WashU weekly Neuroscience publications: November 5, 2023

Putting the emotion regulation process into person-specific context: An experience sampling and mobile sensing study
(2023) Journal of Research in Personality, 107, art. no. 104428, . 

Springstein, T., English, T.

Washington University in St. Louis, United States

Abstract
Emotion regulation is theorized to be situation-dependent. Thus far, researchers have looked for situational predictors of emotion regulation across individuals without considering that associations could vary from person to person. In a 14-day experience sampling and mobile sensing study (N = 164), we used Group Iterative Multiple Model Estimation (GIMME) to test how the emotion regulation process (goals, motives, strategies, and success) is linked to aspects of situations. A variety of idiographic associations between situations and emotion regulation emerged. Both self-reported subjective situations and passively sensed objective situations predicted emotion regulation, though more effects emerged for self-reported subjective situations (e.g., perceived negativity, sociality, or duty). Implications are discussed for personalized prediction of and intervention on daily emotion regulation. © 2023 Elsevier Inc.

Author Keywords
Emotion regulation;  Experience sampling;  Idiographic;  Mobile sensing;  Situations

Document Type: Article
Publication Stage: Final
Source: Scopus

Functional connectivity between the amygdala and prefrontal cortex underlies processing of emotion ambiguity
(2023) Translational Psychiatry, 13 (1), art. no. 334, . 

Sun, S.^a b , Yu, H.^c , Yu, R.^d , Wang, S.^e

^a Frontier Research Institute for Interdisciplinary Sciences, Tohoku University 6-3 Aramaki aza Aoba, Aoba-ku, Sendai, 980-8578, Japan
^b Research Institute of Electrical Communication, Tohoku University 2-1-1 Katahira, Aoba-ku, Sendai, 980-8577, Japan
^c Department of Psychological & Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, United States
^d Department of Management, Marketing, and Information Systems, Hong Kong Baptist University, Hong Kong
^e Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Processing facial expressions of emotion draws on a distributed brain network. In particular, judging ambiguous facial emotions involves coordination between multiple brain areas. Here, we applied multimodal functional connectivity analysis to achieve network-level understanding of the neural mechanisms underlying perceptual ambiguity in facial expressions. We found directional effective connectivity between the amygdala, dorsomedial prefrontal cortex (dmPFC), and ventromedial PFC, supporting both bottom-up affective processes for ambiguity representation/perception and top-down cognitive processes for ambiguity resolution/decision. Direct recordings from the human neurosurgical patients showed that the responses of amygdala and dmPFC neurons were modulated by the level of emotion ambiguity, and amygdala neurons responded earlier than dmPFC neurons, reflecting the bottom-up process for ambiguity processing. We further found parietal-frontal coherence and delta-alpha cross-frequency coupling involved in encoding emotion ambiguity. We replicated the EEG coherence result using independent experiments and further showed modulation of the coherence. EEG source connectivity revealed that the dmPFC top-down regulated the activities in other brain regions. Lastly, we showed altered behavioral responses in neuropsychiatric patients who may have dysfunctions in amygdala-PFC functional connectivity. Together, using multimodal experimental and analytical approaches, we have delineated a neural network that underlies processing of emotion ambiguity. © 2023, The Author(s).

Funding details
National Science FoundationNSFBCS-1945230, IIS-2114644
National Institutes of HealthNIHR01MH129426
Air Force Office of Scientific ResearchAFOSRFA9550-21-1-0088
Dana FoundationDF
Japan Society for the Promotion of ScienceKAKEN22K15626
Frontier Research Institute for Interdisciplinary Sciences, Tohoku UniversityFRIS

Document Type: Article
Publication Stage: Final
Source: Scopus

A multi- and mixed-method adaptation study of a patient-centered perioperative mental health intervention bundle
(2023) BMC Health Services Research, 23 (1), art. no. 1175, . 

Abraham, J.^a b c , Meng, A.^a , Baumann, A.^d , Holzer, K.J.^a , Lenard, E.^e , Freedland, K.E.^e , Lenze, E.J.^e , Avidan, M.S.^a , Politi, M.C.^d

^a Department of Anesthesiology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^b Institute for Informatics, Data Science and Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Division of Biology and Biomedical Sciences, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Division of Public Health Sciences, Department of Surgery, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Psychiatry, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: Anxiety and depression are common among older adults and can intensify during perioperative periods, but few mental health interventions are designed for older surgical patients’ unique needs. As part of the feasibility trial, we developed and adapted a perioperative mental health (PMH) bundle for older patients comprised of behavioral activation (BA) and medication optimization (MO) to ameliorate anxiety and depressive symptoms before, during, and after cardiac, orthopedic, and oncologic surgery. Methods: We used mixed-methods including workshop studios with patients, caregivers, clinicians, researchers, and interventionists; intervention refinement and reflection meetings; patient case review meetings; intervention session audio-recordings and documentation forms; and patient and caregiver semi-structured interviews. We used the results to refine our PMH bundle. We used multiple analytical approaches to report the nature of adaptations, including hybrid thematic analysis and content analysis informed by the Framework for Reporting Adaptations and Modifications – Expanded. Results: Adaptations were categorized by content (intervention components), context (how the intervention is delivered, based on the study, target population, intervention format, intervention delivery mode, study setting, study personnel), training, and evaluation. Of 51 adaptations, 43.1% involved content, 41.2% involved context, and 15.7% involved training and evaluation. Several key adaptations were noted: (1) Intervention content was tailored to patient preferences and needs (e.g., rewording elements to prevent stigmatization of mental health needs; adjusting BA techniques and documentation forms to improve patient buy-in and motivation). (2) Cohort-specific adaptations were recommended based on differing patient needs. (3) Compassion was identified by patients as the most important element. Conclusions: We identified evidence-based mental health intervention components from other settings and adapted them to the perioperative setting for older adults. Informed by mixed-methods, we created an innovative and pragmatic patient-centered intervention bundle that is acceptable, feasible, and responsive to the needs of older surgical populations. This approach allowed us to identify implementation strategies to improve the reach, scalability, and sustainability of our bundle, and can guide future patient-centered intervention adaptations. Clinical trials Registration: NCT05110690 (11/08/2021). © 2023, The Author(s).

