The effects of neighborhood disadvantage and adverse childhood experiences on conditioned pain modulation in adults with chronic low back pain
(2025) Journal of Pain, 26, art. no. 104706, .
Thomas, P.A.a , Ditta, P.V.a , Stocking, S.Q.a , Webb, C.a , Meints, S.M.b c , Owens, M.A.d , Quinn, T.a , Aroke, E.N.e , Morris, M.C.f , Sorge, R.E.a , Goodin, B.R.a g , Overstreet, D.S.h
a College of Arts and Science, Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35205, United States
b Perioperative and Pain Medicine, Department of Anesthesiology, Brigham and Woman’s Hospital, 75 Francis Street, Boston, MA 02411, United States
c Harvard Medical School, Boston, MA 02115, United States
d Department of Psychiatry and Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35205, United States
e School of Nursing, Nurse Anesthesia Program, Department of Acute, Chronic, & Continuing Care, University of Alabama at Birmingham, Birmingham, AL, United States
f Vanderbilt University Medical Center, Department of Anesthesiology, Nashville, TN 37232, United States
g Washington University Pain Center, Department of Anesthesiology, Washington University, St. Louis, MO 63110, United States
h School of Medicine, Department of Surgery, Division of Gastrointestinal, University of Alabama at Birmingham, Birmingham, AL 35203, United States
Abstract
Chronic low back pain (cLBP) remains a major health crisis worldwide. Current conceptualizations of cLBP utilize the biopsychosocial model, yet research on social factors remains limited. Adverse childhood experiences (ACEs) are a risk factor for a variety of chronic health problems, including cLBP. However, the extent to which socioeconomic context might influence associations between ACEs and cLBP remains unclear. Socioeconomic factors such as healthcare access and living conditions, which cluster at the neighborhood level, may affect how ACEs relate to cLBP in adulthood. This study examined (1) the relationship between ACEs and conditioned pain modulation (CPM), and (2) the moderating effect of area-level deprivation index (ADI) in a sample of community-dwelling adults with cLBP. 183 adults with cLBP (53% female, 62.8% non-Hispanic Black) reported on ACEs, ADI, sociodemographics, and completed experimental testing of conditioned pain modulation (CPM). Greater ACEs were associated with a less efficient CPM response for individuals residing in low neighborhood deprivation (p < 0.01). ACEs were not significantly associated with CPM for those residing in average (p = 0.31) or high deprivation (p = 0.15). Our findings suggest that a history of ACEs is associated with diminished ability to inhibit pain, especially among individuals living in less deprived neighborhoods. The association between ACEs and CPM was weakest for the portion of our sample residing in neighborhoods with the most deprivation. People from disadvantaged backgrounds may experience numerous psychosocial stressors that hinder CPM, making it difficult to assess the specific impact of ACEs on CPM. Trial registration: This study utilized baseline data collected as part of a parent trial titled “Examining Racial and SocioEconomic Disparities in Chronic Low Back Pain” (ERASED – ClinicalTrials.gov ID: NCT03338192). Perspective: This study demonstrates that early life adversity is associated with abnormal endogenous pain modulation, particularly for participants who live in neighborhoods characterized by less deprivation. © 2024 United States Association for the Study of Pain, Inc.
Author Keywords
Adverse childhood experiences; Area level deprivation; Chronic low back pain; Conditioned pain modulation; Social determinants of pain
Funding details
National Institutes of HealthNIH
National Institute on Minority Health and Health DisparitiesNIMHDR01MD010441, R01 MD017565
National Institute on Minority Health and Health DisparitiesNIMHD
National Cancer InstituteNCIU54 CA267746
National Cancer InstituteNCI
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSR01 AR079178
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
Document Type: Article
Publication Stage: Final
Source: Scopus
Building compressed causal models of the world
(2024) Cognitive Psychology, 155, art. no. 101682, .
Kinney, D.a , Lombrozo, T.b
a Department of Philosophy and Program in Philosophy-Neuroscience Psychology, Washington University in St. Louis, United States
b Department of Psychology, Princeton University, United States
Abstract
A given causal system can be represented in a variety of ways. How do agents determine which variables to include in their causal representations, and at what level of granularity? Using techniques from Bayesian networks, information theory, and decision theory, we develop a formal theory according to which causal representations reflect a trade-off between compression and informativeness, where the optimal trade-off depends on the decision-theoretic value of information for a given agent in a given context. This theory predicts that, all else being equal, agents prefer causal models that are as compressed as possible. When compression is associated with information loss, however, all else is not equal, and our theory predicts that agents will favor compressed models only when the information they sacrifice is not informative with respect to the agent’s anticipated decisions. We then show, across six studies reported here (N=2,364) and one study reported in the supplemental materials (N=182), that participants’ preferences over causal models are in keeping with the predictions of our theory. Our theory offers a unification of different dimensions of causal evaluation identified within the philosophy of science (proportionality and stability), and contributes to a more general picture of human cognition according to which the capacity to create compressed (causal) representations plays a central role. © 2024 The Author(s)
Author Keywords
Bayesian networks; Causal models; Compression; Proportionality; Stability; Value of information
Document Type: Article
Publication Stage: Final
Source: Scopus
Relationship between MRI brain-age heterogeneity, cognition, genetics and Alzheimer’s disease neuropathology
(2024) eBioMedicine, 109, art. no. 105399, .
