Dorsal hippocampus to nucleus accumbens projections drive reinforcement via activation of accumbal dynorphin neurons
(2024) Nature Communications, 15 (1), art. no. 750, .
Ibrahim, K.M.a b , Massaly, N.a b c , Yoon, H.-J.a b , Sandoval, R.a b , Widman, A.J.a b , Heuermann, R.J.a b d , Williams, S.a b , Post, W.a b , Pathiranage, S.a b , Lintz, T.a b , Zec, A.a b , Park, A.a b , Yu, W.e f , Kash, T.L.e f , Gereau, R.W., IVa b g , Morón, J.A.a b g h
a Department of Anesthesiology, Washington University Pain Center, St. Louis, MO 63110, United States
b Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, United States
c Department of Anesthesiology and Perioperative Medicine, University of California, Los Angeles, CA 90095, United States
d Department of Neurology, Washington University Pain Center, St. Louis, MO 63110, United States
e Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, United States
f Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, United States
g Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
h Department of Psychiatry, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
The hippocampus is pivotal in integrating emotional processing, learning, memory, and reward-related behaviors. The dorsal hippocampus (dHPC) is particularly crucial for episodic, spatial, and associative memory, and has been shown to be necessary for context- and cue-associated reward behaviors. The nucleus accumbens (NAc), a central structure in the mesolimbic reward pathway, integrates the salience of aversive and rewarding stimuli. Despite extensive research on dHPC→NAc direct projections, their sufficiency in driving reinforcement and reward-related behavior remains to be determined. Our study establishes that activating excitatory neurons in the dHPC is sufficient to induce reinforcing behaviors through its direct projections to the dorso-medial subregion of the NAc shell (dmNAcSh). Notably, dynorphin-containing neurons specifically contribute to dHPC-driven reinforcing behavior, even though both dmNAcSh dynorphin- and enkephalin-containing neurons are activated with dHPC stimulation. Our findings unveil a pathway governing reinforcement, advancing our understanding of the hippocampal circuity’s role in reward-seeking behaviors. © 2024, The Author(s).
Funding details
National Institutes of HealthNIHDA042499, DA045463, DA054900, DA055047
Brain and Behavior Research FoundationBBRF
National Alliance for Research on Schizophrenia and DepressionNARSAD
Philippe Foundation
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
Light pollution disrupts circadian clock gene expression in two mosquito vectors during their overwintering dormancy
(2024) Scientific Reports, 14 (1), art. no. 2398, .
Fyie, L.R.a , Westby, K.M.b , Meuti, M.E.a
a Department of Entomology, The Ohio State University, 2021 Coffey Rd, Columbus, OH 43210, United States
b Tyson Research Center, Washington University in St. Louis, 6750 Tyson Valley Road, Eureka, MO 63025, United States
Abstract
Artificial light at night (ALAN) is an increasingly important form of environmental disturbance as it alters Light:Dark cycles that regulate daily and seasonal changes in physiology and phenology. The Northern house mosquito (Culex pipiens) and the tiger mosquito (Aedes albopictus) enter an overwintering dormancy known as diapause that is cued by short days. These two species differ in diapause strategy: Cx. pipiens diapause as adult females while Ae. albopictus enter a maternally-programmed, egg diapause. Previous studies found that ALAN inhibits diapause in both species, but the mechanism is unknown. As the circadian clock is implicated in the regulation of diapause in many insects, we examined whether exposure to ALAN altered the daily expression of core circadian cloc genes (cycle, Clock, period, timeless, cryptochrome 1, cryptochrome 2, and Par domain protein 1) in these two species when reared under short-day, diapause-inducing conditions. We found that exposure to ALAN altered the abundance of several clock genes in adult females of both species, but that clock gene rhythmicity was maintained for most genes. ALAN also had little effect on clock gene abundance in mature oocytes that were dissected from female Ae. albopictus that were reared under short day conditions. Our findings indicate that ALAN may inhibit diapause initiation through the circadian clock in two medically-important mosquitoes. © 2024, The Author(s).
Funding details
National Science FoundationNSFIOS-1944323
National Institute of Food and AgricultureNIFANE 1943
Sustainability Institute, Ohio State UniversitySI
Tyson Research Center
Document Type: Article
Publication Stage: Final
Source: Scopus
GlioPredictor: a deep learning model for identification of high-risk adult IDH-mutant glioma towards adjuvant treatment planning
(2024) Scientific Reports, 14 (1), art. no. 2126, .