Author Keywords
Anesthesia;  Anxiety;  Depression;  Geriatric;  Psychiatry;  Surgery;  Tailoring;  Wellness

Funding details
National Institute of Mental HealthNIMHP50MH122351

Document Type: Article
Publication Stage: Final
Source: Scopus

Characteristics and predictors of disease course in children initially presenting with ADEM
(2023) Multiple Sclerosis and Related Disorders, 80, art. no. 105075, . 

Rutatangwa, A.^a , Aaen, G.^b , Krysko, K.M.^a c , Belman, A.^d , Benson, L.A.^e , Chitnis, T.^f , Gorman, M.^e , Goyal, M.^g , Graves, J.S.^h , Wheeler, Y.ⁱ , Krupp, L.^d , Lotze, T.^j , Mar, S.^g , Ness, J.^k , Rensel, M.^l , Rodriguez, M.^m , Rose, J.ⁿ , Schreiner, T.^o , Tillema, J.-M.^m , Weinstock-Guttman, B.^p , Waltz, M.^q , Casper, T.C.^q , Waubant, E.^a , U.S. Network of Pediatric MS Centers^r

^a UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, United States
^b Department of Pediatrics, Loma Linda University, Loma Linda, CA, United States
^c Division of Neurology, Department of Medicine, St. Michael’s Hospital, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, ON, Canada
^d Department of Neurology, NYU Grossman School of Medicine, New York City, NY, United States
^e Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^f Department of Neurology, Division of Child Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^g Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
^h Department of Neurology, University of California San Diego, La Jolla, CA, United States
ⁱ Department of Nursing, University of Alabama at Birmingham, Birmingham, AL, United States
^j Department of Neurology, Texas Children’s Hospital, Houston, TX, United States
^k Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
^l The Mellen Center, Cleveland Clinic, Cleveland, OH, United States
^m Department of Neurology, Mayo Clinic, Rochester, MN, United States
ⁿ Department of Neurology, University of Utah, Salt Lake City, UT, United States
^o Department of Neurology & Pediatrics, University of Colorado, Aurora, CO, United States
^p Department of Neurology, State University of New York at Buffalo, Buffalo, NY, United States
^q Department of Pediatrics, University of Utah, Salt Lake City, UT, United States

Abstract
ADEM is an inflammatory disease, with new onset polyfocal neurologic symptoms, encephalopathy and multifocal demyelination, typically in childhood. Initial diagnosis of ADEM is challenging and up to 20 % of children with MS or NMOSD are initially diagnosed with ADEM. We describe characteristics of patients with monophasic ADEM vs. recurrent demyelinating syndromes at onset and identify features consistent with monophasic course. This is a multicenter observational study of children with demyelinating disease, followed at 12 regional pediatric MS centers. Descriptive statistics were used to report patient characteristics, clinical/imaging features and outcomes. Logistic regression was used to predict features associated with monophasic course. As of July 2019, 837 children with final diagnosis of ADEM (n = 79), MS (n = 646) or NMOSD (n = 112) were identified. The mean follow-up was 5·7 +/- 3·2 years. ADEM patients were youngest with mean age at first event 5·2 +/- 3·8 years (p < 0.001) and male predominant (66 %) (p < 0·001). After 2 years of follow-up, 83 % of patients initially diagnosed with monophasic ADEM retained this diagnosis. In multivariable analysis, older age (OR 1·16 [95 % CI 1·02 – 1·33] for 1-year increase, p = 0·02), presenting with optic neuritis (OR 8.18 [95 % CI 1.88 – 35.64], p = 0·005) and presence of gadolinium enhancement (OR 4.08 [95 % CI 1.38 – 12.08], p = 0·011) were associated with reclassification of ADEM to MS, NMOSD or DDNOS within 2 years. Children with monophasic ADEM vs. those reclassified as other demyelinating disorders are younger at onset, and less likely to have optic neuritis or gadolinium-enhancing lesions at onset. © 2023

Author Keywords
Acute disseminated encephalomyelitis;  Childhood demyelinating disease;  CNS demyelinating disease;  Multiple sclerosis;  Neuromyelitis optica spectrum disorder

Funding details
National Multiple Sclerosis SocietyNMSSSI-1808–32326

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive impact of multidomain intervention and omega 3 according to blood Aβ42/40 ratio: a subgroup analysis from the randomized MAPT trial
(2023) Alzheimer’s Research and Therapy, 15 (1), art. no. 183, . 

Delrieu, J.^a , Vellas, B.^a , Guyonnet, S.^a , Cantet, C.^a , Ovod, V.^b , Li, Y.^b , Bollinger, J.^b , Bateman, R.^b c , Andrieu, S.^d

^a Maintain Aging Research team, CERPOP, Université de Toulouse, Inserm, Université Paul Sabatier, Toulouse, France; Gérontopôle, Department of Geriatrics, Toulouse CHU, Toulouse, France
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^d Maintain Aging Research team, CERPOP, Université de Toulouse, Inserm, Université Paul Sabatier, Toulouse, France; Department of Epidemiology and Public Health, Toulouse CHU, Toulouse, France