Antoniades, M.a , Srinivasan, D.a , Wen, J.a q , Erus, G.a , Abdulkadir, A.a p , Mamourian, E.a , Melhem, R.a , Hwang, G.a r , Cui, Y.a , Govindarajan, S.T.a , Chen, A.A.b , Zhou, Z.a , Yang, Z.a , Chen, J.a , Pomponio, R.c , Sotardi, S.d , An, Y.e , Bilgel, M.e , LaMontagne, P.f , Singh, A.g , Benzinger, T.f , Beason-Held, L.e , Marcus, D.S.f , Yaffe, K.h , Launer, L.i , Morris, J.C.j , Tosun, D.k , Ferrucci, L.l , Bryan, R.N.m , Resnick, S.M.e , Habes, M.a n , Wolk, D.o , Fan, Y.m , Nasrallah, I.M.m , Shou, H.g , Davatzikos, C.a
a AI<sup>2</sup>D, Center for AI and Data Science for Integrated Diagnostics, and Center for Biomedical Image Computing and Analytics, University of Pennsylvania, Philadelphia, PA, United States
b Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Biostatistics, Colorado School of Public Health, Aurora, CO 80045, United States
d Department of Radiology, Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, United States
e Laboratory of Behavioral Neuroscience, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, United States
h University of California, San Francisco, CA, United States
i Neuroepidemiology Section, Intramural Research Program, National Institute on Aging, Bethesda, MD, United States
j Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
k Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States
l National Institute on Aging, National Institute of Health, Baltimore, MD 21224, United States
m Department of Radiology, University of Pennsylvania, Philadelphia, PA, United States
n Neuroimage Analytics Laboratory (NAL) and the Biggs Institute Neuroimaging Core (BINC), Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, TX, United States
o Department of Neurology, University of Pennsylvania, Philadelphia, PA, United States
p Department of Clinical Neuroscience, Center for Research in Neuroscience, Lausanne University Hospital, Lausanne, Switzerland
q Laboratory of AI and Biomedical Science (LABS), University of Southern California, Los Angeles, CA, United States
r Department of Psychiatry and Behavioral Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
Abstract
Background: Brain ageing is highly heterogeneous, as it is driven by a variety of normal and neuropathological processes. These processes may differentially affect structural and functional brain ageing across individuals, with more pronounced ageing (older brain age) during midlife being indicative of later development of dementia. Here, we examined whether brain-ageing heterogeneity in unimpaired older adults related to neurodegeneration, different cognitive trajectories, genetic and amyloid-beta (Aβ) profiles, and to predicted progression to Alzheimer’s disease (AD). Methods: Functional and structural brain age measures were obtained for resting-state functional MRI and structural MRI, respectively, in 3460 cognitively normal individuals across an age range spanning 42–85 years. Participants were categorised into four groups based on the difference between their chronological and predicted age in each modality: advanced age in both (n = 291), resilient in both (n = 260) or advanced in one/resilient in the other (n = 163/153). With the resilient group as the reference, brain-age groups were compared across neuroimaging features of neuropathology (white matter hyperintensity volume, neuronal loss measured with Neurite Orientation Dispersion and Density Imaging, AD-specific atrophy patterns measured with the Spatial Patterns of Abnormality for Recognition of Early Alzheimer’s Disease index, amyloid burden using amyloid positron emission tomography (PET), progression to mild cognitive impairment and baseline and longitudinal cognitive measures (trail making task, mini mental state examination, digit symbol substitution task). Findings: Individuals with advanced structural and functional brain-ages had more features indicative of neurodegeneration and they had poor cognition. Individuals with a resilient brain-age in both modalities had a genetic variant that has been shown to be associated with age of onset of AD. Mixed brain-age was associated with selective cognitive deficits. Interpretation: The advanced group displayed evidence of increased atrophy across all neuroimaging features that was not found in either of the mixed groups. This is in line with biomarkers of preclinical AD and cerebrovascular disease. These findings suggest that the variation in structural and functional brain ageing across individuals reflects the degree of underlying neuropathological processes and may indicate the propensity to develop dementia in later life. Funding: The National Institute on Aging, the National Institutes of Health, the Swiss National Science Foundation, the Kaiser Foundation Research Institute and the National Heart, Lung, and Blood Institute. © 2024 The Authors
Author Keywords
Ageing; Alzheimer’s disease; Brain age; Cognition; Multimodal
Document Type: Article
Publication Stage: Final
Source: Scopus
“Moderating Role of Self-Regulation Difficulties in the Momentary Associations Between Depressive Symptoms and Participation Poststroke” (2024) The American Journal of Occupational Therapy : Official publication of the American Occupational Therapy Association
Moderating Role of Self-Regulation Difficulties in the Momentary Associations Between Depressive Symptoms and Participation Poststroke
(2024) The American Journal of Occupational Therapy : Official publication of the American Occupational Therapy Association, 78 (6), .
Lee, Y.a , Foster, E.R.b , Baum, C.c , Connor, L.T.d
a Yejin Lee, PhD, is Postdoctoral Research Associate, Program in Occupational Therapy, School of Medicine, Washington University, St. Louis, MO;
b Erin R. Foster, OTR/L, Program in Occupational Therapy, Department of Neurology and Department of Psychiatry, School of Medicine, Washington University, is Associate Professor, St. Louis, MO, United States
c OTR, Program in Occupational Therapy, School of Medicine, Washington University, is Emeritus Professor, St. Louis, MO, United States
d OTR/L, Program in Occupational Therapy and Department of Neurology, School of Medicine, Washington University, is Professor, St. Louis, MO, United States
Abstract
IMPORTANCE: Because depressive symptoms are momentarily associated with lower levels of participation poststroke, it is crucial to investigate what moderates such associations to identify a potential intervention target to reduce the momentary links between depressive symptoms and participation poststroke. Self-regulation seems to be a potential moderator of such associations. OBJECTIVE: To investigate the extent to which difficulties in self-regulation moderate the momentary associations between depressive symptoms and participation poststroke. DESIGN: This study uses a real-time, repeated-measures design using smartphone-based ecological momentary assessment surveys five times a day for 10 days. We performed multilevel modeling to uncover the momentary associations among the study variables. SETTING: Community. PARTICIPANTS: 39 people with stroke. OUTCOMES AND MEASURES: We obtained real-time data for difficulties in self-regulation (total, cognitive, behavioral, and emotion regulation), depressive symptoms, and participation in daily activities (performance in daily activities and satisfaction with performing daily activities). RESULTS: We included 1,612 survey responses in the analysis. Higher depressive symptoms were momentarily associated with lower levels of performance (β = -0.05 to -0.07, p < .001) and satisfaction (β = -0.04 to -0.06, p < .05), regardless of adjusting for self-regulation variables and other covariates. Difficulties in total self-regulation (β = -0.01, p < .001) and emotion regulation (β = -0.02, p < .001) magnified the negative associations between depressive symptoms and satisfaction with performing daily activities. CONCLUSIONS AND RELEVANCE: Using self-regulation and emotion regulation strategies may be a target for just-in-time intervention for reducing the momentary associations between depressive symptoms and satisfaction with performing daily activities poststroke. Plain-Language Summary: Depressive symptoms have immediate and real-time associations with lower levels of participation in daily activities in people with stroke. Self-regulation, including cognitive regulation (e.g., goal setting, planning strategies), behavioral regulation (e.g., controlling impulsive behaviors), and emotion regulation (e.g., managing negative feelings), may be an intervention target for reducing the immediate associations between depressive symptoms and lower levels of participation poststroke. Thus, we investigated whether difficulties in self-regulation variables magnify the negative real-time associations between depressive symptoms and participation poststroke. To obtain real-time data on difficulties in self-regulation variables, depressive symptoms, and participation (i.e., performance and satisfaction), we asked 39 community-dwelling people with stroke to answer smartphone surveys. The results showed that difficulties in total self-regulation and emotion regulation magnified the negative associations between depressive symptoms and satisfaction with performing daily activities. Our findings suggest that self-regulation and emotion regulation strategies may be a target for real-time intervention for reducing the momentary associations between depressive symptoms and satisfaction with performing daily activities poststroke. Copyright © 2024 by the American Occupational Therapy Association, Inc.