Zheng, S.a , Rammohan, N.b , Sita, T.a , Teo, P.T.a , Wu, Y.c , Lesniak, M.d , Sachdev, S.a , Thomas, T.O.a e
a Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
b Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Mathematics, DigiPen Institute of Technology, Redmond, WA, United States
d Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
e Department of Radiation Oncology, Northwestern Medical Group, Northwestern Memorial Hospital, Northwestern University Feinberg School of Medicine, Chicago, United States
Abstract
Identification of isocitrate dehydrogenase (IDH)-mutant glioma patients at high risk of early progression is critical for radiotherapy treatment planning. Currently tools to stratify risk of early progression are lacking. We sought to identify a combination of molecular markers that could be used to identify patients who may have a greater need for adjuvant radiation therapy machine learning technology. 507 WHO Grade 2 and 3 glioma cases from The Cancer Genome Atlas, and 1309 cases from AACR GENIE v13.0 datasets were studied for genetic disparities between IDH1-wildtype and IDH1-mutant cohorts, and between different age groups. Genetic features such as mutations and copy number variations (CNVs) correlated with IDH1 mutation status were selected as potential inputs to train artificial neural networks (ANNs) to predict IDH1 mutation status. Grade 2 and 3 glioma cases from the Memorial Sloan Kettering dataset (n = 404) and Grade 3 glioma cases with subtotal resection (STR) from Northwestern University (NU) (n = 21) were used to further evaluate the best performing ANN model as independent datasets. IDH1 mutation is associated with decreased CNVs of EGFR (21% vs. 3%), CDKN2A (20% vs. 6%), PTEN (14% vs. 1.7%), and increased percentage of mutations for TP53 (15% vs. 63%), and ATRX (10% vs. 54%), which were all statistically significant (p < 0.001). Age > 40 was unable to identify high-risk IDH1-mutant with early progression. A glioma early progression risk prediction (GlioPredictor) score generated from the best performing ANN model (6/6/6/6/2/1) with 6 inputs, including CNVs of EGFR, PTEN and CDKN2A, mutation status of TP53 and ATRX, patient’s age can predict IDH1 mutation status with over 90% accuracy. The GlioPredictor score identified a subgroup of high-risk IDH1-mutant in TCGA and NU datasets with early disease progression (p = 0.0019, 0.0238, respectively). The GlioPredictor that integrates age at diagnosis, CNVs of EGFR, CDKN2A, PTEN and mutation status of TP53, and ATRX can identify a small cohort of IDH-mutant with high risk of early progression. The current version of GlioPredictor mainly incorporated clinically often tested genetic biomarkers. Considering complexity of clinical and genetic features that correlate with glioma progression, future derivatives of GlioPredictor incorporating more inputs can be a potential supplement for adjuvant radiotherapy patient selection of IDH-mutant glioma patients. © 2024, The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Clinical importance in Alzheimer’s disease: effects of anchor agreement and disease severity
(2024) Aging Clinical and Experimental Research, 36 (1), art. no. 5, .
Stojanovic, M.a , Mikula, C.b , John, S.c , Kiselica, A.d
a Department of Psychological and Brain Sciences, Washington University in St. Louis, One Brookings Drive, Box 1125, St. Louis, MO 63130, United States
b Institute of Human Nutrition, Columbia University, New York, NY 10032, United States
c Department of Brain Health, University of Nevada-Las Vegas, Las Vegas, NV 89154, United States
d Department of Health Psychology, University of Missouri-Columbia, Columbia, MO 65211, United States
Abstract
Objectives: Methods of evaluating clinically meaningful decline are critical in research on Alzheimer’s disease. A common method of quantifying clinically meaningful change is to calculate an anchor-based minimal clinically important difference (MCID) score. In this approach, individuals who report a meaningful change serve as the “anchors”, and the mean level of change for this group serves as the MCID. In research on Alzheimer’s disease, there are several possible anchors, including patients, knowledgeable observers (e.g., a family member), and clinicians. The goal of this study was to examine the extent to which agreement among anchors impacts MCID estimation and whether this relationship is moderated by cognitive severity status. Methods: Analyses were completed on a longitudinal sample of 2247 adults, aged 50–103, from the Uniform Data Set. Outcome measures included the Montreal Cognitive Assessment, Clinical Dementia Rating—Sum of Boxes, and Functional Activities Questionnaire. Results: For all of the outcomes, the MCID estimate was significantly higher when meaningful decline was endorsed by all of the anchors compared to when there was disagreement among the anchors. In addition, the MCID estimate was higher with increasing severity of cognitive impairment. Finally, cognitive severity status moderated the influence of agreement among anchors on MCID estimation; as disease severity increased, anchor agreement demonstrated less influence on the MCID. Conclusions: MCID estimates based on one anchor may underestimate meaningful change, and researchers should consider the viewpoints of multiple anchors in constructing MCIDs, particularly in the early stages of cognitive decline. © 2024, The Author(s).
Author Keywords
Alzheimer’s disease; Clinical trials; Dementia; Minimal clinically important difference
Funding details
National Institutes of HealthNIHU24 AG072122
National Institute on AgingNIA
Document Type: Article
Publication Stage: Final
Source: Scopus
Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease
(2024) Current Research in Translational Medicine, 72 (2), art. no. 103433, .
Heitzer, A.M.a , Rashkin, S.R.b , Trpchevska, A.a , Longoria, J.N.a , Rampersaud, E.c , Olufadi, Y.d , Wang, W.C.b , Raches, D.a , Potter, B.a , Steinberg, M.H.e , King, A.A.f , Kang, G.d , Takemoto, C.M.b , Hankins, J.S.b g
a Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
b Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
c Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, United States
d Biostatistics Department, St. Jude Children’s Research Hospital, Memphis, TN, United States
e Department of Medicine, Boston University Chobanian & Avidesian School of Medicine, Boston, MA, United States
f Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University, St. Louis, MO, United States
g Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, United States
Abstract
Purpose: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. Patients and Methods: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). Results: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts’ data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. Conclusion: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions. © 2023 Elsevier Masson SAS
Author Keywords
Catechol O-methyltransferase; Dopamine; Polymorphism, Single nucleotide; Sickle cell disease
Funding details
American Lebanese Syrian Associated CharitiesALSAC5U01HL133994, K23HL166697, K24 HL148305, R01 87681, R01 HL 068970, RC2 HL 101212, U01HL133994
Document Type: Article
Publication Stage: Final
Source: Scopus
Polygenic risk for depression predicting temperament trajectories over 15 years – A general population study
(2024) Journal of Affective Disorders, 350, pp. 388-395.
