 ratio (p =.009 and p <.001, respectively). For TS/CTD the ratio was 1.2:1 (p >.15). We conclude that VISITTS is a feasible tic screening tool in a minority population, that CHW community outreach increases enrollment of Black participants, that TS/CTD is no less common in this population, and that tics were as common in female as in male respondents. © 2023 Society of Clinical Child and Adolescent Psychology.

Funding details
National Center for Research ResourcesNCRRRR024992
University of WashingtonUW
Tourette Association of AmericaTAA

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

The Influence of Pandemic-Related Worries During Pregnancy on Child Development at 12 Months
(2023) Child Psychiatry and Human Development, . 

White, L.K.^a g h , Himes, M.M.^a , Waller, R.^b , Njoroge, W.F.M.^a c g h , Chaiyachati, B.H.^a c d , Barzilay, R.^a g h , Kornfield, S.L.^e , Burris, H.H.^d , Seidlitz, J.^a , Parish-Morris, J.^f g h , Brady, R.G.ⁱ , Gerstein, E.D.^j , Laney, N.^a , Gur, R.E.^a g h , Duncan, A.F.^d

^a Lifespan Brain Institute, 3400 Spruce St. 10th floor, Gates Pavilion, Philadelphia, PA 19104, United States
^b Department of Psychology, University of Pennsylvania, Philadelphia, PA, United States
^c Policy Lab, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^d Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
^e Department of Psychiatry, Perelman School of Medicine, Penn Center for Women’s Behavioral Wellness, University of Pennsylvania, Philadelphia, PA, United States
^f Center for Autism Research, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^g Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^h Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ⁱ Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Psychological Sciences, University of Missouri–St. Louis, 325 Stadler Hall, 1 University Blvd., St. Louis, MO, United States

Abstract
The COVID-19 pandemic has been linked to increased risk for perinatal anxiety and depression among parents, as well as negative consequences for child development. Less is known about how worries arising from the pandemic during pregnancy are related to later child development, nor if resilience factors buffer negative consequences. The current study addresses this question in a prospective longitudinal design. Data was collected from a sub-study (n = 184) of a longitudinal study of pregnant individuals (total n = 1173). During pregnancy (April 17–July 8, 2020) and the early postpartum period (August 11, 2020–March 2, 2021), participants completed online surveys. At 12 months postpartum (June 17, 2021–March 23, 2022), participants completed online surveys and a virtual laboratory visit, which included parent–child interaction tasks. We found more pregnancy-specific pandemic worries were prospectively related to lower levels of child socioemotional development based on parent report (B = − 1.13, SE =.43, p =.007) and observer ratings (B = − 0.13, SE =.07, p =.045), but not to parent-reported general developmental milestones. Parental emotion regulation in the early postpartum period moderated the association between pregnancy-specific pandemic worries and child socioemotional development such that pregnancy-specific pandemic worries did not relate to worse child socioemotional development among parents with high (B = −.02, SE =.10, t = −.14, p =.89) levels of emotion regulation. Findings suggest the negative consequences of parental worry and distress during pregnancy on the early socioemotional development of children in the context of the COVID-19 pandemic. Results highlight that parental emotion regulation may represent a target for intervention to promote parental resilience and support optimized child development. © 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Child development;  Emotion regulation;  Pandemic;  Parenting;  Parent–child interactions

Funding details
National Institute of Mental HealthNIMHK08MH129657, R01 MH125904, R01 MH128593

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

Utility of a Clinical Prediction Tool for Persisting Postconcussive Symptoms in a Multicenter Sample of Youth Athletes With Concussion: The Sport Concussion Outcomes in Pediatrics (SCOPE) Study
(2023) American Journal of Sports Medicine, . 