Abstract
Background: In MAPT (Multidomain Alzheimer Preventive Trial), a cognitive effect of multidomain intervention (MI) was showed in non-demented subjects with positive amyloid PET. However, screening eligible patients for multidomain intervention by PET is difficult to generalize in real-world settings. Methods: MAPT study was a 3-year, randomized, placebo-controlled trial followed by a 2-year observational and optional extension. All participants were non-demented and randomly assigned (1:1:1:1) to the MI plus omega 3, MI plus placebo, omega 3 alone, or placebo alone group. The objectives were to assess the cognitive effect of MAPT interventions (omega 3 supplementation, MI, combined intervention) in non-demented subjects according to amyloid blood status at 12, 36, and 60 months. In this subgroup analysis (n = 483), amyloid status was defined by plasma Aβ42/40 ratio (cutoff ≤ 0.0107). The primary outcome measure was the change in cognitive composite score after a 1, 3, and 5-year clinical follow-up. Results: The intention-to-treat (ITT) population included 483 subjects (161 positive and 322 negative amyloid participants based on plasma Aβ42/40 ratio). In the positive amyloid ITT population, we showed a positive effect of MI plus omega 3 on the change in composite cognitive score in 12 (raw p =.0350, 0.01917, 95% CI = [0.0136 to 0.3699]) and 36 months (raw p =.0357, 0.2818, 95% CI = [0.0190 to 0.5446]). After correction of multiple comparisons and adjustments, these differences were not significant (adjusted p =.1144 and.0690). In the per-protocol positive amyloid group (n = 154), we observed a significant difference between the combined intervention and placebo groups at 12 (p =.0313, 0.2424, 0.0571 to 0.4276) and 36 months (p =.0195, 0.3747, 0.1055 to 0.6439) persisting after adjustment. In the ITT and per-protocol analyses, no cognitive effect was observed in the positive and negative amyloid group at 60-month visit. Conclusions: These findings suggest a benefit of MI plus omega 3 in positive blood amyloid subjects. This promising trend needs to be confirmed before using blood biomarkers for screening in preventive trials. Trial registration: ClinicalTrials.gov Identifier: NCT01513252 . © 2023, BioMed Central Ltd., part of Springer Nature.

Author Keywords
Alzheimer’s disease;  Amyloid blood biomarker;  Clinical trial;  Prevention

Funding details
UMR 1027
National Institute on AgingNIAR56AG061900
Avid Radiopharmaceuticals
Institut de Recherche Pierre FabreIRPF
Ministère des Affaires Sociales et de la Santé
Centre Hospitalier Universitaire de Toulouse

Document Type: Article
Publication Stage: Final
Source: Scopus

Does asset poverty moderate how food insecurity is associated with adolescent problematic behavior? An application of the family stress model using multi-group path analyses
(2023) Children and Youth Services Review, 155, art. no. 107248, . 

Chen, J.-H.^a , Wu, C.-F.^b , Jin, M.^c , Liao, C.-F.^d , Chiang, M.^a , Jonson-Reid, M.^a , Drake, B.^a

^a George Warren Brown School of Social Work, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
^b School of Social Work, University of Illinois at Urbana-Champaign, 1010 W Nevada St, Urbana, IL 61801, United States
^c Silver School of Social Work, New York University, 1 Washington Square North, New York, NY 10003-6654, United States
^d McKelvey School of Engineering, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States

Abstract
The Family Stress Model framework suggests that food insecurity could be associated with adolescent problematic behaviors through caregiver psychological distress. While assets such as savings could buffer the impacts of income on food insecurity, it remains unclear whether such moderating effects can be applied to other associations in the Family Stress Model framework. Using the 2017 and 2019 Panel Study of Income Dynamics and 2019 and 2020 Child Development Supplement data including 643 children (Mage = 13.7, SD = 2.6), multi-group path analyses found that the family stress process manifests differently in asset poor families and non-asset poor families. More specifically, the direct and indirect associations embedded by income, food insecurity, caregiver psychological distress, and child problematic behaviors are statistically stronger in the asset poor families than the non-asset poor families. These findings suggest the necessity to offer more comprehensive interventions to address economic needs (i.e., low income, food insecurity) and non-economic needs (i.e., caregiver mental health, child development) for the economically vulnerable. © 2023 Elsevier Ltd

Author Keywords
Assets;  Caregiver psychological distress;  Family Stress Model;  Food insecurity;  Income;  Problematic behaviors

Document Type: Article
Publication Stage: Final
Source: Scopus

Pain and itch coding mechanisms of polymodal sensory neurons
(2023) Cell Reports, 42 (11), art. no. 113316, . 

Guo, C.^a , Jiang, H.^a , Huang, C.-C.^a , Li, F.^a , Olson, W.^b , Yang, W.^a , Fleming, M.^b , Yu, G.^a , Hoekel, G.^a , Luo, W.^b , Liu, Q.^a

^a Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, United States
^b Department of Neuroscience, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, United States

Abstract
Pain and itch coding mechanisms in polymodal sensory neurons remain elusive. MrgprD+ neurons represent a major polymodal population and mediate both mechanical pain and nonhistaminergic itch. Here, we show that chemogenetic activation of MrgprD+ neurons elicited both pain- and itch-related behavior in a dose-dependent manner, revealing an unanticipated compatibility between pain and itch in polymodal neurons. While VGlut2-dependent glutamate release is required for both pain and itch transmission from MrgprD+ neurons, the neuropeptide neuromedin B (NMB) is selectively required for itch signaling. Electrophysiological recordings further demonstrated that glutamate synergizes with NMB to excite NMB-sensitive postsynaptic neurons. Ablation of these spinal neurons selectively abolished itch signals from MrgprD+ neurons, without affecting pain signals, suggesting a dedicated itch-processing central circuit. These findings reveal distinct neurotransmitters and neural circuit requirements for pain and itch signaling from MrgprD+ polymodal sensory neurons, providing new insights on coding and processing of pain and itch. © 2023

Author Keywords
CP: Neuroscience;  glutamate;  itch;  MrgprD;  neural coding;  neuromedin B;  neurotransmitters;  pain;  polymodal sensory neurons

Funding details
National Institutes of HealthNIH1R01AI125743, 1R01AI163146, NS083702, R01EY024704

Document Type: Article
Publication Stage: Final
Source: Scopus

Participation and Its Association With Health Among Community-Dwelling Adults With Chronic Stroke
(2023) The American Journal of Occupational Therapy: Official Publication of the American Occupational Therapy Association, 77 (6), . 