Document Type: Article
Publication Stage: Final
Source: Scopus
The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study protocol
(2024) BMC Neurology, 24 (1), art. no. 403, .
Chahine, L.M.a , Louie, N.b , Solle, J.b , Akçimen, F.c , Ameri, A.d , Augenbraun, S.e , Avripas, S.e , Breaux, S.f , Causey, C.g , Chandra, S.h , Dean, M.i , Disbrow, E.A.g , Fanty, L.j , Fernandez, J.e , Foster, E.R.a , Furr Stimming, E.h , Hall, D.l , Hinson, V.d , Johnson-Turbes, A.e , Jonas, C.m , Kilbane, C.n , Norris, S.A.k , Nguyen, B.-T.e , Padmanaban, M.o , Paquette, K.p , Parry, C.e , Pessoa Rocha, N.h , Rawls, A.j , Shamim, E.A.m , Shulman, L.M.q , Sipma, R.i , Staisch, J.f , Traurig, R.p , von Coelln, R.q , Wild Crea, P.p , Xie, T.o , Fang, Z.-H.r , O’Grady, A.b , Kopil, C.M.b , McGuire Kuhl, M.b , Singleton, A.c p , Blauwendraat, C.s , Bandres-Ciga, S.p , Parker, T.t , Baker, D.t , Clark, K.t , Alessi-Fox, C.t , Kostrzebski, M.t , Abdollah Zadegan, S.t , Woodhouse, D.t , Williamson, J.t , Williams, M.t , Weimer, R.t , Volcy, M.t , Vanegas, J.t , Valdez, O.t , Thomas-Dean, F.t , Thompson, K.t , Thomas, H.t , Thomas, D.t , Terrell, E.t , Smith, V.t , Smith, J.t , Senette, T.t , Sajewski, K.t , Ruffrage, L.t , Rosenbaum, M.t , Chamorro, A.R.t , Robinson, C.t , Rizer, K.t , Richardson, J.t , Peters, A.t , Patel, D.t , Parker, J.R.t , Mesaros, M.t , Mercado, C.t , Marathonitis, S.t , Levenes, E.t , Krinickas, N.t , Hudson, J.t , Hines, J.t , Heliste, J.t , Hawkins, A.t , Griffin, C.t , Guilluly, H.t , Franklin, T.t , Foli, R.t , Flowers, J.t , Delaune, M.t , Davis, K.t , Crovetto, N.t , Cromer, C.t , Chauppetta, B.t , Bonano, A.t , Bean, M.t , Baskin, L.t , Toms, J.t , Tholanikunnel, T.t , Standaert, D.t , Kelley, R.t , Javalkar, V.t , Elkasaby, M.t , Coleman, J.t , Alfradique-Dunham, I.t , the BLAAC PD Study and the Global Parkinson’s Genetics Program (GP2)t
a University of Pittsburgh, 3471 Fifth Avenue, Pittsburgh, PA 15213, United States
b The Michael J. Fox Foundation for Parkinson’s Research, New York, NY, United States
c Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, United States
d Medical University of South Carolina, Charleston, SC, United States
e NORC at the University of Chicago, Chicago, IL, United States
f Ochsner Clinic Foundation, New Orleans, LA, United States
g Louisiana State University Health Sciences Center Shreveport, Shreveport, LA, United States
h The University of Texas Health Science Center at Houston, Houston, TX, United States
i University of Alabama at Birmingham, Birmingham, AL, United States
j University of Florida, Gainesville, FL, United States
k Washington University in St. Louis, St. Louis, MO, United States
l Rush University Medical Center, Chicago, IL, United States
m Kaiser Permanente Mid-Atlantic States, Largo, MD, United States
n University Hospitals Cleveland Medical Center, Cleveland, OH, United States
o University of Chicago, Chicago, IL, United States
p Center for Alzheimer’s Disease and Related Dementias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
q University of Maryland, Baltimore, MD, United States
r German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
s Coalition for Aligning Science, Chevy Chase, MD, United States
Abstract
Determining the genetic contributions to Parkinson’s disease (PD) across diverse ancestries is a high priority as this work can guide therapeutic development in a global setting. The genetics of PD spans the etiological risk spectrum, from rare, highly deleterious variants linked to monogenic forms with Mendelian patterns of inheritance, to common variation involved in sporadic disease. A major limitation in PD genomics research is lack of racial and ethnic diversity. Enrollment disparities have detrimental consequences on the generalizability of results and exacerbate existing inequities in care. The Black and African American Connections to Parkinson’s Disease (BLAAC PD) study is part of the Global Parkinson’s Genetics Program, supported by the Aligning Science Across Parkinson’s initiative. The goal of the study is to investigate the genetic architecture underlying PD risk and progression in the Black and/or African American populations. This cross-sectional multicenter study in the United States has a recruitment target of up to 2,000 individuals with PD and up to 2,000 controls, all of Black and/or African American ancestry. The study design incorporates several strategies to reduce barriers to research participation. The multifaceted recruitment strategy aims to involve individuals with and without PD in various settings, emphasizing community outreach and engagement. The BLAAC PD study is an important first step toward informing understanding of the genetics of PD in a more diverse population. © The Author(s) 2024.
Author Keywords
African admixed; African American ancestry; Genetics; Parkinson’s disease; Racial health disparities; Risk
Funding details
University of ChicagoU of C
National Institute of Neurological Disorders and StrokeNINDS
Office of Transportation Delivery
Texas A&M University Health Science Center
National Institutes of HealthNIH
Aligning Science Across Parkinson’sASAP
National Opinion Research CenterNORC
National Institute on AgingNIA
Document Type: Article
Publication Stage: Final
Source: Scopus
Sensory-Motor Neuropathy in Mfn2 T105M Knock-in Mice and Its Reversal by a Novel Piperine-Derived Mitofusin Activator
(2024) The Journal of Pharmacology and Experimental Therapeutics, 391 (2), pp. 361-374.
Weigele, J., Zhang, L., Franco, A., Cartier, E., Dorn, G.W., 2nd
Department of Internal Medicine (Pharmacogenomics), Washington University School of Medicine (J.W., L.Z., A.F., E.C., St. Louis Missouri, Inc. (J.W.
