The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND
(2025) Genetics in Medicine, 27 (3), art. no. 101337, .
Qebibo, L.a b c , Davakan, A.d e , Nesson-Dauphin, M.c , Boulali, N.d e , Siquier-Pernet, K.c , Afenjar, A.b , Amiel, J.f , Bartholdi, D.g , Barth, M.h , Blondiaux, E.i , Cristian, I.j , Frazier, Z.k , Goldenberg, A.l , Good, J.-M.m , Salussolia, C.L.k , Sahin, M.k , McCullagh, H.n , McDonald, K.o , McRae, A.p , Morrison, J.j , Pinner, J.q , Shinawi, M.r , Toutain, A.s , Vyhnálková, E.t , Wheeler, P.G.j , Wilnai, Y.u , Hausman-Kedem, M.v , Coolen, M.c , Cantagrel, V.c , Burglen, L.a b c , Lory, P.d e
a Pediatric Neurogenetics Laboratory, Department of Genetics, Armand-Trousseau Hospital, AP-HP. Sorbonne Université, Paris, France
b Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France
c Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France
d IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France
e LabEx “Ion Channel Science and Therapeutics,”, Montpellier, France
f Service de Médecine Génomique des Maladies Rares, Necker Enfants Malades University Hospital, APHP, Paris, France
g Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Switzerland
h Department of Biochemistry and Genetics, Angers University Hospital, Angers, France
i Department of Radiology, Armand-Trousseau Hospital, APHP, Sorbonne University, Paris, France
j Arnold Palmer Hospital for Children, Orlando HealthFL
k Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children’s Hospital, Harvard Medical School, Boston, MA
l Université Rouen Normandie, INSERM U1245, CHU de Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, France
m Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
n Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom
o Department of Pediatrics, University of Louisville, Norton Children’s Hospital, Louisville, KY
p Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL
q Centre for Clinical Genetics, Sydney Children’s Hospitals Network and University of New South Wales, Sydney, Australia
r Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO
s Unité fonctionnelle de Génétique Médicale, Centre Hospitalier Universitaire, Tours, France
t Charles University, Motol University Hospital, Prague, Czech Republic
u Tel Aviv Sourasky Medical Center, Genetic Institute, Tel Aviv, Israel
v Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Medical Center and Faculty of Medical and Health Science, Tel-Aviv University, Tel-Aviv, Israel
Abstract
Purpose: Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. Methods: We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. Results: We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. Conclusion: This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia. © 2024 American College of Medical Genetics and Genomics
Author Keywords
CACNA1G gene; Cerebellum; Neurodevelopment; Spinocerebellar ataxia; T-type voltage-gated calcium channel
Document Type: Article
Publication Stage: Final
Source: Scopus
Exploring the neuroprotective potential of immunosuppressants in Parkinson’s disease
(2025) Parkinsonism and Related Disorders, 132, art. no. 107294, .
Mubarak, H.M.a , Racette, B.A.a b c , Killion, J.A.a , Faust, I.M.a , Laurido-Soto, O.J.b , Doddamreddy, S.A.a , Searles Nielsen, S.b
a Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, United States
b Department of Neurology, Washington University School of Medicine in St. Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
c School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 27 St Andrews Rd, Parktown2193, South Africa
Abstract
Introduction: Neuroprotective therapy to slow Parkinson’s disease (PD) progression is a critical unmet need. Neuroinflammation likely represents an important pathophysiologic mechanism for disease progression. Medications that target this inflammation, such as immunosuppressants, represent potential disease-modifying therapies for PD. The relation between these medications and PD risk might inform candidate selection. Methods: We conducted a population-based case-control study using Medicare data from the United States. The study included 207,532 incident PD cases and 975,177 controls from 2016 to 2018, age 67–110. We examined the association between PD risk and immunosuppressant use before PD diagnosis/control selection. We considered 37 immunosuppressants, representing >10 medication classes, in Part D prescription claims. We used logistic regression to estimate the relative risk (RR) and 95 % confidence interval (CI) between each medication and PD, while accounting for age, sex, race/ethnicity, smoking, and healthcare utilization. In sensitivity analyses we applied exposure lagging, restricted to