Kersey, J.^a , Skidmore, E.^b , Hammel, J.^c , Baum, C.^d

^a Jessica Kersey, PhD, OTR/L, is Instructor, Program in Occupational Therapy, Washington University in St. Louis, St. Louis, MO; . At the time of the research, Kersey was Postdoctoral Research Associate, Department of Occupational Therapy, University of Illinois Chicago, Chicago
^b OTR/L, Department of Occupational Therapy, University of Pittsburgh, is Professor, Pittsburgh, PA, United States
^c OTR/L, Department of Occupational Therapy, University of Illinois Chicago, is Professor, Chicago, Mexico
^d OTR/L, Program in Occupational Therapy, Washington University in St. Louis, is Professor, St. Louis, MO, United States

Abstract
IMPORTANCE: Little is known about the severity of participation restrictions among people living in the community with chronic stroke. Even less is known about the association between participation and health in this population. OBJECTIVE: To describe participation among people with chronic stroke and examine the association between participation and physical and mental health. DESIGN: Secondary analysis of baseline data from an intervention study. SETTING: The parent multisite intervention study was conducted in the community, and assessments were administered in participants’ homes. PARTICIPANTS: Thirty-one community-dwelling adults with chronic stroke. OUTCOMES AND MEASURES: Participation was measured with the Activity Card Sort (percentage of prestroke activities retained) and the Enfranchisement Scale of the Community Participation Indicators. Health was measured with the PROMIS®-29 Physical Health and Mental Health subscales. We calculated descriptive statistics for participation measures and Spearman’s ρ correlations between participation and health outcomes. RESULTS: Participation scores were poor on all measures of participation. Most striking, 94.9% of participants retained less than 80% of their prestroke activities. All measures of participation were modestly correlated with physical health (ρ = .28-.46) and were moderately correlated with mental health (ρ = .42-.63). CONCLUSIONS AND RELEVANCE: Participation restrictions are prevalent among adults with chronic stroke, with potential implications for mental health. Stronger community-based rehabilitation and support services to enhance participation of this high-risk population are warranted. What This Article Adds: This report highlights the severity of participation restrictions among people with chronic stroke. Moreover, this report shows that people with stroke feel a lack of inclusion in the community and that participation is associated with mental and physical health. Copyright © 2023 by the American Occupational Therapy Association, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

Hearing, β-Amyloid Deposition and Cognitive Test Performance in Black and White Older Adults: The ARIC-PET Study
(2023) The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 78 (11), pp. 2105-2110. 

Deal, J.A.^a b , Jiang, K.^a b , Rawlings, A.^a c , Sharrett, A.R.^a , Reed, N.S.^a b , Knopman, D.^d , Mosley, T.^e , Wong, D.^f , Zhou, Y.^g , Lin, F.R.^a h , Gottesman, R.F.ⁱ

^a Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
^b Cochlear Center for Hearing and Public Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States
^c Kaiser Permanente Center for Health Research, Portland, Oregon, USA
^d Department of Neurology, Mayo Clinic, Rochester, MN, United States
^e MIND Center, University of Mississippi Medical Center, Jackson, MS, United States
^f Millinckrodt Institute of Radiology, Washington University School of St. Louis, St. Louis, MO, United States
^g Department of Radiology, Section of High Resolution Brain PET Imaging, Johns Hopkins School of Medicine, Baltimore, MD, United States
^h Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins School of Medicine, Bethesda, MD, United States
ⁱ Stroke Branch, National Institute of Neurological Disorders and Stroke Intramural Research Program, National Institute of Health, Bethesda, MD, United States

Abstract
BACKGROUND: Hearing loss is a risk factor for dementia; whether the association is causal or due to a shared pathology is unknown. We estimated the association of brain β-amyloid with hearing, hypothesizing no association. As a positive control, we quantified the association of hearing loss with neurocognitive test performance. METHODS: Cross-sectional analysis of Atherosclerosis Risk in Communities-Positron Emission Tomography study data. Amyloid was measured using global cortical and temporal lobe standardized uptake value ratios (SUVRs) calculated from florbetapir-positron emission tomography scans. Composite global and domain-specific cognitive scores were created from 10 neurocognitive tests. Hearing was measured using an average of better-ear air conduction thresholds (0.5-4 kHz). Multivariable-adjusted linear regression estimated mean differences in hearing by amyloid and mean differences in cognitive scores by hearing, stratified by race. RESULTS: In 252 dementia-free adults (72-92 years, 37% Black race, and 61% female participants), cortical or temporal lobe SUVR was not associated with hearing (models adjusted for age, sex, education, and APOE ε4). Each 10 dB HL increase in hearing loss was associated with a 0.134 standard deviation lower mean global cognitive factor score (95% CI: -0.248, -0.019), after adjustment for demographic and cardiovascular factors. Observed hearing-cognition associations were stronger in Black versus White participants. CONCLUSIONS: Amyloid is not associated with hearing, suggesting that pathways linking hearing and cognition are independent of this pathognomonic Alzheimer’s-related brain change. This is the first study to show that the impact of hearing loss on cognition may be stronger in Black versus White adults. © The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Alzheimer’s;  Cognition;  Epidemiology;  Sensory

Document Type: Article
Publication Stage: Final
Source: Scopus

Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability
(2023) Cell, 186 (22), pp. 4898-4919.e25. 