Abstract
Mitochondrial dysfunction is a hallmark of many genetic neurodegenerative diseases, but therapeutic options to reverse mitochondrial dysfunction are limited. While recent studies support the possibility of improving mitochondrial fusion/fission dynamics and motility to correct mitochondrial dysfunction and resulting neurodegeneration in Charcot-Marie-Tooth disease (CMT) and other neuropathies, the clinical utility of reported compounds and relevance of preclinical models are uncertain. Here, we describe motor and sensory neuron dysfunction characteristic of clinical CMT type 2 A in a CRISPR/Casp-engineered Mfn2 Thr105Met (T105M) mutant knock-in mouse. We further demonstrate that daily oral treatment with a novel mitofusin activator derived from the natural product piperine can reverse these neurologic phenotypes. Piperine derivative 8015 promoted mitochondrial fusion and motility in Mfn2-deficient cells in a mitofusin-dependent manner and reversed mitochondrial dysfunction in cultured fibroblasts and reprogrammed motor neurons from a human CMT2A patient carrying the MFN2 T105M mutation. Like previous mitofusin activators, 8015 exhibited stereospecific functionality, but the more active stereoisomer, 8015-P2, is unique in that it has subnanomolar potency and undergoes entero-hepatic recirculation which extends its in vivo half-life. Daily administration of 8015-P2 to Mfn2 T105M knock-in mice for 6 weeks normalized neuromuscular and sensory dysfunction and corrected histological/ultrastructural neurodegeneration and neurogenic myoatrophy. These studies describe a more clinically relevant mouse model of CMT2A and an improved mitofusin activator derived from piperine. We posit that 8015-P2 and other piperine derivatives may benefit CMT2A or other neurodegenerative conditions wherein mitochondrial dysdynamism plays a contributory role. SIGNIFICANCE STATEMENT: Mitochondrial dysfunction is widespread and broadly contributory in neurodegeneration, but difficult to target therapeutically. Here, we describe 8015-P2, a new small molecule mitofusin activator with ∼10-fold greater potency and improved in vivo pharmacokinetics versus comparators, and demonstrate its rapid reversal of sensory and motor neuron dysfunction in an Mfn2 T105M knock-in mouse model of Charcot-Marie-Tooth disease type 2 A. These findings further support the therapeutic approach of targeting mitochondrial dysdynamism in neurodegeneration. Copyright © 2024 by The Author(s).
Document Type: Article
Publication Stage: Final
Source: Scopus
Inhibitory Actions of Potentiating Neuroactive Steroids in the Human α1β3γ2L γ-Aminobutyric Acid Type A Receptor
(2024) Molecular Pharmacology, 106 (5), pp. 264-277.
Pierce, S.R., Germann, A.L., Covey, D.F., Evers, A.S., Steinbach, J.H., Akk, G.
Departments of Anesthesiology (S.R.P., A.L.G., D.F.C., Developmental Biology (D.F.C., the Taylor Family Institute for Innovative Psychiatric Research (D.F.C., A.S.E., Washington University School of Medicine, St Louis, MO, United States
Abstract
The γ-aminobutyric acid type A (GABAA) receptor is modulated by a number of neuroactive steroids. Sulfated steroids and 3β-hydroxy steroids inhibit, while 3α-hydroxy steroids typically potentiate the receptor. Here, we have investigated inhibition of the α1β3γ2L GABAA receptor by the endogenous neurosteroid 3α-hydroxy-5β-pregnan-20-one (3α5βP) and the synthetic neuroactive steroid 3α-hydroxy-5α-androstane-17β-carbonitrile (ACN). The receptors were expressed in Xenopus oocytes. All experiments were done using two-electrode voltage-clamp electrophysiology. In the presence of low concentrations of GABA, 3α5βP and ACN potentiate the GABAA receptor. To reveal inhibition, we conducted the experiments on receptors activated by the combination of a saturating concentration of GABA and propofol to fully activate the receptors and mask potentiation, or on mutant receptors in which potentiation is ablated. Under these conditions, both steroids inhibited the receptor with IC50s of ∼13 μM and maximal inhibitory effects of 70-90%. Receptor inhibition by 3α5βP was sensitive to substitution of the α1 transmembrane domain (TM) 2-2′ residue, previously shown to ablate inhibition by pregnenolone sulfate. However, results of coapplication studies and the apparent lack of state dependence suggest that pregnenolone sulfate and 3α5βP inhibit the GABAA receptor independently and through distinct mechanisms. Mutations to the neurosteroid binding sites in the α1 and β3 subunits statistically significantly, albeit weakly and incompletely, reduced inhibition by 3α5βP and ACN. SIGNIFICANCE STATEMENT: The heteromeric GABAA receptor is inhibited by sulfated steroids and 3β-hydroxy steroids, while 3α-hydroxy steroids are considered to potentiate the receptor. We show here that 3α-hydroxy steroids have inhibitory effects on the α1β3γ2L receptor, which are observed in specific experimental settings and are expected to manifest under different physiological conditions. Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.
Document Type: Article
Publication Stage: Final
Source: Scopus
Novel SGCE Mutation in a Patient With Myoclonus-Dystonia
(2024) Neurology: Genetics, 10 (2), art. no. e200128, .
Klinman, E.a , Gooch, C.b , Perlmutter, J.S.a , Davis, A.A.a , Maiti, B.a
a The Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
b Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
Abstract
Objectives Characterize the presentation, workup, and management of SGCE myoclonus-dystonia, a rare genetic condition, in a patient with atypical presenting symptoms and no family history of movement abnormalities. Methods A woman with myoclonus and dystonia was identified based on clinical history and physical examination. Workup was conducted to determine the cause of her symptoms, including whole-exome sequencing. Myoclonus-dystonia is associated with more than 100 distinct mutations in MYC/DYT-SGCE that account for only half of the total myoclonus-dystonia patients. As such, this case required intensive genetic analyses rather than screening only for a small subset of well-characterized mutations. Results Childhood onset myoclonus and worsening dystonia with age were identified in a young woman. She underwent screening for common causes of twitching movements, followed by whole-exome sequencing which identified a de novo novel variant in the SGCE gene, resulting in a diagnosis of SGCE myoclonus-dystonia. Discussion Myoclonus-dystonia should be considered in patients with symptoms of head and upper extremity myoclonus early in life, especially with co-occurring dystonia, even in the absence of a family history of similar symptoms. Diagnosis of this condition should take place using sequencing, as new mutations continue to be discovered. Copyright © 2024 The Author(s).
Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSK23NS125107
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
A 39UTR Insertion Is a Candidate Causal Variant at the TMEM106B Locus Associated With Increased Risk for FTLD-TDP
(2024) Neurology: Genetics, 10 (1), art. no. e200124, .
Chemparathy, A.a , Le Guen, Y.a b , Zeng, Y.c , Gorzynski, J.c d , Jensen, T.D.c , Yang, C.e , Kasireddy, N.a , Talozzi, L.a , Belloy, M.a , Stewart, I.a , Gitler, A.D.c , Wagner, A.D.f g , Mormino, E.f g , Henderson, V.W.a h , Wyss-Coray, T.a , Ashley, E.c d , Cruchaga, C.e , Greicius, M.D.a
a The Department of Neurology and Neurological Sciences, Stanford University School of MedicineCA, United States
b Quantitative Sciences Unit, Department of Medicine, Stanford University School of MedicineCA, United States
c Department of Genetics, Stanford University School of MedicineCA, United States
d Division of Cardiology, Department of Medicine, Stanford University School of MedicineCA, United States
e Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
f Wu Tsai Neurosciences Institute, Stanford UniversityCA, United States
g Department of Psychology, Stanford UniversityCA, United States
h Department of Epidemiology and Population Health, Stanford UniversityCA, United States
Abstract
Background and Objectives Single-nucleotide variants near TMEM106B associate with the risk of frontotemporal lobar dementia with TDP-43 inclusions (FTLD-TDP) and Alzheimer disease (AD) in genome-wide association studies (GWASs), but the causal variant at this locus remains unclear. Here, we asked whether a novel structural variant on TMEM106B is the causal variant. Methods An exploratory analysis identified structural variants on neurodegeneration-related genes. Subsequent analyses focused on an Alu element insertion on the 39UTR of TMEM106B. This study included data from longitudinal aging and neurogenerative disease cohorts at Stanford University, case-control cohorts in the Alzheimer Disease Sequencing Project (ADSP), and expression and proteomics data from Washington University in St. Louis (WUSTL). Four hundred thirty-two individuals from 2 Stanford aging cohorts were whole-genome long-read and short-read sequenced. A total of 16,906 samples from ADSP were short-read sequenced. Genotypes, transcriptomics, and proteomics data were available in 1,979 participants from an aging and dementia cohort at WUSTL. Selection criteria were specific to each cohort. In primary analyses, the linkage disequilibrium between the TMEM106B locus variants in the FTLD-TDP GWAS and the 39UTR insertion was estimated. We then estimated linkage by ancestry in the ADSP and evaluated the effect of the TMEM106B lead variant on mRNA and protein levels. Results The primary analysis included 432 participants (52.5% female, age range 45–92 years). We identified a 316 bp Alu insertion overlapping the TMEM106B 39UTR tightly linked with top GWAS variants rs3173615(C) and rs1990622(A). In ADSP European ancestry participants, this insertion is in equivalent linkage with rs1990622(A) (R2 = 0.962, D’ = 0.998) and rs3173615(C) (R2 = 0.960, D’ = 0.996). In African ancestry participants, the insertion is in stronger linkage with rs1990622(A) (R2 = 0.992, D’ = 0.998) than with rs3173615(C) (R2 = 0.811, D’ = 0.994). In public data sets, rs1990622 was consistently associated with TMEM106B protein levels but not with mRNA expression. In the WUSTL data set, rs1990622 is associated with TMEM106B protein levels in plasma and CSF, but not with TMEM106B mRNA expression. Discussion We identified a novel Alu element insertion in the 39UTR of TMEM106B in tight linkage with the lead FTLD-TDP risk variant. The lead variant is associated with TMEM106B protein levels, but not expression. The 39UTR insertion is a lead candidate for the causal variant at this complex locus, pending confirmation with functional studies. Copyright © 2024 The Author(s).
Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s AssociationAAP01AG003991, RF1AG053303, RF1AG074007, RF1AG058501, U01AG058922, R01AG044546, AARF-20-683984
Alzheimer’s AssociationAA
National Institutes of HealthNIHK99AG075238, R01AG048076, RO1AG060747, R01AG074339, P30AG066515, R35AG072290
National Institutes of HealthNIH
P30AG066444, P01AG03991, P01AG026276
U.S. Department of DefenseDODW81XWH2010849, ZEN-22-848604
U.S. Department of DefenseDOD
Document Type: Article
Publication Stage: Final
Source: Scopus
Tuck, A.B.a , Feldman, M.J.b , Lindquist, K.A.b , Thompson, R.J.a
a Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
b Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, United States
Abstract
Growing evidence suggests that social contexts may prompt qualitatively distinct experiences of emotions than nonsocial contexts. In this study of people’s naturalistic daily emotional experiences, we examined in adults with and without major depressive disorder (MDD) whether experiencing emotions in a social context (with others) versus nonsocial context (without others) was associated with greater emotional clarity and attention to one’s emotional experience (i.e., emotional awareness). Based on evidence that social stimuli are highly salient to social species, we predicted that interactions with social others—and especially close social others—would be associated with greater emotional awareness. We furthermore expected that individuals with MDD, who tend to have diminished emotional clarity and social deficits, might experience less emotional awareness in social settings than healthy controls. Across a 2-week experience sampling study that concluded in 2019, we assessed emotional awareness when people were interacting with others (vs. not) and interacting with close (vs. nonclose) others among adults with current MDD (n = 53), remitted MDD (n = 80), and healthy controls (n = 87). As expected, attention to emotion and emotional clarity were higher in social versus nonsocial contexts and when interacting with close versus nonclose others. Contrary to expectations that these effects would be weaker among those with current MDD, the current MDD group showed enhanced emotional clarity in social versus nonsocial settings compared to the other two groups. Insofar as emotional clarity is beneficial to well-being, these findings suggest those with MDD may especially benefit from social contexts. © 2024 American Psychological Association
Author Keywords
depression; emotional awareness; social
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
PET clinical study of novel antipsychotic LB-102 demonstrates unexpectedly prolonged dopamine receptor target engagement
(2024) Neuropsychopharmacology, .