immunosuppressant users, and corrected for multiple comparisons. Results: Medicare beneficiaries using the calcineurin inhibitor tacrolimus (RR 0.49, CI 0.40–0.60) and mTOR inhibitors everolimus (RR 0.38, CI 0.26–0.56) and sirolimus (RR 0.59, CI 0.37–0.93) had a lower risk of PD compared to those not taking the medication. The TNF inhibitor certolizumab was also associated with lower PD risk (RR 0.54, CI 0.34–0.84). Tacrolimus and everolimus remained significant after Bonferroni correction. Sensitivity analyses otherwise confirmed results for all four medications. Conclusion: Calcineurin or mTOR inhibition might reduce PD risk. Future studies should examine whether these medications or structurally similar agents might have potential as disease-modifying therapies for PD. © 2025 Elsevier Ltd
Author Keywords
Disease modifying therapy; Immunosuppressant; Neurodegenerative; Neuroprotective; Parkinson’s disease
Document Type: Article
Publication Stage: Final
Source: Scopus
Female mice lacking GluA3 show early onset of hearing loss, cochlear synaptopathy, and afferent terminal swellings in ambient sound levels
(2025) iScience, 28 (2), art. no. 111799, .
Pal, I.a , Bhattacharyya, A.b , V-Ghaffari, B.b , Williams, E.D.a , Xiao, M.b , Rutherford, M.A.b , Rubio, M.E.a c
a Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
b Department of Otolaryngology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, United States
Abstract
AMPA-type glutamate receptors (AMPARs) mediate excitatory cochlear transmission. However, unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8 postnatal weeks. Here, we studied the role of X-linked Gria3 in cochlear function and synapse anatomy in females. Auditory brainstem responses (ABRs) were similar in 3-week-old female Gria3WT and Gria3KO mice raised in quiet. However, after switching to ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-week and older in Gria3KO. A quiet vivarium precluded this effect. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were more frequent, and swollen afferent terminals were observed only in female Gria3KO mice in ambient sound. Synaptic GluA4:GluA2 ratios increased relative to Gria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs in Gria3KO. We propose that lack of GluA3 induces a sex-dependent vulnerability to AMPAR-mediated excitotoxicity. © 2025 The Author(s)
Author Keywords
Cellular neuroscience; Neuroscience; Sensory neuroscience
Document Type: Article
Publication Stage: Final
Source: Scopus
Precision data-driven modeling of cortical dynamics reveals person-specific mechanisms underpinning brain electrophysiology
(2025) Proceedings of the National Academy of Sciences of the United States of America, 122 (3), art. no. e2409577121, .
Singh, M.F.a b c d e f , Braver, T.S.e , Cole, M.f , Ching, S.N.d
a Department of Statistics, University of Illinois, Urbana-Champaign, Champaign, IL 61820, United States
b Beckman Institute for Advanced Science and Technology, University of Illinois, Urbana-Champaign, Champaign, IL 61801, United States
c Department of Psychology, University of Illinois, Urbana-Champaign, Champaign, IL 61820, United States
d Department of Electrical & Systems Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
e Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States
f Center for Molecular and Behavioral Neuroscience, Rutgers University, Newark, NJ 07102, United States
Abstract
Task-free brain activity affords unique insight into the functional structure of brain network dynamics and has been used to identify neural markers of individual differences. In this work, we present an algorithmic optimization framework that directly inverts and parameterizes brain-wide dynamical-systems models involving hundreds of interacting neural populations, from single-subject M/EEG timeseries recordings. This technique provides a powerful neurocomputational tool for interrogating mechanisms underlying individual brain dynamics (“precision brain models”) and making quantitative predictions. We extensively validate the models’ performance in forecasting future brain activity and predicting individual variability in key M/EEG metrics. Last, we demonstrate the power of our technique in resolving individual differences in the generation of alpha and beta-frequency oscillations. We characterize subjects based upon model attractor topology and a dynamical-systems mechanism by which these topologies generate individual variation in the expression of alpha vs. beta rhythms. We trace these phenomena back to global variation in excitatory–inhibitory balance, highlighting the explanatory power of our framework to generate mechanistic insights. Copyright © 2025 the Author(s).