Gall-Duncan, T.^a b , Luo, J.^a b , Jurkovic, C.-M.^c , Fischer, L.A.^d , Fujita, K.^e , Deshmukh, A.L.^a , Harding, R.J.^f g , Tran, S.^a b , Mehkary, M.^a b , Li, V.^a b , Leib, D.E.^h , Chen, R.ⁱ , Tanaka, H.^e , Mason, A.G.^j , Lévesque, D.^c , Khan, M.^a b , Razzaghi, M.^k , Prasolava, T.^a , Lanni, S.^a , Sato, N.^a , Caron, M.-C.^l , Panigrahi, G.B.^a , Wang, P.^a , Lau, R.^a , Castel, A.L.^m , Masson, J.-Y.^l , Tippett, L.^n o , Turner, C.^p , Spies, M.^k , La Spada, A.R.^q r s , Campos, E.I.^a b , Curtis, M.A.^o t , Boisvert, F.-M.^c , Faull, R.L.M.^o t , Davidson, B.L.^h , Nakamori, M.^u , Okazawa, H.^e , Wold, M.S.^k , Pearson, C.E.^a f

^a Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada
^b Molecular Genetics, University of Toronto, Toronto, ON, Canada
^c Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada
^d Developmental Biology and Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
^e Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
^f Structural Genomics Consortium, University of Toronto, Toronto, ON M5G 1L7, Canada
^g Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
^h Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19146, United States
ⁱ Pediatrics, Division of Hematology and Oncology, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Human Genetics, Leiden University Medical Center, Leiden, Netherlands
^k Biochemistry and Molecular Biology, Carver College of Medicine, University of Iowa, Iowa City, IA, United States
^l CHU de Québec-Université Laval, Oncology Division, Molecular Biology, Medical Biochemistry, and Pathology, Laval University Cancer Research Center, Québec, QC, Canada
^m BIOTECMED, University of Valencia, Valencia, Spain
ⁿ School of Psychology, University of Auckland, Auckland, New Zealand
^o University Research Centre for Brain Research, University of Auckland, Auckland, New Zealand
^p Anatomical Pathology, LabPlus, Auckland City Hospital, Auckland, New Zealand
^q Pathology & Laboratory Medicine, Neurology, and Biological Chemistry, University of California, Irvine School of Medicine, Irvine, CA, United States
^r Neurobiology & Behavior, University of California, Irvine, Irvine, CA, United States
^s Center for Neurotherapeutics, University of California, Irvine, Irvine, CA 92697, United States
^t Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand
^u Neurology, Osaka University Graduate School of Medicine, Osaka, Japan

Abstract
Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA’s suppression of disease-associated repeat expansions, which may extend to other DNA processes. © 2023 Elsevier Inc.

Author Keywords
Alternative replication protein A (Alt-RPA);  BioID protein interactome;  DNA repair (FAN1, MSH2, MSH3, MSH6, HTT);  Huntington’s disease (HD);  Replication protein A (RPA);  RPA1, RPA2, RPA3, RPA4;  slipped-DNA;  Spinocerebellar ataxia type 1 (SCA1);  tandem repeat expansions;  trinucleotide CAG repeat expansions

Document Type: Article
Publication Stage: Final
Source: Scopus

A cellular resolution atlas of Broca’s area
(2023) Science Advances, 9 (41), p. eadg3844. 

Costantini, I.^a b c , Morgan, L.^d , Yang, J.^e , Balbastre, Y.^d f , Varadarajan, D.^d f , Pesce, L.^a , Scardigli, M.^a g h , Mazzamuto, G.^a c g , Gavryusev, V.^a g , Castelli, F.M.^a g i , Roffilli, M.ⁱ , Silvestri, L.^a c g , Laffey, J.^j , Raia, S.^j , Varghese, M.^j , Wicinski, B.^j , Chang, S.^k , Chen, I.A.^e , Wang, H.^d f , Cordero, D.^d , Vera, M.^d , Nolan, J.^d , Nestor, K.^d f , Mora, J.^d f , Iglesias, J.E.^d f l m , Garcia Pallares, E.^d , Evancic, K.^d f , Augustinack, J.C.^d f , Fogarty, M.^n o , Dalca, A.V.^d m , Frosch, M.P.^p , Magnain, C.^d f , Frost, R.^d f , van der Kouwe, A.^d f q , Chen, S.-C.^r , Boas, D.A.^e , Pavone, F.S.^a c g , Fischl, B.^d f m s , Hof, P.R.^j

^a European Laboratory for Non-Linear Spectroscopy (LENS), University of Florence, Sesto Fiorentino (FI), Italy
^b Department of Biology, University of Florence, Florence, Italy
^c National Institute of Optics (INO), National Research Council (CNR), Sesto Fiorentino, Italy
^d Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
^e Department of Biomedical Engineering, Boston University, Boston, MA, United States
^f Department of Radiology, Harvard Medical School, Boston, MA, United States
^g Department of Physics and Astronomy, University of Florence, Sesto Fiorentino (FI), Italy
^h Division of Physiology, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
ⁱ Cesena, Italy
^j Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount SinaiNY, United States
^k Department of Electrical and Computer Engineering, Boston University, Boston, MA, United States
^l Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
^m Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, United States
ⁿ Imaging Science Program, Washington University McKelvey School of EngineeringMO, United States
^o Department of Radiology, Washington University School of MedicineMO, United States
^p C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^q Department of Human Biology, University of Cape Town, Cape Town, South Africa
^r Department of Mechanical and Automation Engineering, The Chinese University of Hong Kong, Shatin, Hong Kong
^s Massachusetts Institute of Technology, Cambridge, MA, United States

Abstract
Brain cells are arranged in laminar, nuclear, or columnar structures, spanning a range of scales. Here, we construct a reliable cell census in the frontal lobe of human cerebral cortex at micrometer resolution in a magnetic resonance imaging (MRI)-referenced system using innovative imaging and analysis methodologies. MRI establishes a macroscopic reference coordinate system of laminar and cytoarchitectural boundaries. Cell counting is obtained with a digital stereological approach on the 3D reconstruction at cellular resolution from a custom-made inverted confocal light-sheet fluorescence microscope (LSFM). Mesoscale optical coherence tomography enables the registration of the distorted histological cell typing obtained with LSFM to the MRI-based atlas coordinate system. The outcome is an integrated high-resolution cellular census of Broca’s area in a human postmortem specimen, within a whole-brain reference space atlas.