Wong, D.F.a b c d , Chand, G.B.a , Caito, N.a , Eramo, A.e , Grattan, V.T.e , Hixon, M.S.f , Nicol, G.b , Lessie, E.a , Prensky, Z.e , Kuwabara, H.g , Tian, L.a , Valenta, I.a , Schindler, T.H.a , Gründer, G.h , Vaino, A.R.e
a Mallinckrodt Institute of Radiology, and Department of Radiology, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University in Saint Louis, St. Louis, MO, United States
c Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
d Department of Neuroscience, Washington University in Saint Louis, St. Louis, MO, United States
e LB Pharmaceuticals Inc., New York, NY, United States
f Mark S. Hixon Consulting LLC, San Diego, CA, United States
g Johns Hopkins University Department of Radiology, Baltimore, MD, United States
h Central Institute of Mental Health, Department of Molecular Neuroimaging, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
Abstract
Regulation of dopamine activity has important clinical consequences, most notably in schizophrenia. LB-102, N-methyl amisulpride, is a novel dopamine D2/3/5-HT7 inhibitor being developed as a treatment for schizophrenia and other psychiatric disorders. The characteristic that is common to all current antipsychotics is their engagement of D2 dopamine receptors. The goal of this study was to measure the dopamine receptor occupancy of orally administered LB-102 at three different doses (50, 75, and 100 mg as single doses and 50 and 100 mg as multiple doses) and at different timepoints in healthy volunteers using positron emission tomography (PET) with 11C raclopride as a radiotracer. Results of this study (NCT04588129) showed that steady-state once daily oral dosing of 50 mg LB-102 afforded striatal dopamine occupancy (RO) in the desired 60–80% range consistently over the course of 24 h. Contrary to the often observed relationship between RO vs plasma concentrations, maximum dopamine RO significantly lagged maximum plasma concentration and showed little variability under steady state conditions. A similar phenomenon has recently been reported with a non-racemic version of amisulpride [1]. LB-102 was generally safe and well-tolerated at all doses. Results of this study were used to inform dosing in a subsequent Phase 2 clinical study in schizophrenia patients. © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Methylomic signature of current cannabis use in two first-episode psychosis cohorts
(2024) Molecular Psychiatry, .
Dempster, E.L.a , Wong, C.C.Y.b , Burrage, J.a , Hannon, E.a , Quattrone, D.b , Trotta, G.b , Rodriguez, V.c , Alameda, L.c , Spinazzola, E.c , Tripoli, G.c , Austin-Zimmerman, I.b , Li, Z.b , Gayer-Anderson, C.d , Freeman, T.P.e , Johnson, E.C.f , Jongsma, H.E.g , Stilo, S.h , La Cascia, C.i , Ferraro, L.i , La Barbera, D.i , Lasalvia, A.j , Tosato, S.j , Tarricone, I.k , D’Andrea, G.k , Galatolo, M.k , Tortelli, A.l , Pompili, M.m , Selten, J.-P.n , de Haan, L.o , Menezes, P.R.p , Del Ben, C.M.p , Santos, J.L.q , Arrojo, M.r , Bobes, J.s , Sanjuán, J.t , Bernardo, M.u , Arango, C.v , Jones, P.B.w , Breen, G.b , Mondelli, V.x , Dazzan, P.x , Iyegbe, C.y , Vassos, E.b , Morgan, C.x , Mukherjee, D.z , van Os, J.c aa ab , Rutten, B.aa , O’Donovan, M.C.ac , Sham, P.b ad ae , Mill, J.a , Murray, R.c , Di Forti, M.b
a Department of Clinical &#x0026; amp; Biomedical Sciences, University of Exeter Medical School, University of Exeter, Exeter, United Kingdom
b Department of Social, Genetic and Developmental Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
c Department of Psychosis Studies, Institute of Psychiatry, Psychology &#x0026; amp; Neuroscience, King’s College London, London, United Kingdom
d Department of Health Service and Population Research, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
e Addiction and Mental Health Group (AIM), Department of Psychology, University of Bath, Bath, United Kingdom
f Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
g Centre for Transcultural Psychiatry ‘Veldzicht’, Balkbrug, Netherlands
h Department of Mental Health and Addiction Services, ASP Crotone, Crotone, Italy
i Biomedicine, Neuroscience and Advanced Diagnostic Department, Psychiatry Section, University of Palermo, Palermo, Italy
j Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
k Department of Medical and Surgical Science, Psychiatry Unit, Alma Mater Studiorum Università di Bologna, Bologna, Italy
l Institut Mondor de recherché biomedicale, Creteil, France
m Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy
n Rivierduinen Institute for Mental Health Care, Leiden, Netherlands
o Early Psychosis Section, Amsterdam UMC, Academic Medical Centre, University of Amsterdam, Meibergdreef 5, AZ, Amsterdam, 1105, Netherlands
p Department of Preventive Medicine, Faculdade de Medicina, Universidade of São Paulo, São Paulo, Brazil
q Department of Psychiatry, Servicio de Psiquiatría Hospital “Virgen de la Luz”, Cuenca, Spain
r Department of Psychiatry, Psychiatric Genetic Group, Instituto de Investigación Sanitaria de Santiago de Compostela, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago, Spain
s Department of Medicine, Psychiatry Area, School of Medicine, Universidad de Oviedo, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Oviedo, Spain
t Department of Psychiatry, School of Medicine, Universidad de Valencia, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Valencia, Spain
u Barcelona Clinic Schizophrenia Unit, Neuroscience Institute, Hospital Clinic of Barcelona, University of Barcelona, Institut d’Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Biomedical Research Networking Centre in Mental Health (CIBERSAM), Barcelona, Spain
v Department of Child and Adolescent Psychiatry, Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain
w Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
x Department of Psychological Medicine, Kings College London, London, United Kingdom
y Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
z MRC Centre for Neurodevelopmental Disorders, King’s College London, London, United Kingdom
aa Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, South Limburg Mental Health Research and Teaching Network, Maastricht University Medical Centre, Maastricht, Netherlands
ab Department Psychiatry, Brain Centre Rudolf Magnus, Utrecht University Medical Centre, Utrecht, Netherlands
ac Division of Psychological Medicine and Clinical Neurosciences, Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, United Kingdom
ad Department of Psychiatry, the University of Hong Kong, Hong Kong
ae Centre for Genomic Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong
Abstract
The rising prevalence and legalisation of cannabis worldwide have underscored the need for a comprehensive understanding of its biological impact, particularly on mental health. Epigenetic mechanisms, specifically DNA methylation, have gained increasing recognition as vital factors in the interplay between risk factors and mental health. This study aimed to explore the effects of current cannabis use and high-potency cannabis on DNA methylation in two independent cohorts of individuals experiencing first-episode psychosis (FEP) compared to control subjects. The combined sample consisted of 682 participants (188 current cannabis users and 494 never users). DNA methylation profiles were generated on blood-derived DNA samples using the Illumina DNA methylation array platform. A meta-analysis across cohorts identified one CpG site (cg11669285) in the CAVIN1 gene that showed differential methylation with current cannabis use, surpassing the array-wide significance threshold, and independent of the tobacco-related epigenetic signature. Furthermore, a CpG site localised in the MCU gene (cg11669285) achieved array-wide significance in an analysis of the effect of high-potency (THC = &#x003E; 10%) current cannabis use. Pathway and regional analyses identified cannabis-related epigenetic variation proximal to genes linked to immune and mitochondrial function, both of which are known to be influenced by cannabinoids. Interestingly, a model including an interaction term between cannabis use and FEP status identified two sites that were significantly associated with current cannabis use with a nominally significant interaction suggesting that FEP status might moderate how cannabis use affects DNA methylation. Overall, these findings contribute to our understanding of the epigenetic impact of current cannabis use and highlight potential molecular pathways affected by cannabis exposure. © The Author(s) 2024.