Lavonius, V.a , Keltikangas-Järvinen, L.a , Hamal Mishra, B.b c , Sormunen, E.d , Kähönen, M.e , Raitakari, O.f g h , Hietala, J.d , Cloninger, C.R.i , Lehtimäki, T.b c , Saarinen, A.a
a Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Finland
b Department of Clinical Chemistry, Fimlab Laboratories, Finnish Cardiovascular Research Center, Tampere, Finland
c Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
d Department of Psychiatry, University of Turku and Turku University Hospital, Turku, Finland
e Department of Clinical Physiology, Tampere University Hospital, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
f Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
g Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
h Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Finland
i Department of Psychiatry, Washington University, St. Louis, United States
Abstract
Background: A great number of case-control and population-based studies have shown that depression patients differ from healthy controls in their temperament traits. We investigated whether polygenic risk for depression predicts trajectories of temperament traits from early adulthood to middle age. Methods: Participants came from the population-based Young Finns Study (n = 2212). The calculation for Polygenic risk for depression (PRS) was based on the most recent genome-wide association study. Temperament traits of Harm Avoidance, Novelty Seeking, Reward Dependence, and Persistence were assessed with the Temperament and Character Inventory in 1997, 2001, 2007, and 2012 (participants being 24–50-year-olds). As covariates, we used depressive symptoms as assessed by a modified version of the Beck Depression Inventory, psychosocial family environment from parent-filled questionnaires, and socioeconomic factors from adulthood. Results: High PRS predicted higher Persistence from early adulthood to middle age (p = 0.003) when controlling for depressive symptoms, psychosocial family environment, and socioeconomic factors. PRS did not predict trajectories of Novelty Seeking (p = 0.063–0.416 in different models) or Reward Dependence (p = 0.531–0.736). The results remained unaffected when participants with diagnosed affective disorders were excluded. Additionally, we found an interaction between PRS and depressive symptoms when predicting the Harm Avoidance subscale Anticipatory Worry, indicating that the association of Anticipatory Worry with depressive symptoms is stronger in individuals with higher (vs. lower) PRS. Limitations: There was some attrition due to the long follow-up. Conclusions: High polygenic risk for major depression may predict differences in temperament trajectories among those who have not developed any severe affective disorders. © 2024 The Authors
Author Keywords
Depressive symptoms; Longitudinal study; Persistence; Polygenic risk score; TCI; Temperament
Funding details
Yrjö Jahnssonin Säätiö
European Research CouncilERC742927
Academy of FinlandAKA104821, 117797, 121584, 124282, 126925, 129378, 134309, 141071, 255381, 256474, 283115, 286284, 314389, 319060, 320297, 322098, 330809, 338395
Suomen KulttuurirahastoSKR
Juho Vainion Säätiö
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö220255
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Tampereen Tuberkuloosisäätiö
Horizon 2020755320, 848146
Diabetesliitto
Paavo Nurmen Säätiö
Tays
Syöpäsäätiö
Turun Yliopistollinen KeskussairaalaAUCSX51001
Suomen kliinisen kemian yhdistysFSCC
Document Type: Article
Publication Stage: Final
Source: Scopus
Exercise-Related Physical Activity Relates to Brain Volumes in 10,125 Individuals
(2024) Journal of Alzheimer’s Disease, 97 (2), pp. 829-839.
Raji, C.A.a b , Meysami, S.c d , Hashemi, S.e , Garg, S.b , Akbari, N.e , Gouda, A.e , Chodakiewitz, Y.G.e , Nguyen, T.D.e , Niotis, K.f g , Merrill, D.A.c d h , Attariwala, R.e i
a Washington University School of Medicine in St Louis, Mallinckrodt Institute of Radiology, St. Louis, MO, United States
b Department of Neurology, Washington University in St. LouisMO, United States
c Pacific Brain Health Center, Pacific Neuroscience Institute and Foundation, Santa Monica, CA, United States
d Saint John’s Cancer Institute, Providence Saint John’s Health Center, Santa Monica, CA, United States
e Prenuvo, VA, Canada of Voxelwise Imaging Technology, Vancouver, Canada
f Early Medical, Austin, TX, United States
g Institute of Neurodegenerative Diseases-Parkinson’s & Alzheimer’s Research Education Foundation, Boca Raton, FL, United States
h Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
i AIM Medical Imaging, Vancouver, Canada
Abstract
Objective: To investigate the relationships between regular moderate to vigorous physical activity and quantified brain volumes on magnetic resonance neuroimaging. Methods: A total of 10,125 healthy participants underwent whole-body MRI scans, with brain sequences including isotropic MP-RAGE. Three deep learning models analyzed axial, sagittal, and coronal views from the scans. Moderate to vigorous physical activity, defined by activities increasing respiration and pulse rate for at least 10 continuous minutes, was modeled with brain volumes via partial correlations. Analyses adjusted for age, sex, and total intracranial volume, and a 5% Benjamini-Hochberg False Discovery Rate addressed multiple comparisons. Results: Participant average age was 52.98 ± 13.04 years (range 18–97) and 52.3% were biologically male. Of these, 7,606 (75.1%) reported engaging in moderate or vigorous physical activity approximately 4.05 ± 3.43 days per week. Those with vigorous activity were slightly younger (p < 0.00001), and fewer women compared to men engaged in such activities (p = 3.76e-15). Adjusting for age, sex, body mass index, and multiple comparisons, increased days of moderate to vigorous activity correlated with larger normalized brain volumes in multiple regions including: total gray matter (Partial R = 0.05, p = 1.22e-7), white matter (Partial R = 0.06, p = 9.34e-11), hippocampus (Partial R = 0.05, p = 5.96e-7), and frontal, parietal, and occipital lobes (Partial R = 0.04, p ≤ 1.06e-5). Conclusions: Exercise-related physical activity is associated with increased brain volumes, indicating potential neuroprotective effects. © 2024 IOS Press. All rights reserved.
Author Keywords
Alzheimer’s disease; brain volumes; deep learning; magnetic resonance imaging; physical activity
Funding details
National Institute on AgingNIA1RF1AG072637-01, R01AG070883
Document Type: Article
Publication Stage: Final
Source: Scopus
Categorical and Latent Profile Approaches to Temperamental Infant Reactivity and Early Trajectories of Socioemotional Adjustment
(2024) Developmental Psychology, .