Document Type: Article
Publication Stage: Final
Source: Scopus

Focused Ultrasound-Mediated Delivery of Anti-Programmed Cell Death-Ligand 1 Antibody to the Brain of a Porcine Model
(2023) Pharmaceutics, 15 (10), art. no. 2479, . 

Fadera, S.^a , Chukwu, C.^a , Stark, A.H.^a , Yue, Y.^a , Xu, L.^a , Chien, C.-Y.^a , Yuan, J.^a , Chen, H.^a b

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Immune checkpoint inhibitor (ICI) therapy has revolutionized cancer treatment by leveraging the body’s immune system to combat cancer cells. However, its effectiveness in brain cancer is hindered by the blood-brain barrier (BBB), impeding the delivery of ICIs to brain tumor cells. This study aimed to assess the safety and feasibility of using focused ultrasound combined with microbubble-mediated BBB opening (FUS-BBBO) to facilitate trans-BBB delivery of an ICI, anti-programmed cell death-ligand 1 antibody (aPD-L1) to the brain of a large animal model. In a porcine model, FUS sonication of targeted brain regions was performed after intravenous microbubble injection, which was followed by intravenous administration of aPD-L1 labeled with a near-infrared fluorescent dye. The permeability of the BBB was evaluated using contrast-enhanced MRI in vivo, while fluorescence imaging and histological analysis were conducted on ex vivo pig brains. Results showed a significant 4.8-fold increase in MRI contrast-enhancement volume in FUS-targeted regions compared to nontargeted regions. FUS sonication enhanced aPD-L1 delivery by an average of 2.1-fold, according to fluorescence imaging. In vivo MRI and ex vivo staining revealed that the procedure did not cause significant acute tissue damage. These findings demonstrate that FUS-BBBO offers a noninvasive, localized, and safe delivery approach for ICI delivery in a large animal model, showcasing its potential for clinical translation. © 2023 by the authors.

Author Keywords
blood-brain barrier;  brain drug delivery;  focused ultrasound;  immune checkpoint inhibitors;  immunotherapy

Funding details
National Institutes of HealthNIHR01CA276174, R01EB027223, R01EB030102, R01MH116981, R01NS128461
Charlie Teo FoundationCTF

Document Type: Article
Publication Stage: Final
Source: Scopus

A Drosophila glial cell atlas reveals a mismatch between transcriptional and morphological diversity
(2023) PLoS Biology, 21 (10), art. no. e3002328, . 

Lago-Baldaia, I.^a , Cooper, M.^a , Seroka, A.^b , Trivedi, C.^a , Powell, G.T.^a , Wilson, S.W.^a , Ackerman, S.D.^c d , Fernandes, V.M.^a

^a Department of Cell and Developmental Biology, University College London, London, United Kingdom
^b Institute of Neuroscience, Howard Hughes Medical Institute, University of Oregon, Eugene, OR, United States
^c Department of Pathology and Immunology, Brain Immunology and Glia Center, Washington University School of Medicine, Saint Louis, MO, United States
^d Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Morphology is a defining feature of neuronal identity. Like neurons, glia display diverse morphologies, both across and within glial classes, but are also known to be morphologically plastic. Here, we explored the relationship between glial morphology and transcriptional signature using the Drosophila central nervous system (CNS), where glia are categorised into 5 main classes (outer and inner surface glia, cortex glia, ensheathing glia, and astrocytes), which show within-class morphological diversity. We analysed and validated single-cell RNA sequencing data of Drosophila glia in 2 well-characterised tissues from distinct developmental stages, containing distinct circuit types: the embryonic ventral nerve cord (VNC) (motor) and the adult optic lobes (sensory). Our analysis identified a new morphologically and transcriptionally distinct surface glial population in the VNC. However, many glial morphological categories could not be distinguished transcriptionally, and indeed, embryonic and adult astrocytes were transcriptionally analogous despite differences in developmental stage and circuit type. While we did detect extensive within-class transcriptomic diversity for optic lobe glia, this could be explained entirely by glial residence in the most superficial neuropil (lamina) and an associated enrichment for immune-related gene expression. In summary, we generated a single-cell transcriptomic atlas of glia in Drosophila, and our extensive in vivo validation revealed that glia exhibit more diversity at the morphological level than was detectable at the transcriptional level. This atlas will serve as a resource for the community to probe glial diversity and function. © 2023 Lago-Baldaia 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.

Funding details
210472/Z/18/Z
National Institutes of HealthNIHK99/R00NS121137
Wellcome TrustWT104682/Z/14/Z

Document Type: Article
Publication Stage: Final
Source: Scopus

Bayesian Surprise Predicts Human Event Segmentation in Story Listening
(2023) Cognitive Science, 47 (10), art. no. e13343, . 

Kumar, M.^a , Goldstein, A.^b c , Michelmann, S.^a , Zacks, J.M.^d , Hasson, U.^a e , Norman, K.A.^a e

^a Princeton Neuroscience Institute, Princeton University, United States
^b Department of Cognitive and Brain Sciences and Business School, Hebrew University, Israel
^c Google Research, Tel-Aviv, Israel
^d Department of Psychological & Brain Sciences, Washington University in St. Louis, United States
^e Department of Psychology, Princeton University, United States

Abstract
Event segmentation theory posits that people segment continuous experience into discrete events and that event boundaries occur when there are large transient increases in prediction error. Here, we set out to test this theory in the context of story listening, by using a deep learning language model (GPT-2) to compute the predicted probability distribution of the next word, at each point in the story. For three stories, we used the probability distributions generated by GPT-2 to compute the time series of prediction error. We also asked participants to listen to these stories while marking event boundaries. We used regression models to relate the GPT-2 measures to the human segmentation data. We found that event boundaries are associated with transient increases in Bayesian surprise but not with a simpler measure of prediction error (surprisal) that tracks, for each word in the story, how strongly that word was predicted at the previous time point. These results support the hypothesis that prediction error serves as a control mechanism governing event segmentation and point to important differences between operational definitions of prediction error. © 2023 The Authors. Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society (CSS).