Funding details
Medical Research CouncilMRCMR/T007818/1
King’s College LondonKCLNIHR203318
Seventh Framework ProgrammeFP7HEALTH-F2-2010-241909
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Dementia risk scores, apolipoprotein E, and risk of Alzheimer’s disease: One size does not fit all
(2024) Alzheimer’s and Dementia, .
Andrews, S.J.a , Boeriu, A.I.a , Belloy, M.E.b c d , Renton, A.E.e , Fulton-Howard, B.e , Brenowitz, W.D.f g , Yaffe, K.a g h , for the Alzheimer’s Disease Neuroimaging Initiativei
a Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, United States
b Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
c NeuroGenomics and Informatics Center, Washington University School of Medicine, St.Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St.Louis, MO, United States
e Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
f Kaiser Permanente Center for Health Research, Portland, OR, United States
g Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, United States
h Department of Neurology, University of California San Francisco, San Francisco, CA, United States
Abstract
INTRODUCTION: Evaluating the generalizability of dementia risk scores, primarily developed in non-Latinx White (NLW) participants, and interactions with genetic risk factors in diverse populations is crucial for addressing health disparities. METHODS: We analyzed the association of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) and modified CAIDE (mCAIDE) scores with dementia risk using logistic regression models stratified by race/ethnicity in National Alzheimer’s Coordinating Center (NACC) and Alzheimer’s Disease Neuroimaging Initiative (ADNI), and assessed their interaction with apolipoprotein E (APOE). RESULTS: Higher CAIDE scores were associated with an increased risk of dementia in Asian, Latinx, and NLW participants but not in Black participants. In contrast, higher mCAIDE scores were also associated with an increased risk of dementia in Black participants. Unfavorable mCAIDE risk profiles exacerbated the apolipoprotein E*ε4 (APOE*ε4) risk effect and attenuated the APOE*ε2 protective effect. DISCUSSION: Our findings underscore the importance of evaluating the validity of dementia risk scores in diverse populations for their use in personalized medicine approaches to promote brain health. Highlights: Dementia risk scores demonstrate race/ethnic-specific effects on dementia risk. Unfavorable modifiable risk profiles moderate the effect of APOE on dementia risk. Dementia risk scores need to be validated in diverse populations. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
APOE; dementia; dementia risk scores; race/ethnicity
Funding details
Alzheimer’s AssociationAA
BioClinica
National Institute of Biomedical Imaging and BioengineeringNIBIB
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
National Institute on AgingNIA
Alzheimer’s Drug Discovery FoundationADDF
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
BiogenR35AG071916, ABA‐22‐969581, 5U24AG072122, U19AG069701, K01AG062722
National Institutes of HealthNIHU24 AG072122, U01 AG024904
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Intraspinal microstimulation of the ventral horn has therapeutically relevant cross-modal effects on nociception
(2024) Brain Communications, 6 (5), art. no. fcae280, .
Bandres, M.F.a b , Gomes, J.L.b , McPherson, J.G.a b c d e
a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
b Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO 63108, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63108, United States
d Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63108, United States
e Program in Neurosciences, Washington University School of Medicine, St. Louis, MO 63108, United States
Abstract
Electrical stimulation of spinal networks below a spinal cord injury is a promising approach to restore functions compromised by inadequate and/or inappropriate neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared descending motor pathways and spinal motoneurons rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by spinal cord injury. Debilitating spasms, spasticity and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. Whereas spasms and spasticity can often be managed pharmacologically, spinal cord injury-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from aetiologies other than spinal cord injury, and the limited evidence available to date suggests that it holds considerable promise for reducing spinal cord injury-related neuropathic pain, as well. Spinal stimulation for pain amelioration has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for rehabilitation of movement impairments. Thus, we hypothesize that spinal stimulation intended to increase the ability to move voluntarily may simultaneously reduce transmission in spinal pain pathways. To test this hypothesis, we coupled a rat model of incomplete thoracic spinal cord injury, which results in moderate to severe bilateral movement impairments and spinal cord injury-related neuropathic pain, with in vivo electrophysiological measures of neural transmission in networks of spinal neurons integral to the development and persistence of the neuropathic pain state. We find that when intraspinal microstimulation is delivered to the ventral horn with the intent of enhancing voluntary movement, transmission through nociceptive specific and wide dynamic range neurons is significantly depressed in response to pain-related sensory feedback. By comparison, spinal responsiveness to non-pain-related sensory feedback is largely preserved. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with spinal cord injury. © The Author(s) 2024.
Author Keywords
movement impairments; neuromodulation; neuropathic pain; neurorehabilitation; spinal cord injury
Funding details
National Institutes of HealthNIHR01NS111234-S1
Document Type: Article
Publication Stage: Final
Source: Scopus
Gene expression differences associated with alcohol use disorder in human brain
(2024) Molecular Psychiatry, .