Anaya, B.a , Bierstedt, L.b , Tucker, N.c , Buss, K.A.c , LoBue, V.b , Pérez-Edgar, K.c
a Department of Psychiatry, School of Medicine, Washington University in St. Louis, United States
b Department of Psychology, Rutgers University, United States
c Department of Psychology, The Pennsylvania State University, United States
Abstract
This article examines the patterns, and consequences, of infant temperamental reactivity to novel sensory input in a large (N = 357; 271 in current analysis) and diverse longitudinal sample through two approaches. First, we examined profiles of reactivity in 4-month-old infants using the traditional theory-driven analytic approach laid out by Jerome Kagan and colleagues, and derived groups characterized by extreme patterns of negative reactivity and positive reactivity. We then used a theory-neutral, data-driven approach to create latent profiles of reactivity from the same infants. Despite differences in sample characteristics and recruitment strategy, we noted similar reactivity groups relative to prior cohorts. The current data-driven approach found four profiles: high positive, high negative, high motor, and low reactive. Follow-up analyses found differential predictions of internalizing, externalizing, dysregulation, and competence trajectories across 12, 18, and 24 months of life based on 4-month reactivity profiles. Findings are discussed in light of the initial formulation of early reactivity by Kagan and the four decades of research that has followed to refine, bolster, and expand on this approach to child-centered individual differences. © 2024 American Psychological Association
Author Keywords
infancy; internalizing problems; latent profile analysis; temperamental reactivity
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR01 MH109692
National Institute of Neurological Disorders and StrokeNINDSF99K00 NS120411
Pennsylvania State UniversityPSU
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The forkhead transcription factor Foxj1 controls vertebrate olfactory cilia biogenesis and sensory neuron differentiation
(2024) PLoS Biology, 22 (1), art. no. e3002468, .
Rayamajhi, D.a , Ege, M.b , Ukhanov, K.c , Ringers, C.b d , Zhang, Y.a , Jung, I.b e , D’Gama, P.P.b , Li, S.S.a , Cosacak, M.I.f , Kizil, C.g , Park, H.-C.e , Yaksi, E.d h , Martens, J.R.c , Brody, S.L.i , Jurisch-Yaksi, N.b d , Roy, S.a j k
a Institute of Molecular and Cell Biology, Agency for Science Technology and Research, Singapore, Singapore
b Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
c Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, United States
d Kavli Institute for Systems Neuroscience, Centre for Neural Computation, Norwegian University of Science and Technology, Trondheim, Norway
e Department of Biomedical Sciences, Korea University, Ansan, South Korea
f German Center for Neurodegenerative Diseases (DZNE) Dresden, Helmholtz Association, Dresden, Germany
g Department of Neurology, The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, United States
h Koç University Research Center for Translational Medicine, Koç University, School of Medicine, Istanbul, Turkey
i Department of Medicine, Washington University, School of Medicine, St. Louis, MO, United States
j Department of Biological Sciences, National University of Singapore, Singapore, Singapore
k Department of Paediatrics, National University of Singapore, Singapore, Singapore
Abstract
In vertebrates, olfactory receptors localize on multiple cilia elaborated on dendritic knobs of olfactory sensory neurons (OSNs). Although olfactory cilia dysfunction can cause anosmia, how their differentiation is programmed at the transcriptional level has remained largely unexplored. We discovered in zebrafish and mice that Foxj1, a forkhead domain-containing transcription factor traditionally linked with motile cilia biogenesis, is expressed in OSNs and required for olfactory epithelium (OE) formation. In keeping with the immotile nature of olfactory cilia, we observed that ciliary motility genes are repressed in zebrafish, mouse, and human OSNs. Strikingly, we also found that besides ciliogenesis, Foxj1 controls the differentiation of the OSNs themselves by regulating their cell type-specific gene expression, such as that of olfactory marker protein (omp) involved in odor-evoked signal transduction. In line with this, response to bile acids, odors detected by OMP-positive OSNs, was significantly diminished in foxj1 mutant zebrafish. Taken together, our findings establish how the canonical Foxj1-mediated motile ciliogenic transcriptional program has been repurposed for the biogenesis of immotile olfactory cilia, as well as for the development of the OSNs. © 2024 Rayamajhi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma
(2024) Journal of Neuro-Oncology, .
Gonzalez-Aponte, M.F.a , Damato, A.R.a , Trebucq, L.L.b , Simon, T.a , Cárdenas-García, S.P.a , Cho, K.c d , Patti, G.J.c d , Golombek, D.A.b e , Chiesa, J.J.b , Rubin, J.B.f g , Herzog, E.D.a
a Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
b Laboratorio de Cronobiología, Universidad Nacional de Quilmes-CONICET, Buenos Aires, Argentina
c Departments of Chemistry and Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Center for Metabolomics and Isotope Tracing, Washington University in St. Louis, St. Louis, MO, United States
e Laboratorio Interdisciplinario del Tiempo (LITERA), Universidad de San Andrés, Buenos Aires, Victoria, B1644BID, Argentina
f Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
g Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
Abstract
Background: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. Methods and results: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. Conclusion: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy. Graphical abstract: [Figure not available: see fulltext.]. © 2024, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
Chronotherapy; Circadian medicine; Circadian rhythms; DNA repair; GBM; TMZ
Funding details
National Institutes of HealthNIHF31CA250161, R25GM103757-10, T32NS121881-01
National Institute of Neurological Disorders and StrokeNINDSR21NS120003
University of WashingtonUW
Agencia Nacional de Promoción Científica y TecnológicaANPCyTPICT 1745-2017
Universidad Nacional de QuilmesUNQPUNQ 2285/22
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Brain–Computer Interfaces for Communication in Patients with Disorders of Consciousness: A Gap Analysis and Scientific Roadmap
(2024) Neurocritical Care, .