Author Keywords
attractors; brain dynamics; individual differences; MEG; resting-state
Document Type: Article
Publication Stage: Final
Source: Scopus
A human single-neuron dataset for object recognition
(2025) Scientific Data, 12 (1), p. 79.
Cao, R.a , Brunner, P.b , Brandmeir, N.J.c , Willie, J.T.b , Wang, S.a
a Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63110, United States
c Department of Neurosurgery, West Virginia University, Morgantown, WV 26506, United States
Abstract
Object recognition is fundamental to how we interact with and interpret the world around us. The human amygdala and hippocampus play a key role in object recognition, contributing to both the encoding and retrieval of visual information. Here, we recorded single-neuron activity from the human amygdala and hippocampus when neurosurgical epilepsy patients performed a one-back task using naturalistic object stimuli. We employed two sets of naturalistic object images from leading datasets extensively used in primate neural recordings and computer vision models: we recorded 1204 neurons using the ImageNet stimuli, which included broader object categories (10 different images per category for 50 categories), and we recorded 512 neurons using the Microsoft COCO stimuli, which featured a higher number of images per category (50 different images per category for 10 categories). Together, our extensive dataset, offering the highest spatial and temporal resolution currently available in humans, will not only facilitate a comprehensive analysis of the neural correlates of object recognition but also provide valuable opportunities for training and validating computational models. © 2025. The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Brain Age Modeling and Cognitive Outcomes in Young Adults With and Without Sickle Cell Anemia
(2025) JAMA Network Open, 8 (1), p. e2453669.
Ford, A.L.a b , Fellah, S.a , Wang, Y.a , Unger-Levinson, K.a , Hagan, M.a , Reis, M.N.b , Mirro, A.c , Lewis, J.B.a , Ying, C.b , Guilliams, K.P.a b c , Fields, M.E.c , An, H.b , King, A.A.c d , Chen, Y.a
a Department of Neurology, Washington University in St Louis School of Medicine, St Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University in St Louis School of Medicine, St Louis, MO, United States
c Department of Pediatrics, Washington University in St Louis School of Medicine, St Louis, MO, United States
d Program in Occupational Therapy, Washington University in St Louis School of Medicine, St Louis, MO, United States
Abstract
Importance: Both sickle cell anemia (SCA) and socioeconomic status have been associated with altered brain structure and cognitive disability, yet precise mechanisms underlying these associations are unclear. Objective: To determine whether brains of individuals with and without SCA appear older than chronological age and if brain age modeling using brain age gap (BAG) can estimate cognitive outcomes and mediate the association of socioeconomic status and disease with these outcomes. Design, Setting, and Participants: In this cross-sectional study of 230 adults with and without SCA, individuals underwent brain magnetic resonance imaging (MRI) and cognitive assessment. Brain age was estimated using DeepBrainNet, a model trained to estimate chronological age from 14 468 structural MRIs from healthy individuals across the lifespan. BAG was defined as estimated brain age minus chronological age. Linear regression examined clinical factors associated with BAG and the ability of BAG to estimate cognitive performance compared to neuroimaging metrics of brain health and ischemic brain injury, such as normalized whole brain volume, white matter mean diffusivity (MD), and infarct volume. BAG and white matter MD were tested further as mediators of the association of socioeconomic status and SCA with cognitive performance. Data were analyzed from October 15, 2023, to July 1, 2024. Exposures: SCA disease status and economic deprivation as measured using the area deprivation index (ADI). Main Outcome and Measures: Executive function, crystallized function, processing speed, and full-scale intelligence quotient (FSIQ) were derived from the National Institutes of Health (NIH) Toolbox and Wechsler Abbreviated Scale of Intelligence, Second Edition. Results: Among 230 included adults, 123 individuals had SCA (median [IQR] age, 26.4 [21.8-34.3] years; 77 female [63%]) and 107 individuals did not (control cohort; median [IQR] age, 30.1 [26.3-34.8] years; 77 female [72%]). Participants with SCA had a larger median (IQR) BAG compared to individuals in the control cohort (14.2 [8.0-19.2] vs 7.3 [3.2-11.1] years; median difference, 6.13 years; 95% CI, 4.29-8.05 years; P < .001). Individuals in the control cohort demonstrated a larger BAG relative to the reference