Miller, S.M.^a , Valovich McLeod, T.C.^b , Zaslow, T.L.^c , Wilson, J.C.^d , Master, C.L.^e , Snedden, T.R.^f , Halstead, M.E.^g , Grady, M.F.^e , Fazekas, M.L.^h , Santana, J.A.ⁱ , Coel, R.A.^j , Howell, D.R.^d

^a Scottish Rite for Children and UT Southwestern Medical Center, Dallas, TX, United States
^b A.T. Still University, Mesa, AZ, United States
^c Cedars Sinai Kerlan Jobe Institute, Los Angeles, CA, United States
^d Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora, CO, United States
^e Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f University of Wisconsin–Madison School of Nursing, Madison, WI, United States
^g St Louis Children’s Hospital, Washington University School of Medicine, St Louis, MO, United States
^h Joe DiMaggio Children’s Hospital, Hollywood, FL, United States
ⁱ Children’s Hospital Los Angeles and Keck School of Medicine of USC, Los Angeles, CA, United States
^j Kapi’olani Medical Center for Women and Children, University of Hawai’i John A. Burns School of Medicine, Honolulu, HI, United States

Abstract
Background: A validated clinical risk tool has been developed to identify pediatric and adolescent patients at risk of developing persisting symptoms after concussion, but has not been prospectively investigated within a sample of athletes seen after concussion by primary care sports medicine physicians and/or athletic trainers. Purpose: To determine whether a validated clinical risk prediction tool for persistent postconcussive symptoms (PPCSs) predicted which patients would develop PPCSs when obtained within 14 days of concussion among a multicenter sample of adolescent athletes. Study Design: Cohort study; Level of evidence, 2. Methods: Pediatric and adolescent patients (8-18 years of age) from 7 pediatric medical centers and 6 secondary school athletic training facilities who were diagnosed with a concussion and presented ≤14 days after concussion were enrolled as part of the Sport Concussion Outcomes in Pediatrics (SCOPE) study during their initial visit and were followed until symptom resolution. Clinical risk scores (Predicting and Preventing Post-concussive Problems in Pediatrics [5P]) and total symptom severity were obtained using the Post-Concussion Symptom Inventory at the initial visit (mean, 4.9 ± 2.9 days after concussion). Participants were then compared based on symptom resolution time: PPCS group (≥28 days to symptom resolution) and no-PPCS group (<28 days). The authors assessed the odds of developing PPCSs based on the 5P risk score using a binary logistic regression model and the utility of the clinical risk prediction tool to identify total time to symptom resolution using a Cox proportional hazards model. Results: A total of 184 participants enrolled, underwent initial evaluation, and were followed until symptom resolution (mean age, 15.2 ± 2.1 years; 35% female). The mean time to symptom resolution across the entire sample was 17.6 ± 3.7 days; 16% (n = 30) of participants developed PPCS. Those in the PPCS group had significantly greater mean initial total 5P risk scores than those in the no-PPCS group (7.9 ± 1.7 vs 5.9 ± 2.3, respectively; P <.001). After adjustment for initial symptom severity, time to assessment, and assessment setting, a higher initial total 5P risk score was associated with a significantly greater odds of developing PPCSs (adjusted odds ratio, 1.49; 95% CI, 1.07-2.08; P =.019). Furthermore, a higher 5P risk score was significantly associated with longer total symptom resolution time (hazard ratio, 0.80; 95% CI, 0.74-0.88; P <.001). Conclusion: In a multicenter sample of youth athletes seen in different outpatient health care settings, the 5P risk score accurately predicted which athletes may be at risk for developing PPCSs. © 2023 The Author(s).

Author Keywords
adolescent athlete;  concussion;  persistent postconcussive symptoms

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH21C0103, W81XWH2210590
Centers for Disease Control and PreventionCDC1U01CE003479-01-00
National Eye InstituteNEI1R34EY030582-01A1, 2R01EY023261-06
National Institute of Nursing ResearchNINR5R01NR018425-03
National Institute of Neurological Disorders and StrokeNINDS5R01NS097549-06, R01NS100952, R43NS108823
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS1R13AR080451
National Center for Advancing Translational SciencesNCATSUL1 TR002535
Children’s Hospital of PhiladelphiaCHOP
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR01HD108133, R03HD094560
Colorado Clinical and Translational Sciences InstituteCCTSI
Taisei Foundation
Chuck Noll Foundation for Brain Injury Research
American Medical Society for Sports MedicineAMSSM

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

Human deprivation amblyopia: treatment insights from animal models
(2023) Frontiers in Neuroscience, 17, art. no. 1249466, . 

