WashU weekly Neuroscience publications: August 13, 2023

Neural manifolds for odor-driven innate and acquired appetitive preferences
(2023) Nature Communications, 14 (1), art. no. 4719, . 

Chandak, R., Raman, B.

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Sensory stimuli evoke spiking neural responses that innately or after learning drive suitable behavioral outputs. How are these spiking activities intrinsically patterned to encode for innate preferences, and could the neural response organization impose constraints on learning? We examined this issue in the locust olfactory system. Using a diverse odor panel, we found that ensemble activities both during (‘ON response’) and after stimulus presentations (‘OFF response’) could be linearly mapped onto overall appetitive preference indices. Although diverse, ON and OFF response patterns generated by innately appetitive odorants (higher palp-opening responses) were still limited to a low-dimensional subspace (a ‘neural manifold’). Similarly, innately non-appetitive odorants evoked responses that were separable yet confined to another neural manifold. Notably, only odorants that evoked neural response excursions in the appetitive manifold could be associated with gustatory reward. In sum, these results provide insights into how encoding for innate preferences can also impact associative learning. © 2023, Springer Nature Limited.

Funding details
National Science FoundationNSF1453022, 1724218, 2021795
Office of Naval ResearchONRN00014-19-1-2049, N00014-21-1-2343
Michigan State UniversityMSU

Document Type: Article
Publication Stage: Final
Source: Scopus

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma
(2023) Neuro-oncology, 25 (8), pp. 1498-1506. 

Plotkin, S.R.^a , Allen, J.^b , Dhall, G.^c , Campian, J.L.^d , Clapp, D.W.^e , Fisher, M.J.^f , Jain, R.K.^a , Tonsgard, J.^g , Ullrich, N.J.^h , Thomas, C.ⁱ , Edwards, L.J.ⁱ , Korf, B.ⁱ , Packer, R.^j , Karajannis, M.A.^b , Blakeley, J.O.^k

^a Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^b NYU Langone HealthNY, United States
^c University of Southern California, Los Angeles, CA, United States
^d Washington University, St. Louis, MO, United States
^e University of Indiana, Indianapolis, IN, United States
^f Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^g University of Chicago, Chicago, IL, United States
^h Boston Children’s Hospital, Boston, MA, United States
ⁱ University of Alabama, Birmingham, AL, United States
^j Children’s National Medical Center, Washington, District of Columbia, USA
^k Johns Hopkins University, Baltimore, MD, United States

Abstract
BACKGROUND: Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS: Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS: Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS: Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population. © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Author Keywords
bevacizumab;  maintenance;  neurofibromatosis 2;  NF2;  vestibular schwannoma

Document Type: Article
Publication Stage: Final
Source: Scopus

Clinical, histological, and molecular features of gliomas in adults with neurofibromatosis type 1
(2023) Neuro-oncology, 25 (8), pp. 1474-1486. 

Romo, C.G.^a , Piotrowski, A.F.^b , Campian, J.L.^c , Diarte, J.^b , Rodriguez, F.J.^d , Bale, T.A.^b , Dahiya, S.^c , Gutmann, D.H.^c , Lucas, C.-H.G.^e , Prichett, L.^a , Mellinghoff, I.^b , Blakeley, J.O.^a

^a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Departments of Neurology and Pathology, Memorial Sloan Kettering Cancer CenterNY, United States
^c Departments of Neurology and Pathology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pathology, University of California Los Angeles, Los Angeles, CA, United States
^e Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
BACKGROUND: People with NF1 have an increased prevalence of central nervous system malignancy. However, little is known about the clinical course or pathologic features of NF1-associated gliomas in adults, limiting clinical care and research. METHODS: Adults (≥18 years) with NF1 and histologically confirmed non-optic pathway gliomas (non-OPGs) at Johns Hopkins Hospital, Memorial Sloan Kettering Cancer Center, and Washington University presenting between 1990 and 2020 were identified. Retrospective data were collated, and pathology was reviewed centrally. RESULTS: Forty-five patients, comprising 23 females (51%), met eligibility criteria, with a median of age 37 (18-68 years) and performance status of 80% (30%-100%). Tissue was available for 35 patients. Diagnoses included infiltrating (low-grade) astrocytoma (9), glioblastoma (7), high-grade astrocytoma with piloid features (4), pilocytic astrocytoma (4), high-grade astrocytoma (3), WHO diagnosis not reached (4) and one each of gliosarcoma, ganglioglioma, embryonal tumor, and diffuse midline glioma. Seventy-one percent of tumors were midline and underwent biopsy only. All 27 tumors evaluated were IDH1-wild-type, independent of histology. In the 10 cases with molecular testing, the most common genetic variants were NF1, EGFR, ATRX, CDKN2A/B, TP53, TERT, and MSH2/3 mutation. While the treatments provided varied, the median overall survival was 24 months [2-267 months] across all ages, and 38.5 [18-109] months in individuals with grade 1-2 gliomas. CONCLUSIONS: Non-OPGs in adults with NF1, including low-grade tumors, often have an aggressive clinical course, indicating a need to better understand the pathobiology of these NF1-associated gliomas. © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
glioma;  Neurofibromatosis type 1;  Non-optic pathway glioma;  overall survival;  treatment outcome