Schiff, N.D.a , Diringer, M.b , Diserens, K.c , Edlow, B.L.d , Gosseries, O.e , Hill, N.J.f g , Hochberg, L.R.h i j , Ismail, F.Y.k l , Meyer, I.A.c m , Mikell, C.B.n , Mofakham, S.n o , Molteni, E.p , Polizzotto, L.q , Shah, S.A.r , Stevens, R.D.s , Thengone, D.t
a Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States
b Departments of Neurology and Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
c Neurology and Acute Neurorehabilitation Unit, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
d Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
e Coma Science Group, GIGA-Consciousness, Centre du Cerveau, University Hospital of Liège, University of Liège & Centre du Cerveau, Liège, Belgium
f National Center for Adaptive Neurotechnologies, Stratton VA Medical Center, Albany, NY, United States
g Electrical & Computer Engineering Department, State University of New York at Albany, Albany, NY, United States
h Veterans Affairs Rehabilitation Research & Development Center for Neurorestoration and Neurotechnology, Rehabilitation Research & Development Service, Providence VA Medical Center, Providence, RI, United States
i School of Engineering and Carney Institute for Brain Science, Brown University, Providence, RI, United States
j Center for Neurotechnology and Neurorecovery, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
k Department of Pediatrics, United Arab Emirates University, Al Ain, United Arab Emirates
l Department of Neurology, Adjunct Johns Hopkins University School of Medicine, Baltimore, MD, United States
m Centre for Advanced Research in Sleep Medicine and Integrated Trauma Centre, Integrated University Health and Social Services Centre (CIUSSS) du Nord-de-L’Île-de-Montréal, Montreal, QC, Canada
n Department of Neurosurgery, Stony Brook University Hospital, Stony Brook, NY, United States
o Department of Electrical and Computer Engineering, Stony Brook University, Stony Brook, NY, United States
p School of Biomedical Engineering and Imaging Sciences, and Centre for Medical Engineering, King’s College London, London, United Kingdom
q Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, United States
r Department of Radiology, Weill Cornell Medical College, New York, NY, United States
s Departments of Anesthesiology and Critical Care Medicine, Neurology, and Neurosurgery, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
t Brown University, Providence, RI, United States
Abstract
Background: We developed a gap analysis that examines the role of brain–computer interfaces (BCI) in patients with disorders of consciousness (DoC), focusing on their assessment, establishment of communication, and engagement with their environment. Methods: The Curing Coma Campaign convened a Coma Science work group that included 16 clinicians and neuroscientists with expertise in DoC. The work group met online biweekly and performed a gap analysis of the primary question. Results: We outline a roadmap for assessing BCI readiness in patients with DoC and for advancing the use of BCI devices in patients with DoC. Additionally, we discuss preliminary studies that inform development of BCI solutions for communication and assessment of readiness for use of BCIs in DoC study participants. Special emphasis is placed on the challenges posed by the complex pathophysiologies caused by heterogeneous brain injuries and their impact on neuronal signaling. The differences between one-way and two-way communication are specifically considered. Possible implanted and noninvasive BCI solutions for acute and chronic DoC in adult and pediatric populations are also addressed. Conclusions: We identify clinical and technical gaps hindering the use of BCI in patients with DoC in each of these contexts and provide a roadmap for research aimed at improving communication for adults and children with DoC, spanning the clinical spectrum from intensive care unit to chronic care. © 2024, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.
Author Keywords
Cognitive motor dissociation; Coma; Communication; Electroencephalography; Functional magnetic resonance imaging; Head injury; Neural repair
Funding details
National Institutes of HealthNIHDP2HD101400
National Institute of Biomedical Imaging and BioengineeringNIBIBP41EB018783
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration
(2024) JCI Insight, 9 (2), art. no. e162771, .
Kanan, M.K.a , Sheehan, P.W.a , Haines, J.N.a , Gomez, P.G.a , Dhuler, A.a , Nadarajah, C.J.a , Wargel, Z.M.a , Freeberg, B.M.a , Nelvagal, H.R.b , Izumo, M.c , Takahashi, J.S.c d , Cooper, J.D.b , Davis, A.A.a , Musiek, E.S.a e
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Departments of Pediatrics, Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, United States
d Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, United States
e Center On Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, MO, United States
Abstract
Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cellautonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after a-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD. © 2024, Kanan et al.
Funding details
National Institutes of HealthNIHK08NS101118, R01AG054517, T32AG058518
Howard Hughes Medical InstituteHHMI
National Cancer InstituteNCIP30 CA91842, UL1TR002345
Document Type: Article
Publication Stage: Final
Source: Scopus
Intraindividual variability in post-stroke cognition and its relationship with activities of daily living and social functioning: an ecological momentary assessment approach
(2024) Topics in Stroke Rehabilitation, .