Willis, C.a , White, J.D.a , Minto, M.S.a , Quach, B.C.a , Han, S.b , Tao, R.b , Shin, J.H.b , Deep-Soboslay, A.b , Hyde, T.M.b , Mayfield, R.D.c , Webb, B.T.a , Johnson, E.O.a d , Kleinman, J.E.b , Bierut, L.J.e , Hancock, D.B.a
a GenOmics and Translational Research Center, RTI International, Research Triangle Park, NC, United States
b Lieber Institute for Brain Development (LIBD), Baltimore, MD, United States
c Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, TX, United States
d Fellow Program, RTI International, Research Triangle Park, NC, United States
e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Excessive alcohol consumption is a leading cause of preventable death worldwide. To improve understanding of neurobiological mechanisms associated with alcohol use disorder (AUD) in humans, we compared gene expression data from deceased individuals with and without AUD across two addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Bulk RNA-seq data from NAc and DLPFC (N ≥50 with AUD, ≥46 non-AUD) were analyzed for differential gene expression using modified negative binomial regression adjusting for technical and biological covariates. The region-level results were meta-analyzed with those from an independent dataset (NNAc = 28 AUD, 29 non-AUD; NPFC = 66 AUD, 77 non-AUD). We further tested for heritability enrichment of AUD-related phenotypes, gene co-expression networks, gene ontology enrichment, and drug repurposing. We identified 176 differentially expressed genes (DEGs; 12 in both regions, 78 in NAc only, 86 in DLPFC only) for AUD in our new dataset. After meta-analyzing with published data, we identified 476 AUD DEGs (25 in both regions, 29 in NAc only, 422 in PFC only). Of these DEGs, 17 were significant when looked up in GWAS of problematic alcohol use or drinks per week. Gene co-expression analysis showed both concordant and unique gene networks across brain regions. We also identified 29 and 436 drug compounds that target DEGs from our meta-analysis in NAc and PFC, respectively. This study identified robust AUD-associated DEGs, contributing novel neurobiological insights into AUD and highlighting genes targeted by known drug compounds, generating opportunity for drug repurposing to treat AUD. © The Author(s) 2024.
Funding details
National Institute on Alcohol Abuse and AlcoholismNIAAAR01 AA027049, R01 AA012404, U01 AA020926
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Interceptive abilities in autism spectrum disorder: Comparing naturalistic and virtual visuomotor tasks
(2024) Autism Research, .
Park, S.-W.a b c , Cardinaux, A.c , Crozier, D.d e , Russo, M.f , Bond, S.b g , Kjelgaard, M.h , Sinha, P.c , Sternad, D.b e i
a Department of Kinesiology, University of Texas at San Antonio, San Antonio, TX, United States
b Department of Biology, Northeastern University, Boston, MA, United States
c Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States
d Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Physics, Northeastern University, Boston, MA, United States
f Department of Neurology, Tor Vergata Polyclinic & Laboratory of Neuromotor Physiology, Fondazione Santa Lucia, Rome, Italy
g Department of Anesthesiology, Perioperative and Pain Medicine, Stanford School of Medicine, Palo Alto, CA, United States
h Department of Communication Sciences and Disorders, Bridgewater State University, Bridgewater, MA, United States
i Department of Electrical & Computer Engineering, Northeastern University, Boston, MA, United States
Abstract
A growing body of research reveals that autistic individuals exhibit motor coordination challenges. Multiple theoretical frameworks propose that the seemingly disparate features of autism may arise from a common underlying process: a diminished ability to make predictions. Sensorimotor skills, such as catching a ball, critically rely on predicting the ball’s trajectory as well as anticipatory coordination of the entire body. Here, we assessed four different naturalistic and virtual interception tasks with 31 neurotypical and 23 autistic children (ages 7–12). In a naturalistic setting, participants caught the ball either with their hands or a hand-held funnel with an enlarged catch area that also prevented the ball from bouncing off. A virtual setup reduced whole-body demands, as children only moved a paddle to catch or bounce a ball on a screen. Control tasks, involving rapid reaching to grasp a static object and quiet standing, which largely eliminated the requirements for prediction, were also tested. Results from all task variations demonstrated that autistic children completed fewer successful interceptions, suggesting that predictive requirements, inherent to all interception tasks, played a critical role. Effect sizes in the virtual tasks were smaller. Correlations of the task metrics with behavioral assessments rendered the strongest correlations with Praxis scores. The control tasks showed no differences between autistic and neurotypical children. These findings lend support to the emerging hypothesis that predictive challenges are present in autism. Further research with larger sample sizes will help identify to what extent these visuomotor differences may inform core domains of autism. © 2024 The Author(s). Autism Research published by International Society for Autism Research and Wiley Periodicals LLC.
Author Keywords
autism; interception; motor behavior; naturalistic environment; praxis; prediction; virtual environment
Funding details
National Institutes of HealthNIH
Massachusetts Institute of TechnologyMIT
Simons Center for the Social Brain, Massachusetts Institute of TechnologySCSB
Simons Foundation Autism Research InitiativeSFARISFARI‐192901
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A Pilot Study of Factors Influencing Engagement with an mHealth Intervention Among Teens with Eating Disorder Symptoms
(2024) Journal of Technology in Behavioral Science, .
Kasson, E.a , Vázquez, M.M.a , Li, X.a , Doroshenko, C.a , Szlyk, H.S.a , Montayne, A.a , Fitzsimmons-Craft, E.E.a , Wilfley, D.E.b , Taylor, C.B.c d , Cavazos-Rehg, P.A.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Psychology, Washington University in St. Louis, St. Louis, MO 63105, United States
c Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford, CA 94305, United States
d Center for m2Health, Palo Alto University, Palo Alto, CA 94304, United States
Abstract
The current pilot study examines engagement with and preliminary effectiveness of an mHealth intervention designed for teens with eating disorders (EDs) to delineate specific user characteristics associated with intervention engagement and the impact of this engagement on ED symptoms. Teens 14–17 years old with or at high-risk for an ED were recruited from social media (n=29) and provided access to an mHealth intervention for 2 months. At baseline, participants were surveyed on ED and other mental health symptoms and demographics. Bivariate analyses were used to examine associations between baseline characteristics and time spent in the app (<10 vs. ≥ 10 minutes). Qualitative feedback from participants on intervention content and usability was also collected and reported. Out of the 29 participants, 22 (76%) utilized the app at least once after gaining access. The median number of logins for these users was 6, with an interquartile range spanning from 3 to 15. Over half of teens spent 10 minutes or more engaging with the app during the study period (n=15, 52%). Compared to those who spent less than 10 minutes with the app, those who spent more than 10 minutes engaging with the app were slightly younger, more likely to endorse less chronic ED symptoms, and less likely to report social anxiety disorder (ps < 0.05). Teens’ distinct user characteristics impact rates of uptake and engagement with an ED-focused mHealth intervention and should be considered in the design and iteration of these tools. mHealth tools have the potential to improve ED recovery outcomes among teens, and future studies should further evaluate the effectiveness of these tools and integration of content to support severe ED symptoms and other comorbid mental health issues. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.
Author Keywords
Adolescents; Eating disorders; Engagment; mHealth; Social media
Funding details
National Institute on Drug AbuseNIDAK02 DA043657
National Institute of Mental HealthNIMHR34 MH119170, K08 MH120341
Document Type: Article
Publication Stage: Article in Press
Source: Scopus