Document Type: Article
Publication Stage: Final
Source: Scopus

Evaluation of a combined, online intervention for binge-type eating disorders and high body weight in young adults
(2023) Eating Behaviors, 50, art. no. 101789, . 

Grammer, A.C.^a , Monterubio, G.E.^b , D’Adamo, L.^a c , Balantekin, K.N.^d , Taylor, C.B.^e f , Fitzsimmons-Craft, E.E.^a , Wilfley, D.E.^a

^a Department of Psychiatry, Washington University School of Medicine, Mailstop 8134-29-2100, 660 S. Euclid Ave., St. Louis, MO 63110, United States
^b Department of Psychology, Cardinal Glennon Children’s Hospital, 1465 S Grand Blvd, St. Louis, MO 63104, United States
^c Department of Psychological and Brain Sciences and Center for Weight, Eating, and Lifestyle Science (WELL Center), Drexel University, 3201 Chestnut St., Philadelphia, PA 19104, United States
^d Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214, United States
^e Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305, United States
^f Center for m²Health, Palo Alto University, 5150 El Camino Real, Los Altos, CA 94022, United States

Abstract
Background: Binge-type eating disorders (EDs; i.e., bulimia nervosa, binge eating disorder) are common among young adults with high body weight, yet few interventions target both conditions. This study tested an online guided self-help intervention that provided cognitive behavioral therapy (CBT) tools for EDs and behavioral weight loss (BWL) content to young adults with binge-type EDs and high body weight. Method: 60 adults aged 18–39 with clinical/subclinical binge-type EDs and high body weight were randomized to a combined condition or a CBT-only condition. Participants received self-help content for 8 weeks and self-reported ED attitudes, frequency of binge eating and compensatory behaviors, and weight at baseline, 4-weeks, and 8-weeks. Linear mixed models and negative binomial models compared changes between conditions in ED attitudes, ED behaviors, and weight at each timepoint. Chi-square test and independent samples t-test compared program completion and session engagement between conditions. Results: No significant differences in weight change or ED symptom change emerged between the conditions. Both conditions achieved significant reductions in ED attitudes, binge episodes, and compensatory behaviors from baseline to 8-weeks (ps < .05). Neither condition demonstrated significant weight loss from baseline to 8-weeks. Program completion (47 %) and session engagement (57 %) were equally high across conditions. Discussion: Both conditions achieved ED symptom change; however, neither condition was associated with weight change. Research is needed to identify the types of strategies and doses of BWL that promote clinically significant weight and ED symptom change in young adults. © 2023 Elsevier Ltd

Author Keywords
Binge eating;  Digital;  Weight;  Young adults

Funding details
National Institutes of HealthNIHF31 HL158000, K01 DK120778, K08 MH120341, R01 MH100455, T32 HL130357

Document Type: Article
Publication Stage: Final
Source: Scopus

Positron emission tomography and magnetic resonance imaging methods and datasets within the Dominantly Inherited Alzheimer Network (DIAN)
(2023) Nature Neuroscience, 26 (8), pp. 1449-1460. Cited 1 time.