Author Keywords
Bayesian surprise;  Entropy;  Event segmentation;  GPT-2;  Narratives;  Surprise

Funding details
National Institutes of HealthNIHDP1HD091948, R01AG062438
James S. McDonnell FoundationJSMF
Multidisciplinary University Research InitiativeMURIN00014‐17‐1‐2961

Document Type: Article
Publication Stage: Final
Source: Scopus

Controversies and progress on standardization of large-scale brain network nomenclature
(2023) Network Neuroscience, 7 (3), pp. 864-905. Cited 1 time.

Uddin, L.Q.^a , Betzel, R.F.^b , Cohen, J.R.^c , Damoiseaux, J.S.^d , De Brigard, F.^e , Eickhoff, S.B.^f , Fornito, A.^g , Gratton, C.^h , Gordon, E.M.ⁱ , Laird, A.R.^j , Larson-Prior, L.^k , McIntosh, A.R.^l , Nickerson, L.D.^m , Pessoa, L.ⁿ , Pinho, A.L.^o , Poldrack, R.A.^p , Razi, A.^g , Sadaghiani, S.^q , Shine, J.M.^r , Yendiki, A.^s , Yeo, B.T.T.^t , Spreng, R.N.^u

^a Department of Psychiatry and Biobehavioral Sciences and Department of Psychology, University of California, Los Angeles, Los Angeles, CA, United States
^b Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, United States
^c Department of Psychology and Neuroscience, University of North Carolina, Chapel Hill, NC, United States
^d Institute of Gerontology and Department of Psychology, Wayne State University, Detroit, MI, United States
^e Department of Philosophy, Duke University, Durham, NC, United States
^f Institute of Systems Neuroscience, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
^g Turner Institute for Brain and Mental Health, Monash University, Melbourne, Australia
^h Department of Psychology, Northwestern University, Evanston, IL, United States
ⁱ Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
^j Department of Physics, Florida International University, Miami, FL, United States
^k Deptartment of Psychiatry and Department of Neurobiology and Developmental Sciences, University of Arkansas for Medical Sciences, Little RockAR, United States
^l Institute for Neuroscience and Neurotechnology, Simon Fraser University, Vancouver, BC, Canada
^m Department of Psychiatry, McLean Hospital, Boston, MA, United States
ⁿ Department of Psychology, University of Maryland, College Park, MD, United States
^o Brain and Mind Institute, Western University, London, ON, Canada
^p Department of Psychology, Stanford University, Stanford, CA, United States
^q Department of Psychology, University of Illinois, Urbana Champaign, IL, United States
^r Brain and Mind Center, University of Sydney, Sydney, Australia
^s Department of Radiology, Massachusetts General Hospital, Boston, MA, United States
^t Department of Electrical and Computer Engineering, National University of Singapore, Singapore
^u Department of Neurology and Neurosurgery, McGill University, Montreal, Canada

Author Keywords
Brain network;  Cognitive neuroscience;  Diffusion weighted imaging;  EEG;  Functional connectivity;  MEG;  Network neuroscience;  Parcellation;  Resting-state fMRI;  Structural connectivity

Funding details
National Science FoundationNSF2048066, FAIN 2218556, R01MH116226, R01MH118370, R01MH119091, R21NS104603, U01DA050987
National Institutes of HealthNIHP50MH106435, R01EB021265, R01NS119911, U01EB026996
National Institute of Mental HealthNIMHMH071589, MH112517
National Institute on AgingNIAR01AG068563
Canadian Institutes of Health ResearchIRSC
Natural Sciences and Engineering Research Council of CanadaNSERC
Fonds de Recherche du Québec – SantéFRQS
Western UniversityUWO
Canada First Research Excellence FundCFREF

Document Type: Article
Publication Stage: Final
Source: Scopus

Simple and complex cells revisited: toward a selectivity-invariance model of object recognition
(2023) Frontiers in Computational Neuroscience, 17, art. no. 1282828, . 

Li, X.^a , Wang, S.^b

^a Department of Computer Science, University at Albany, Albany, NY, United States
^b Department of Radiology, Washington University at St. Louis, St. Louis, MO, United States

Abstract
This paper presents a theoretical perspective on modeling ventral stream processing by revisiting the computational abstraction of simple and complex cells. In parallel to David Marr’s vision theory, we organize the new perspective into three levels. At the computational level, we abstract simple and complex cells into space partitioning and composition in a topological space based on the redundancy exploitation hypothesis of Horace Barlow. At the algorithmic level, we present a hierarchical extension of sparse coding by exploiting the manifold constraint in high-dimensional space (i.e., the blessing of dimensionality). The resulting over-parameterized models for object recognition differ from existing hierarchical models by disentangling the objectives of selectivity and invariance computation. It is possible to interpret our hierarchical construction as a computational implementation of cortically local subspace untangling for object recognition and face representation, which are closely related to exemplar-based and axis-based coding in the medial temporal lobe. At the implementation level, we briefly discuss two possible implementations based on asymmetric sparse autoencoders and divergent spiking neural networks. Copyright © 2023 Li and Wang.

Author Keywords
cortically local subspace untangling;  invariance computation;  object recognition;  selectivity computation;  simple and complex cells

Funding details
National Science FoundationNSFBCS-1945230, HCC-2114644

Document Type: Article
Publication Stage: Final
Source: Scopus

Vancomycin-induced gut microbial dysbiosis alters enteric neuron–macrophage interactions during a critical period of postnatal development
(2023) Frontiers in Immunology, 14, art. no. 1268909, . 