population (mean difference, 7.52 years; 95% CI, 6.32-8.72 years; P < .001). Higher economic deprivation was associated with BAG in the control cohort (β [SE] per 1% ADI increase, 0.079 [0.028]; 95% CI, 0.023 to 0.135; P = .006), while intracranial vasculopathy (β [SE], 6.562 [1.883]; 95% CI, 2.828 to 10.296; P < .001) and hemoglobin S percentage (β [SE] per 1% increase, 0.089 [0.032]; 95% CI, 0.026 to 0.151; P = .006) were associated with BAG in participants with SCA. Across neuroimaging metrics of brain health, BAG demonstrated the largest effect size for cognitive outcomes in the control cohort (eg, executive function: r = -0.430; P = .001), while white matter MD demonstrated the largest effect size for cognitive outcomes (eg, executive function: r = -0.365; P = .001) in the SCA cohort. Across the study population, BAG mediated the association of ADI with cognitive performance (eg, executive function: β [SE] per 1-unit decrease in ADI, -0.031 [0.014]; 95% CI, -0.061 to -0.006), while BAG (eg, FSIQ: β [SE], -3.79 [1.42]; 95% CI, -6.87 to -1.40) and white matter MD (eg, FSIQ: β [SE], -4.55 [1.82]; 95% CI, -8.14 to -0.94) mediated the association of SCA with cognitive performance. Conclusions and Relevance: Adults with SCA and a healthy control cohort with greater economic deprivation demonstrated older brain age, suggestive of insufficient brain development, premature brain aging, or both. Brain estimates of chronological age may inform mechanisms of the association between chronic disease and socioeconomic status with cognitive outcomes in healthy and SCA populations, yet will require confirmation in larger and longitudinal studies.
Document Type: Article
Publication Stage: Final
Source: Scopus
Planned Surgical Trajectory Affects Clinical Motor Outcome in Deep Brain Stimulation Targeted at Subthalamic Nucleus for Parkinson’s Disease
(2024) Operative Neurosurgery, art. no. 10.1227/ons.0000000000001355, .
Wang, L.S.a , Younce, J.R.b , Milchenko, M.c , Ushe, M.a , Alfradique-Dunham, I.a , Tabbal, S.D.d , Dowling, J.L.e , Perlmutter, J.S.a c f g h , Norris, S.A.a c
a Department of Neurology, Washington University in St Louis, St Louis, MO, United States
b Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
c Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
d Department of Neurology, Penn State University, Hershey, PA, United States
e Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
f Department of Neuroscience, Washington University in St Louis, St Louis, MO, United States
g Program in Physical Therapy, Washington University in St Louis, St Louis, MO, United States
h Program in Occupational Therapy, Washington University in St Louis, St Louis, MO, United States
Abstract
BACKGROUND AND OBJECTIVES:Surgical planning is critical to achieve optimal outcome in deep brain stimulation (DBS). The relationship between clinical outcomes and DBS electrode position relative to subthalamic nucleus (STN) is well investigated, but the role of surgical trajectory remains unclear. We sought to determine whether preoperatively planned DBS lead trajectory relates to adequate motor outcome in STN-DBS for Parkinson’s disease (PD).METHODS:In 49 participants who underwent bilateral STN-DBS for PD using a Leksell® frame, we coregistered the frame and participant MRI images to obtain participant-specific anatomical planes. We evaluated relationships between clinical data and planned trajectories relative to their midsagittal and axial planes. We computed percent change in Unified PD Rating Scale subsection 3 (Unified Parkinson’s Disease Rating Scale, part III) scores before and after DBS, and performed binary logistic regression to determine whether planned trajectories affect adequate (>30% Unified Parkinson’s Disease Rating Scale, part III improvement) motor outcome.RESULTS:Preoperatively planned left lead trajectory relative to midsagittal plane predicted likelihood of adequate right body motor outcomes (odds ratio = 0.69, P =.024), even when controlling for ventricular width through Evans index. This effect reflects that increasingly lateral angle of approach reduced odds of adequate motor outcome. Right lead trajectory lacked a similar trend.CONCLUSION:Left DBS lead trajectory predicts adequate right-body motor outcome after bilateral STN-DBS. Greater planned trajectory angle relative to midsagittal plane reduces motor outcomes, independent of patients’ ventricular width. These data may guide patient selection, inform risk/benefit discussions, optimize surgical planning, or support evidence-based evaluation of the methodologies used to select the approach trajectory, with careful consideration of the angle of approach relative to target. © Congress of Neurological Surgeons 2024. Unauthorized reproduction of this article is prohibited.