McKay, N.S.^a , Gordon, B.A.^a , Hornbeck, R.C.^a , Dincer, A.^a , Flores, S.^a , Keefe, S.J.^a , Joseph-Mathurin, N.^a , Jack, C.R.^b , Koeppe, R.^c , Millar, P.R.^a , Ances, B.M.^a , Chen, C.D.^a , Daniels, A.^a , Hobbs, D.A.^a , Jackson, K.^a , Koudelis, D.^a , Massoumzadeh, P.^a , McCullough, A.^a , Nickels, M.L.^a , Rahmani, F.^a , Swisher, L.^a , Wang, Q.^a , Allegri, R.F.^d , Berman, S.B.^e , Brickman, A.M.^f , Brooks, W.S.^g , Cash, D.M.^h i , Chhatwal, J.P.^j , Day, G.S.^k , Farlow, M.R.^l , la Fougère, C.^m n , Fox, N.C.^h i , Fulham, M.^o , Ghetti, B.^l , Graff-Radford, N.^k , Ikeuchi, T.^p , Klunk, W.^e , Lee, J.-H.^q , Levin, J.^r , Martins, R.^s , Masters, C.L.^t , McConathy, J.^u , Mori, H.^v , Noble, J.M.^f , Reischl, G.^m , Rowe, C.^t , Salloway, S.^w , Sanchez-Valle, R.^x , Schofield, P.R.^g y , Shimada, H.^v , Shoji, M.^z , Su, Y.^aa , Suzuki, K.^ab , Vöglein, J.^r ac , Yakushev, I.^ad , Cruchaga, C.^a , Hassenstab, J.^a , Karch, C.^a , McDade, E.^a , Perrin, R.J.^a , Xiong, C.^a , Morris, J.C.^a , Bateman, R.J.^a , Benzinger, T.L.S.^a , Brickman, A.M.^f , la Fougère, C.^m , the Dominantly Inherited Alzheimer Network^ae

^a Washington University in St. Louis, St. Louis, MO, United States
^b Mayo Clinic, Rochester, MN, United States
^c University of Michigan, Ann Arbor, MI, United States
^d Institute of Neurological Research Fleni, Buenos Aires, Argentina
^e University of Pittsburgh, Pittsburgh, PA, United States
^f Columbia University Irving Medical Center, New York, NY, United States
^g Neuroscience Research Australia, Sydney, NSW, Australia
^h UK Dementia Research Institute at University College London, London, United Kingdom
ⁱ University College London, London, United Kingdom
^j Massachusetts General and Brigham & Women’s Hospitals, Harvard Medical School, Boston, MA, United States
^k Mayo Clinic, Jacksonville, FL, United States
^l Indiana University School of Medicine, Bloomington, IN, United States
^m Department of Radiology, University of Tübingen, Tübingen, Germany
ⁿ German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^o Royal Prince Alfred Hospital, Sydney, NSW, Australia
^p Niigata University, Niigata, Japan
^q Asan Medical Center, Seoul, South Korea
^r German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^s Edith Cowan University, Joondalup, WA, Australia
^t University of Melbourne, Melbourne, VIC, Australia
^u University of Alabama at Birmingham, Birmingham, AL, United States
^v Osaka City University, Osaka, Japan
^w Brown University. Butler Hospital, Providence, RI, United States
^x Alzheimer’s Disease and Other Cognitive Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
^y School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia
^z Hirosaki University, Hirosaki, Japan
^aa Banner Alzheimer’s Institute, Phoenix, AZ, United States
^ab University of Tokyo, Tokyo, Japan
^ac Department of Neurology, Ludwig-Maximilians-Universität München, München, Germany
^ad School of Medicine, Technical University of Munich, Munich, Germany