Duffy, K.R.^a , Bear, M.F.^b , Patel, N.B.^c , Das, V.E.^c , Tychsen, L.^d

^a Department of Psychology and Neuroscience, Dalhousie University, Halifax, NS, Canada
^b Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
^c College of Optometry, University of Houston, Houston, TX, United States
^d Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Amblyopia is a common visual impairment that develops during the early years of postnatal life. It emerges as a sequela to eye misalignment, an imbalanced refractive state, or obstruction to form vision. All of these conditions prevent normal vision and derail the typical development of neural connections within the visual system. Among the subtypes of amblyopia, the most debilitating and recalcitrant to treatment is deprivation amblyopia. Nevertheless, human studies focused on advancing the standard of care for amblyopia have largely avoided recruitment of patients with this rare but severe impairment subtype. In this review, we delineate characteristics of deprivation amblyopia and underscore the critical need for new and more effective therapy. Animal models offer a unique opportunity to address this unmet need by enabling the development of unconventional and potent amblyopia therapies that cannot be pioneered in humans. Insights derived from studies using animal models are discussed as potential therapeutic innovations for the remediation of deprivation amblyopia. Retinal inactivation is highlighted as an emerging therapy that exhibits efficacy against the effects of monocular deprivation at ages when conventional therapy is ineffective, and recovery occurs without apparent detriment to the treated eye. Copyright © 2023 Duffy, Bear, Patel, Das and Tychsen.

Author Keywords
amblyopia;  amblyopia therapies;  animal models;  monocular deprivation;  neural plasticity (NP);  neuropathology;  recovery

Funding details
National Eye InstituteNEIR01-EY029245
Research to Prevent BlindnessRPB42894, R01-EY026568
Canadian Institutes of Health ResearchIRSC468904

Document Type: Article
Publication Stage: Final
Source: Scopus

Social Priming: Exploring the Effects of Speaker Race and Ethnicity on Perception of Second Language Accents
(2023) Language and Speech, . 

McLaughlin, D.J.^a b , Van Engen, K.J.^a

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
^b Basque Center on Cognition, Brain and Language, Spain

Abstract
Listeners use more than just acoustic information when processing speech. Social information, such as a speaker’s perceived race or ethnicity, can also affect the processing of the speech signal, in some cases facilitating perception (“social priming”). We aimed to replicate and extend this line of inquiry, examining effects of multiple social primes (i.e., a Middle Eastern, White, or East Asian face, or a control silhouette image) on the perception of Mandarin Chinese-accented English and Arabic-accented English. By including uncommon priming combinations (e.g., a Middle Eastern prime for a Mandarin accent), we aimed to test the specificity of social primes: For example, can a Middle Eastern face facilitate perception of both Arabic-accented English and Mandarin-accented English? Contrary to our predictions, our results indicated no facilitative social priming effects for either of the second language (L2) accents. Results for our examination of specificity were mixed. Trends in the data indicated that the combination of an East Asian prime with Arabic accent resulted in lower accuracy as compared with a White prime, but the combination of a Middle Eastern prime with a Mandarin accent did not (and may have actually benefited listeners to some degree). We conclude that the specificity of priming effects may depend on listeners’ level of familiarity with a given accent and/or racial/ethnic group and that the mixed outcomes in the current work motivate further inquiries to determine whether social priming effects for L2-accented speech may be smaller than previously hypothesized and/or highly dependent on listener experience. © The Author(s) 2023.