Munsell, E.G.S.a b , Bui, Q.c , Kaufman, K.J.a , Tomazin, S.E.a , Regan, B.A.a , Lenze, E.J.d , Lee, J.-M.e , Mohr, D.C.f , Fong, M.W.M.g , Metts, C.L.h , Pham, V.d , Wong, A.W.K.a i
a Center for Rehabilitation Outcomes Research, Shirley Ryan AbilityLab, Chicago, IL, United States
b Center for Education in Health Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Center for Behavioral Intervention Technologies, Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
g Michigan Avenue Neuropsychologists, Chicago, IL, United States
h Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States
i Department of Physical Medicine and Rehabilitation, Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
Abstract
Introduction: Ecological momentary assessment (EMA) is a methodological approach to studying intraindividual variation over time. This study aimed to use EMA to determine the variability of cognition in individuals with chronic stroke, identify the latent classes of cognitive variability, and examine any differences in daily activities, social functioning, and neuropsychological performance between these latent classes. Methods: Participants (N = 202) with mild-to-moderate stroke and over 3-month post-stroke completed a study protocol, including smartphone-based EMA and two lab visits. Participants responded to five EMA surveys daily for 14 days to assess cognition. They completed patient-reported measures and neuropsychological assessments during lab visits. Using latent class analysis, we derived four indicators to quantify cognitive variability and identified latent classes among participants. We used ANOVA and Chi-square to test differences between these latent classes in daily activities, social functioning, and neuropsychological performance. Results: The latent class analysis converged on a three-class model. The moderate and high variability classes demonstrated significantly greater problems in daily activities and social functioning than the low class. They had significantly higher proportions of participants with problems in daily activities and social functioning than the low class. Neuropsychological performance was not statistically different between the three classes, although a trend approaching statistically significant difference was observed in working memory and executive function domains. Discussion: EMA could capture intraindividual cognitive variability in stroke survivors. It offers a new approach to understanding the impact and mechanism of post-stroke cognitive problems in daily life and identifying individuals benefiting from self-regulation interventions. © 2024 Taylor & Francis Group, LLC.
Author Keywords
cognition; cognitive rehabilitation; cognitive variability; ecological momentary assessment; mobile health; remote assessment; Stroke
Funding details
National Institutes of HealthNIH
American Occupational Therapy FoundationAOTF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS–FTD
(2024) Nature Medicine, .
Irwin, K.E.a b , Jasin, P.a , Braunstein, K.E.a , Sinha, I.R.a b , Garret, M.A.c , Bowden, K.D.a b , Chang, K.a d , Troncoso, J.C.a e , Moghekar, A.e , Oh, E.S.a f g , Raitcheva, D.h , Bartlett, D.h , Miller, T.i , Berry, J.D.c , Traynor, B.J.e j k l , Ling, J.P.a , Wong, P.C.a b
a Department of Pathology, Johns Hopkins Medicine, Baltimore, MD, United States
b Department of Neuroscience, Johns Hopkins Medicine, Baltimore, MD, United States
c Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA, United States
d Department and Graduate Institute of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
e Department of Neurology, Johns Hopkins Medicine, Baltimore, MD, United States
f Department of Medicine, Johns Hopkins Medicine, Baltimore, MD, United States
g Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine, Baltimore, MD, United States
h Biogen, Cambridge, MA, United States
i Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
j Neuromuscular Diseases Research Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
k National Institute of Neurological Disorders, National Institutes of Health, Bethesda, MD, United States
l RNA Therapeutics Laboratory, Therapeutics Development Branch, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, United States
Abstract
Although loss of TAR DNA-binding protein 43 kDa (TDP-43) splicing repression is well documented in postmortem tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), whether this abnormality occurs during early-stage disease remains unresolved. Cryptic exon inclusion reflects loss of function of TDP-43, and thus detection of proteins containing cryptic exon-encoded neoepitopes in cerebrospinal fluid (CSF) or blood could reveal the earliest stages of TDP-43 dysregulation in patients. Here we use a newly characterized monoclonal antibody specific to a TDP-43-dependent cryptic epitope (encoded by the cryptic exon found in HDGFL2) to show that loss of TDP-43 splicing repression occurs in ALS–FTD, including in presymptomatic C9orf72 mutation carriers. Cryptic hepatoma-derived growth factor-like protein 2 (HDGFL2) accumulates in CSF at significantly higher levels in familial ALS–FTD and sporadic ALS compared with controls and is elevated earlier than neurofilament light and phosphorylated neurofilament heavy chain protein levels in familial disease. Cryptic HDGFL2 can also be detected in blood of individuals with ALS–FTD, including in presymptomatic C9orf72 mutation carriers, and accumulates at levels highly correlated with those in CSF. Our findings indicate that loss of TDP-43 cryptic splicing repression occurs early in disease progression, even presymptomatically, and that detection of the HDGFL2 cryptic neoepitope serves as a potential diagnostic biomarker for ALS, which should facilitate patient recruitment and measurement of target engagement in clinical trials. © 2024, The Author(s).
Funding details
National Science FoundationNSFOAC 1920103
National Institutes of HealthNIHR01NS095969, R33NS115161, UH3NS115608
U.S. Food and Drug AdministrationFDA1U01FD008129
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDS1ZIAAG000933
Alzheimer’s AssociationAA
ALS AssociationALSA
Richard and Susan Smith Family FoundationRSSFF
Robert Packard Center for ALS Research, Johns Hopkins University
Target ALS
Barnes Family Foundation
Karen Toffler Charitable TrustKTCT
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Patient Outcomes After Peripheral Nerve Injury Depend on Bimanual Dexterity and Preserved Use of the Affected Hand
(2024) Neurorehabilitation and Neural Repair, .
Kim, T.a , Lohse, K.R.b , Mackinnon, S.E.c , Philip, B.A.a
a Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
b Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
c Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Little is known about how peripheral nerve injury affects human performance, behavior, and life. Hand use choices are important for rehabilitation after unilateral impairment, but rarely measured, and are not changed by the normal course of rehabilitation and daily life. Objective: To identify the relationship between hand use (L/R choices), motor performance, and patient-centered outcomes. Methods: Participants (n = 48) with unilateral peripheral nerve injury were assessed for hand use via Block Building Task, Motor Activity Log, and Edinburgh Handedness Inventory; dexterity (separately for each hand) via Nine-Hole Peg Test, Jebsen Taylor Hand Function Test, and a precision drawing task; patient-centered outcomes via surveys of disability, activity participation, and health-related quality of life; and injury-related factors including injury cause and affected nerve. Factor Analysis of Mixed Data was used to explore relationships between these variables. The data were analyzed under 2 approaches: comparing dominant hand (DH) versus non-dominant hand (NH), or affected versus unaffected hand. Results: The data were best explained by 5 dimensions. Good patient outcomes were associated with NH performance, DH performance (separately and secondarily to NH performance), and preserved function and use of the affected hand; whereas poor patient outcomes were associated with preserved but unused function of the affected hand. Conclusion: After unilateral peripheral nerve injury, hand function, hand usage, and patient life arise from a complex interaction of many factors. To optimize rehabilitation after unilateral impairment, new rehabilitation methods are needed to promote performance and use with the NH, as well as the injured hand. © The Author(s) 2024.