Abstract
The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration studying autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations occurring in three genes. Offspring from ADAD families have a 50% chance of inheriting their familial mutation, so non-carrier siblings can be recruited for comparisons in case–control studies. The age of onset in ADAD is highly predictable within families, allowing researchers to estimate an individual’s point in the disease trajectory. These characteristics allow candidate AD biomarker measurements to be reliably mapped during the preclinical phase. Although ADAD represents a small proportion of AD cases, understanding neuroimaging-based changes that occur during the preclinical period may provide insight into early disease stages of ‘sporadic’ AD also. Additionally, this study provides rich data for research in healthy aging through inclusion of the non-carrier controls. Here we introduce the neuroimaging dataset collected and describe how this resource can be used by a range of researchers. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHK01-AG080123-01, K23-AG064029, P01-AG025204, R01-AG052550, R01-AG057840, R01-AG058676, R01-Ag068319, R03-AG072375, RF1-AG073424, RF1-AG079569, U01-AG059798, U19-AG024904, U19-AG053267
National Institute on AgingNIAU19-AG032438
Mayo Clinic
James S. McDonnell FoundationJSMF
Alzheimer’s AssociationAAAARF-21-722077, AARF-22-972678, AARF-D-20-681815, DIAN_ADNI-16-434364, SG-20-690363-DIAN
BrightFocus FoundationBFFA2022013F, A2022014F
University of WashingtonUW
Fondation Brain Canada
Japan Agency for Medical Research and DevelopmentAMEDJP22dk0207049
Washington University School of Medicine in St. LouisWUSM
Chan Zuckerberg InitiativeCZICS-0000000472
GHR FoundationGHR
Canadian Institutes of Health ResearchIRSCTAD-125697
Medical Research CouncilMRCMR/009076/1, MR/L023784/1
Alzheimer’s Society
Deutsche ForschungsgemeinschaftDFG
Alzheimer’s Research UKARUKARUK-PG2017-1946
Bundesministerium für Bildung und ForschungBMBF
Korea Health Industry Development InstituteKHIDI
Instituto de Salud Carlos IIIISCIII
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fonds de recherche du QuébecFRQ

Document Type: Article
Publication Stage: Final
Source: Scopus

Synchronization, clustering, and weak chimeras in a densely coupled transcription-based oscillator model for split circadian rhythms
(2023) Chaos (Woodbury, N.Y.), 33 (8), .

Ocampo-Espindola, J.L.^a , Nikhil, K.L.^b , Li, J.-S.^c , Herzog, E.D.^b , Kiss, I.Z.^a

^a Department of Chemistry, Saint Louis University, 3501 Laclede Ave., St. Louis, MO 63103, United States
^b Department of Biology, Washington University in St. Louis, One Brookings Drive, St. Louis, Missouri 63130-4899, United States
^c Department of Electrical and Systems Engineering, Washington University in St Louis, 1 Brookings Drive, St. Louis, MO 63130, United States

Abstract
The synchronization dynamics for the circadian gene expression in the suprachiasmatic nucleus is investigated using a transcriptional circadian clock gene oscillator model. With global coupling in constant dark (DD) conditions, the model exhibits a one-cluster phase synchronized state, in dim light (dim LL), bistability between one- and two-cluster states and in bright LL, a two-cluster state. The two-cluster phase synchronized state, where some oscillator pairs synchronize in-phase, and some anti-phase, can explain the splitting of the circadian clock, i.e., generation of two bouts of daily activities with certain species, e.g., with hamsters. The one- and two-cluster states can be reached by transferring the animal from DD or bright LL to dim LL, i.e., the circadian synchrony has a memory effect. The stability of the one- and two-cluster states was interpreted analytically by extracting phase models from the ordinary differential equation models. In a modular network with two strongly coupled oscillator populations with weak intragroup coupling, with appropriate initial conditions, one group is synchronized to the one-cluster state and the other group to the two-cluster state, resulting in a weak-chimera state. Computational modeling suggests that the daily rhythms in sleep-wake depend on light intensity acting on bilateral networks of suprachiasmatic nucleus (SCN) oscillators. Addition of a network heterogeneity (coupling between the left and right SCN) allowed the system to exhibit chimera states. The simulations can guide experiments in the circadian rhythm research to explore the effect of light intensity on the complexities of circadian desynchronization. © 2023 Author(s). Published under an exclusive license by AIP Publishing.

Document Type: Article
Publication Stage: Final
Source: Scopus

Multimodal mapping of regional brain vulnerability to focal cortical dysplasia
(2023) Brain: A Journal of Neurology, 146 (8), pp. 3404-3415. 

Lee, H.M.^a , Hong, S.-J.^a b , Gill, R.^a , Caldairou, B.^a , Wang, I.^c , Zhang, J.-G.^d , Deleo, F.^e , Schrader, D.^f , Bartolomei, F.^g , Guye, M.^h , Cho, K.H.ⁱ , Barba, C.^j , Sisodiya, S.^k , Jackson, G.^l , Hogan, R.E.^m , Wong-Kisiel, L.ⁿ , Cascino, G.D.ⁿ , Schulze-Bonhage, A.^o , Lopes-Cendes, I.^p , Cendes, F.^p , Guerrini, R.^q , Bernhardt, B.^r , Bernasconi, N.^a , Bernasconi, A.^a