Author Keywords
foreign accent;  social priming;  Speech perception

Funding details
2022-2025
National Science FoundationNSF2116319, DGE-1745038
Agencia Estatal de InvestigaciónAEI

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

Behavioral and Cognitive Outcomes of Rhesus Macaques Following Neonatal Exposure to Antiseizure Medications
(2023) Annals of Neurology, . 

Colman, R.^a b , Pierre, P.^a , Adriansjach, J.^a , Crosno, K.^a , Noguchi, K.K.^c , Ikonomidou, C.^d

^a Wisconsin National Primate Research Center, Madison, WI, United States
^b Department of Cell and Regenerative Biology, University of Wisconsin, School of Medicine, Madison, WI, United States
^c Department of Psychiatry, Washington University, School of Medicine, St Louis, United States
^d Department of Neurology, University of Wisconsin, School of Medicine, Madison, WI, United States

Abstract
Objective: Exposure of neonatal macaques to the antiseizure medications phenobarbital and midazolam (PbM) causes widespread apoptotic death of neurons and oligodendrocytes. We studied behavior and neurocognitive performance in 12 to 24 month-old macaques treated as neonates with PbM. Methods: A total of 14 monkeys received phenobarbital and midazolam over 24 hours under normothermia (n = 8) or mild hypothermia (n = 6). Controls (n = 8) received no treatment. Animals underwent testing in the human intruder paradigm at ages 12 and 18 months, and a 3-step stimulus discrimination task at ages 12, 18, and 24 months. Results: Animals treated with PbM displayed lower scores for environmental exploration, and higher scores for locomotion and vocalizations compared with controls. Combined PbM and hypothermia resulted in lower scores for aggression and vigilance at 12 months compared with controls and normothermic PbM animals. A mixed-effects generalized linear model was used to test for differences in neurocognitive performance between the control and PbM groups in the first step of the stimulus discrimination task battery (shape center baited to shape center non-baited). The odds of passing this step differed by group (p = 0.044). At any given age, the odds of passing for a control animal were 9.53-fold (95% CI 1.06–85) the odds for a PbM animal. There was also evidence suggesting a higher learning rate in the shape center non-baited for the control relative to the PbM group (Cox model HR 2.13, 95% CI 1.02–4.43; p = 0.044). Interpretation: These findings demonstrate that a 24-hour-long neonatal treatment with a clinically relevant combination of antiseizure medications can have long-lasting effects on behavior and cognition in nonhuman primates. ANN NEUROL 2023. © 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Funding details
HD052664, U54‐HD087011
National Institutes of HealthNIH
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP51ODO11106, R01HD083001‐01A1
Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine in St. LouisIDDRC

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

Antipsychotics and the risk of diabetes and death among adults with serious mental illnesses
(2023) Psychological Medicine, . 

Poulos, J.^a , Normand, S.-L.T.^a b , Zelevinsky, K.^a , Newcomer, J.W.^c d , Agniel, D.^e , Abing, H.K.^a , Horvitz-Lennon, M.^f g

^a Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^b Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA, United States
^c Thriving Mind South Florida, Miami, FL, United States
^d Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
^e RAND Corporation, Santa Monica, CA, United States
^f RAND Corporation, Boston, MA, United States
^g Department of Psychiatry, Cambridge Health Alliance and Harvard Medical School, Cambridge, MA, United States

Abstract
Background Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs’ mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects. Methods Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008-2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication. Results 38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2-2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users’ unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users’ unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1-2.2 percentage points, representing 32.4-64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine’s higher mortality risk held in sensitivity analyses. Conclusions Haloperidol’s, olanzapine’s, and risperidone’s lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine’s higher mortality risk proved robust. Findings expand the evidence on antipsychotics’ risks, suggesting a need for caution in the use of quetiapine among individuals with SMI. Copyright © RAND Corporation and the Author(s), 2023. Published by Cambridge University Press.