Author Keywords
hand dominance; lateralization; manual dexterity; peripheral nerve injury; quality of life
Funding details
National Institute of Neurological Disorders and StrokeNINDSR01 NS114046
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Age-Related Differences in Motor Skill Transfer with Brief Memory Reactivation
(2024) Brain Sciences, 14 (1), art. no. 65, .
Tomlin, K.B.a , Johnson, B.P.b , Westlake, K.P.a
a Department of Physical Therapy and Rehabilitation Science, University of Maryland School of Medicine, Baltimore, MD 21201, United States
b Department of Occupational Therapy, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Motor memories can be strengthened through online practice and offline consolidation. Offline consolidation involves the stabilization of memory traces in post-practice periods. Following initial consolidation of a motor memory, subsequent practice of the motor skill can lead to reactivation and reconsolidation of the memory trace. The length of motor memory reactivation may influence motor learning outcomes; for example, brief, as opposed to long, practice of a previously learned motor skill appears to optimize intermanual transfer in healthy young adults. However, the influence of aging on reactivation-based motor learning has been scarcely explored. Here, the effects of brief and long motor memory reactivation schedules on the retention and intermanual transfer of a visuomotor tracing task are explored in healthy older adults. Forty older adults practiced a virtual star-tracing task either three (“brief reactivation”) or ten (“long reactivation”) times per session over a two-week period. Comparison with a previously reported group of younger adults revealed significant age-related differences in the effect of the motor memory reactivation schedule on the intermanual transfer of the motor task. In older adults, unlike younger adults, no significant between-group differences were found by practice condition in the speed, accuracy, or skill of intermanual task transfer. That is, motor task transfer in healthy younger, but not older, adults appears to benefit from brief memory reactivation. These results support the use of age-specific motor training approaches and may inform motor practice scheduling, with possible implications for physical rehabilitation, sport, and music. © 2024 by the authors.
Author Keywords
aging; intermanual transfer; memory; memory reactivation; motor learning; motor skills
Document Type: Article
Publication Stage: Final
Source: Scopus
Augmenting insect olfaction performance through nano-neuromodulation
(2024) Nature Nanotechnology, .
Gupta, P.a , Chandak, R.b , Debnath, A.a , Traner, M.b , Watson, B.M.c , Huang, H.b d , Derami, H.G.a , Baldi, H.a , Chakrabartty, S.e , Raman, B.b , Singamaneni, S.a
a Department of Mechanical Engineering and Materials Science, and Institute of Materials Science and Engineering, Washington University in St Louis, St Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
c Department of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, Washington University in St Louis, St Louis, MO, United States
e Department of Electrical & Systems Engineering, Washington University in St Louis, St Louis, MO, United States
Abstract
Biological olfactory systems are highly sensitive and selective, often outperforming engineered chemical sensors in highly complex and dynamic environments. As a result, there is much interest in using biological systems to build sensors. However, approaches to read-out information from biological systems, especially neural signals, tend to be suboptimal due to the number of electrodes that can be used and where these can be placed. Here we aim to overcome this suboptimality in neural information read-out by using a nano-enabled neuromodulation strategy to augment insect olfaction-based chemical sensors. By harnessing the photothermal properties of nanostructures and releasing a select neuromodulator on demand, we show that the odour-evoked response from the interrogated regions of the insect olfactory system can not only be enhanced but can also improve odour identification. © 2024, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
Office of Naval ResearchONR000142112343
Air Force Office of Scientific ResearchAFOSR95501910394
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neonatal Neural Responses to Novelty Related to Behavioral Inhibition at 1 Year
(2023) Developmental Psychology, .