Schill, E.M.^a b , Joyce, E.L.^a , Floyd, A.N.^a , Udayan, S.^a , Rusconi, B.^c , Gaddipati, S.^a , Barrios, B.E.^a , John, V.^a , Kaye, M.E.^a , Kulkarni, D.H.^a , Pauta, J.T.^a , McDonald, K.G.^a , Newberry, R.D.^a

^a Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions. This suggests that early-life antibiotic exposure could disrupt these interactions in the neonatal gut. Notably, a subset of tissue-resident intestinal macrophages, muscularis macrophages, has been identified as important contributors to the development of postnatal ENS. We hypothesized that vancomycin-induced neonatal dysbiosis impacts postnatal ENS development through its effects on macrophages. Using a mouse model, we found that exposure to vancomycin in the first 10 days of life, but not in adult mice, resulted in an expansion of pro-inflammatory colonic macrophages by increasing the recruitment of bone-marrow-derived macrophages. Single-cell RNA sequencing of neonatal colonic macrophages revealed that early-life vancomycin exposure was associated with an increase in immature and inflammatory macrophages, consistent with an influx of circulating monocytes differentiating into macrophages. Lineage tracing confirmed that vancomycin significantly increased the non-yolk-sac-derived macrophage population. Consistent with these results, early-life vancomycin exposure did not expand the colonic macrophage population nor decrease enteric neuron density in CCR2-deficient mice. Collectively, these findings demonstrate that early-life vancomycin exposure alters macrophage number and phenotypes in distinct ways compared with vancomycin exposure in adult mice and results in altered ENS development. Copyright © 2023 Schill, Joyce, Floyd, Udayan, Rusconi, Gaddipati, Barrios, John, Kaye, Kulkarni, Pauta, McDonald and Newberry.

Author Keywords
early life antibiotics;  enteric nervous system;  monocyte recruitment;  muscularis macrophage;  neonatal dysbiosis

Funding details
National Institutes of HealthNIHDKR01097317, K01-DK133670, K01DK125606, R01AI1126, R01AI173220, T32DK077653, T32HD043010, U01AI163073
Crohn’s and Colitis FoundationCCF902790, P30DK052574

Document Type: Article
Publication Stage: Final
Source: Scopus

Loss-of-function variants in ZEB1 cause dominant anomalies of the corpus callosum with favourable cognitive prognosis
(2023) Journal of Medical Genetics, art. no. jmg-2023-109293, . 

Heide, S.^a , Argilli, E.^b c , Valence, S.^d , Boutaud, L.^e , Roux, N.^e , Mignot, C.^a , Nava, C.^f , Keren, B.^f , Giraudat, K.^d , Faudet, A.^a , Gerasimenko, A.^a , Garel, C.^g , Blondiaux, E.^g , Rastetter, A.^h , Grevent, D.^i j , Le, C.^c k , Mackenzie, L.^l , Richards, L.^l m , Attié-Bitach, T.^e , Depienne, C.ⁿ , Sherr, E.^b c , Héron, D.^a

^a Department of Genetics, Referral Center for Intellectual Disabilities of Rare Causes, AP-HP, Sorbonne Université, Assistance Publique-Hopitaux de Paris, Pitié-Salpêtrière Hospital, Paris, Paris, 75013, France
^b Department of Neurology, University of California San Francisco, Division of Hospital Medicine, San Francisco, CA, United States
^c Institute of Human Genetics, Weill Institute for Neurosciences, University of California, San Francisco, CA, United States
^d Department of Neuropediatry, Referral Center for Intellectual Disabilities of Rare Causes, AP-HP, Sorbonne Université, Hopital Armand-Trousseau, Paris, France
^e Genomic Medicine of Rare Diseases, UF MP5, Hopital Universitaire Necker-enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France
^f Department of Genetics, Unit of Developmental Genomics, AP-HP, Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France
^g Department of Pediatric and Prenatal Imaging, Armand-Trousseau Hospital, Sorbonne Université, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France
^h Paris Brain Institute, ICM Institut du Cerveau, Sorbonne Université, INSERM, UMR S 1127, Paris, France
ⁱ Radiology Department, Hopital Universitaire Necker-enfants Malades, Paris, France
^j EA Fetus 7328, LUMIERE Platform, Université de Paris, Paris, France
^k Department of Neurology, University of California, Institute of Human Genetics, Weill Institute for Neurosciences, San Francisco, CA, United States
^l Department of Neuroscience, Washington University in St Louis School of Medicine, St Louis, MO, United States
^m Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia
ⁿ Institute of Human Genetics, University Hospital Essen, Universitu Duisburg-Essen, Essen, Germany

Abstract
Background: The neurodevelopmental prognosis of anomalies of the corpus callosum (ACC), one of the most frequent brain malformations, varies extremely, ranging from normal development to profound intellectual disability (ID). Numerous genes are known to cause syndromic ACC with ID, whereas the genetics of ACC without ID remains poorly deciphered. Methods: Through a collaborative work, we describe here ZEB1, a gene previously involved in an ophthalmological condition called type 3 posterior polymorphous corneal dystrophy, as a new dominant gene of ACC. We report a series of nine individuals with ACC (including three fetuses terminated due to ACC) carrying a ZEB1 heterozygous loss-of-function (LoF) variant, identified by exome sequencing. Results: In five cases, the variant was inherited from a parent with a normal corpus callosum, which illustrates the incomplete penetrance of ACC in individuals with an LoF in ZEB1. All patients reported normal schooling and none of them had ID. Neuropsychological assessment in six patients showed either normal functioning or heterogeneous cognition. Moreover, two patients had a bicornuate uterus, three had a cardiovascular anomaly and four had macrocephaly at birth, which suggests a larger spectrum of malformations related to ZEB1. Conclusion: This study shows ZEB1 LoF variants cause dominantly inherited ACC without ID and extends the extraocular phenotype related to this gene. © Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
Genetics, Medical;  Nervous System Malformations;  Neurology

Funding details
National Institutes of HealthNIHR01NS058721

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