Author Keywords
antipsychotic;  mortality;  robust causal estimation;  Serious mental illness;  type 2 diabetes

Funding details
National Institute of Mental HealthNIMHR01 MH106682
National Institute on Minority Health and Health DisparitiesNIMHDR01 MDO12428

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

Amphiphilic Molecules Exhibiting Zwitterionic Excited-State Intramolecular Proton Transfer and Near-Infrared Emission for the Detection of Amyloid β Aggregates in Alzheimer’s Disease**
(2023) Chemistry – A European Journal, . 

Yu, Z.^a , Moshood, Y.^a , Wozniak, M.K.^b , Patel, S.^a , Terpstra, K.^a , Llano, D.A.^c , Dobrucki, L.W.^b , Mirica, L.M.^a d

^a Department of Chemistry, Beckman Institute for Advanced Science and Technology, The Neuroscience Program, Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, IL 61801, United States
^b Beckman Institute for Advanced Science and Technology, Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
^c Beckman Institute for Advanced Science and Technology, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Chromophores with zwitterionic excited-state intramolecular proton transfer (ESIPT) have been shown to have larger Stock shifts and red-shifted emission wavelengths compared to the conventional π-delocalized ESIPT molecules. However, there is still a dearth of design strategies to expand the current library of zwitterionic ESIPT compounds. Herein, a novel zwitterionic excited-state intramolecular proton transfer system is reported, enabled by addition of 1,4,7-triazacyclononane (TACN) fragments on a dicyanomethylene-4H-pyran (DCM) scaffold. The solvent-dependent steady-state photophysical studies, pKa measurements, and computational analysis strongly support that the ESIPT process is more efficient with two TACN groups attached to the DCM scaffold and not affected by polar protic solvents. Impressively, compound DCM-OH-2-DT exhibits a near-infrared (NIR) emission at 740 nm along with an uncommonly large Stokes shift. Moreover, DCM-OH-2-DT shows high affinity towards soluble amyloid β (Aβ) oligomers in vitro and in 5xFAD mouse brain sections, and we have successfully applied DCM-OH-2-DT for the in vivo imaging of Aβ aggregates and demonstrated its potential use as an early diagnostic agent for AD. Overall, this study can provide a general molecular design strategy for developing new zwitterionic ESIPT compounds with NIR emission in vivo imaging applications. © 2023 The Authors. Chemistry – A European Journal published by Wiley-VCH GmbH.

Author Keywords
Alzheimer’s disease;  amyloid-β oligomers;  early diagnosis;  near-infrared fluorescence imaging;  zwitterionic excited-state intramolecular proton transfer

Funding details
National Institutes of HealthNIHR01GM114588

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

Potentiation of the GABAAR reveals variable energetic contributions by etiocholanolone and propofol
(2023) Biophysical Journal, . 

Pierce, S.R.^a , Xu, S.Q.^a , Germann, A.L.^a , Steinbach, J.H.^a b , Akk, G.^a b

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, United States
^b The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri, United States

Abstract
The properties of a potentiator are typically evaluated by measuring its ability to enhance the magnitude of the control response. Analysis of the ability of drugs to potentiate responses from receptor channels takes place in the context of particular models to extract parameters for functional effects. In the often-used coagonist model, the agonist generating control activity and the potentiator enhancing the control activity make additive energetic contributions to stabilize the active state of the receptor. The energetic contributions are fixed and, once known, enable calculation of predicted receptor behavior at any concentration combination of agonist and potentiator. Here, we have examined the applicability of the coagonist model by measuring the relationship between the magnitude of receptor potentiation and the level of background activity. Ternary αβγ GABAA receptors were activated by GABA or the allosteric agonist propofol, or by a gain-of-function mutation, and etiocholanolone- or propofol-mediated potentiation of peak responses was measured. We show that the free energy change contributed by the modulators etiocholanolone or propofol is reduced at higher levels of control activity, thereby being in disagreement with basic principles of the coagonist model. Possible mechanisms underlying this discrepancy are discussed. © 2023 Biophysical Society

Funding details
National Institute of General Medical SciencesNIGMSR35GM140947
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis

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