Schwarzlose, R.F.a , Filippi, C.A.b , Myers, M.J.a , Harper, J.a , Camacho, M.C.a , Smyser, T.A.a , Rogers, C.E.a c , Shimony, J.S.d , Warner, B.B.c , Luby, J.L.a , Barch, D.M.a d e , Pine, D.S.f , Smyser, C.D.c d g , Fox, N.A.h , Sylvester, C.M.a d i
a Department of Psychiatry, Washington University School of Medicine in St. Louis, United States
b Department of Child and Adolescent Psychiatry, New York University School of Medicine, United States
c Department of Pediatrics, Washington University School of Medicine in St. Louis, United States
d Mallinckrodt Institute of Radiology, Washington University School of Medicine in St. Louis, United States
e Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
f Section on Development and Affective Neuroscience (SDAN), Emotion and Development Branch, National Institute of Mental Health, United States
g Department of Neurology, Washington University School of Medicine in St. Louis, United States
h Department of Human Development and Quantitative Methodology, University of Maryland, United States
i The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis, United States
Abstract
Behavioral inhibition (BI), an early-life temperament characterized by vigilant responses to novelty, is a risk factor for anxiety disorders. In this study, we investigated whether differences in neonatal brain responses to infrequent auditory stimuli relate to children’s BI at 1 year of age. Using functional magnetic resonance imaging (fMRI), we collected blood-oxygen-level-dependent (BOLD) data from N=45 full-term, sleeping neonates during an adapted auditory oddball paradigm and measured BI from n = 27 of these children 1 year later using an observational assessment. Whole-brain analyses corrected for multiple comparisons identified 46 neonatal brain regions producing novelty-evokedBOLD responses associatedwith children’s BI scores at 1 year of age. More than half of these regions (n = 24, 52%) were in prefrontal cortex, falling primarily within regions of the default mode or frontoparietal networks or in ventromedial/orbitofrontal regions without network assignments. Hierarchical clustering of the regions based on their patterns of association with BI resulted in two groups with distinct anatomical, network, and response-timing profiles. The first group, located primarily in subcortical and temporal regions, tended to produce larger early oddball responses among infants with lower subsequent BI. The second group, located primarily in prefrontal cortex, produced larger early oddball responses among infants with higher subsequent BI. These results provide preliminary insights into brain regions engaged by novelty in infants that may relate to later BI. The findings may inform understanding of anxiety disorders and guide future research. © 2023 American Psychological Association
Author Keywords
anxiety; auditory; behavioral inhibition; functional magnetic resonance imaging; neonate
Funding details
National Institute of Mental HealthNIMHF32MH132185, R00MH125878, R01MH113883, R01MH122389, R01MH131584, R21MH122976, T32MH014677-40
National Institute of Child Health and Human DevelopmentNICHDK99HD109454, MH002782
Brain and Behavior Research FoundationBBRF26735
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
No Evidence for Chunking in Spatial Memory of Route Experience
(2023) Journal of Experimental Psychology: Learning Memory and Cognition, .
Sargent, J.Q.a b , Richmond, L.L.a c , Kellis, D.M.b d , Smith, M.E.a , Zacks, J.M.a
a Psychological and Brain Sciences, Washington University, St. Louis, United States
b Psychology Department, Francis Marion University, United States
c Department of Psychology, Stony Brook University, United States
d University of South Carolina School of Medicine Columbia, United States
Abstract
Spatial memory is important for supporting the successful completion of everyday activities and is a particularly vulnerable domain in late life. Grouping items together in memory, or chunking, can improve spatial memory performance. In memory for desktop scale spaces and well-learned large-scale environments, error patterns suggest that information is chunked in memory. However, the chunking mechanisms involved in learning new large-scale, navigable environments are poorly understood. In five experiments, two of which included young and older adult samples, participants watched movies depicting routes through building-sized environments while attempting to remember the locations of cued objects. We tested memory for the cued objects with virtual pointing, distance estimation, and map drawing tasks after participants viewed each route. Patterns of error failed to show consistent evidence of chunking in spatial memory across all experiments. One possibility is that chunking in spatial memory relies on visual perceptual grouping mechanisms that are not in play during encoding of large-scale spaces encountered through extended route experiences that do not afford concurrent viewing of target locations. © 2023 American Psychological Association. All Rights Reserved.
Author Keywords
chunking; cognitive aging; navigation; route learning; spatial memory
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Peripheral Retinal Haemorrhages in a Patient with MOG-Associated Optic Neuritis
(2023) Neuro-Ophthalmology, .
Wilke, G.A.a , Spencer, M.b , Gilman, C.A.c , Guerriero, R.c , Bohm, P.d , Van Stavern, G.P.a , Lee, A.R.a
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Department of Paediatrics, Washington University in St. Louis, St. Louis, MO, United States
c Division of Paediatric Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
d Neurology Consultants of Kansas, Wichita, KS, United States
Abstract
A 15-year-old female presented with headaches and bilateral vision loss. Fundoscopic examination revealed bilateral optic nerve oedema as well as peripheral retinal haemorrhages. Magnetic resonance imaging of the brain showed findings consistent with bilateral optic neuritis. The patient was started on high dose intravenous corticosteroids but her vision failed to improve. The presence of retinal haemorrhages raised concern that a vasculitis was underlying her symptoms, prompting an extensive work-up, which was unrevealing. Plasmapheresis was initiated and the patient’s vision eventually improved to 20/20 in both eyes. Ultimately, she was found to be positive for myelin oligodendrocyte glycoprotein (MOG) antibodies, consistent with a diagnosis of MOG-associated optic neuritis. The patient’s course was typical for MOG-associated optic neuritis but her peripheral retinal haemorrhages were atypical, which created diagnostic uncertainty. It is important to be aware of the possibility of retinal findings in this disease. We also review potential causes for retinal haemorrhages in optic neuritis. © 2023 Taylor & Francis Group, LLC.
Author Keywords
corticosteroids; MOG-associated optic neuritis; optic nerve oedema; plasma exchange; retinal haemorrhage
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Construction and Use of Cognitive Maps in Model-Based Control
(2023) Journal of Experimental Psychology: General, .
Karagoz, A.B., Reagh, Z.M., Kool, W.
Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
Abstract
When making decisions, we sometimes rely on habit and at other times plan toward goals. Planning requires the construction and use of an internal representation of the environment, a cognitive map. How are these maps constructed, and how do they guide goal-directed decisions? We coupled a sequential decision-making task with a behavioral representational similarity analysis approach to examine how relationships between choice options change when people build a cognitive map of the task structure. We found that participants who encoded stronger higher-order relationships among choice options showed increased planning and better performance. These higher-order relationships were more strongly encoded among objects encountered in high-reward contexts, indicating a role for motivation during cognitive map construction. In contrast, lower-order relationships such as simple visual co-occurrence of objects did not predict goal-directed planning. These results show that the construction of cognitive maps is an active process, with motivation dictating the degree to which higher-order relationships are encoded and used for planning. © 2023 American Psychological Association. All Rights Reserved.
Author Keywords
behavioral representational similarity; cognitive map; reinforcement learning; two-step task
Document Type: Article
Publication Stage: Article in Press
Source: Scopus