Author Keywords
Deep brain stimulation; Parkinson’s disease; Stereotactic technique
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Pace of Biological Aging Partially Explains the Relationship Between Socioeconomic Status and Chronic Low Back Pain Outcomes
(2024) Journal of Pain Research, 17, pp. 4317-4329.
Aroke, E.N.a , Nagidi, J.G.b , Srinivasasainagendra, V.c , Quinn, T.L.d , Agbor, F.B.A.T.a , Kinnie, K.R.a , Tiwari, H.K.c , Goodin, B.R.e
a Department of Acute, Chronic, and Continuing Care, School of Nursing, University of Alabama at Birmingham, Birmingham, AL, United States
b Department of Computer Science, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL, United States
c Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United States
d Department of Psychology, College of Arts and Sciences, University of Alabama at Birmingham, Birmingham, AL, United States
e Department of Anesthesiology, School of Medicine, Washington University, St Louis, MO, United States
Abstract
Introduction: Having a lower socioeconomic status (SES) is a predictor of age-related chronic conditions, including chronic low back pain (cLBP). We aimed to examine whether the pace of biological aging mediates the relationship between SES and cLBP outcomes – pain intensity, pain interference, and physical performance. Methods: We used the Dunedin Pace of Aging Calculated from the Epigenome (DunedinPACE) software to determine the pace of biological aging in adults ages 18 to 85 years with no cLBP (n = 74), low-impact pain (n = 56), and high-impact pain (n = 77). Results: The mean chronological age of the participants was 40.9 years (SD= 15.1); 107 (51.7%) were female, and 108 (52.2%) were Black. On average, the pace of biological aging was 5% faster [DunedinPACE = 1.05 (SD = 0.14)] in the sample (DunedinPACE value of 1 = normal pace of aging). Individuals with higher levels of education had a significantly slower pace of biological aging than those with lower education levels (F = 5.546, p = 0.001). After adjusting for sex and race, household income level significantly correlated with the pace of biological aging (r = -0.17, p = 0.02), pain intensity (r = -0.21, p = 0.003), pain interference (r = -0.21, p = 0.003), and physical performance (r = 0.20, p = 0.005). In mediation analyses adjusting for sex, race, and body mass index (BMI), the pace of biological aging mediates the relationship between household income (but not education) level and cLBP intensity, interference, as well as physical performance. Discussion: Results indicate that lower SES contributes to faster biological aging, possibly contributing to greater pain intensity and interference, as well as lower physical performance. Future interventions slowing the pace of biological aging may improve cLBP outcomes. Pain language summary: Individuals of lower socioeconomic status (SES) experience worse outcomes from age-related chronic conditions, including chronic low back pain (cLBP). This work examines the relationship between SES, pace of biological aging, and cLBP intensity, interference with daily activities, and physical function. Lower SES correlates with a faster pace of biological aging, as well as cLBP pain intensity, pain interference, and physical performance. The pace of biological aging helps explain the relationship between household income and cLBP intensity, interference, as well as physical performance. Interventions targeting SES disparities may slow biological aging and improve cLBP outcomes. © 2024 Aroke et al.
Author Keywords
chronic low back pain; DunedinPACE; epigenetic clock; health disparities; pace of biological aging; socioeconomic status
Document Type: Article
Publication Stage: Final
Source: Scopus