^a Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute, McGill University, Montreal, Canada
^b Center for Neuroscience Imaging, Research Institute for Basic Science, Department of Global Biomedical Engineering, SungKyunKwan University, Suwon, South Korea
^c Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
^d Department of Functional Neurosurgery, Beijing Tiantan Hospital, Capital Medical UniversityBeijing, China
^e Epilepsy Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milano, Italy
^f Department of Pediatrics, British Columbia Children’s Hospital, Vancouver, Canada
^g Aix Marseille Univ, INSERM, INS, Institut de Neurosciences des Systèmes, Marseille, 13005, France
^h Aix Marseille University, CNRS, CRMBM UMR 7339, Marseille, France
ⁱ Department of Neurology, Yonsei University College of MedicineSeoul, South Korea
^j Neuroscience Department, Children’s Hospital A. Meyer-University of Florence, Florence, Italy
^k Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom
^l Florey Institute of Neuroscience and Mental Health and The University of MelbourneVIC, Australia
^m Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
ⁿ Mayo Clinic, Department of Neurology, Rochester, MN, United States
^o Epilepsy Center, University Medical Center-University of Freiburg, Freiburg, Germany
^p Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP) and the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas SP, Brazil
^q Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas SP, Brazil
^r Multimodal Imaging and Connectome Analysis Lab, McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada

Abstract
Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
epilepsy;  focal cortical dysplasia;  imaging-genetics;  MRI;  neurodevelopment

Document Type: Article
Publication Stage: Final
Source: Scopus

MTHFD1 is critical for the negative regulation of retinoic acid receptor signalling in anencephaly
(2023) Brain: A Journal of Neurology, 146 (8), pp. 3455-3469. 

Xie, X.^a b c , Li, C.^d , Yu, J.^e , Chang, S.^a , Cheng, X.^f , Wang, F.^a , Bao, Y.^a , Zhang, T.^a b , Wang, S.^a b

^a Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of PediatricsBeijing 100020, China
^b Children’s Hospital Capital Institute of Pediatrics, Chinese Academy of Medical Sciences & Peking Union Medical CollegeBeijing 100730, China
^c Department of Clinical Laboratory, Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
^d Division of Nephrology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Basic Medical Sciences, Changzhi Medical College, Changzhi, 046000, China
^f Department of General Medicine, Third Hospital of Hebei Medical UniversityHebei 050000, China

Abstract
Neural tube defects are the most severe congenital malformations that result from failure of neural tube closure during early embryonic development, and the underlying molecular mechanisms remain elusive. Retinoic acid, an active derivative of vitamin A, is critical for neural system development, and retinoic acid receptor (RAR) signalling malfunctions have been observed in human neural tube defects. However, retinoic acid-retinoic acid receptor signalling regulation and mechanisms in neural tube defects are not fully understood. The mRNA expression of RARs and retinoid X receptors in the different human neural tube defect phenotypes, including 11 pairs of anencephaly foetuses, 10 pairs of hydrocephalus foetuses and nine pairs of encephalocele foetuses, was investigated by NanoString nCounter technology. Immunoprecipitation-mass spectrometry was performed to screen the potential interacting targets of retinoic acid receptor γ. The interactions between proteins were confirmed by co-immunoprecipitation and immunofluorescence laser confocal microscopy. Luciferase and chromatin immunoprecipitation with quantitative real-time polymerase chain reaction assays were used to clarify the underlying mechanism. Moreover, a neural tube defect animal model, constructed using excess retinoic acid, was used for further analysis with established molecular biology technologies. We report that level of retinoic acid receptor γ (RARγ) mRNA was significantly upregulated in the brain tissues of human foetuses with anencephaly. To further understand the actions of retinoic acid receptor γ in neural tube defects, methylenetetrahydrofolate dehydrogenase 1 was identified as a specific retinoic acid receptor γ target from IP-MS screening. Additionally, methylenetetrahydrofolate dehydrogenase 1 negatively regulated retinoic acid receptor γ transcription factor activity. Furthermore, low expression of methylenetetrahydrofolate dehydrogenase 1 and activation of retinoic acid receptor signalling were further determined in human anencephaly and a retinoic acid-induced neural tube defect mouse model. This study reveals that methylenetetrahydrofolate dehydrogenase 1, the rate-determining enzyme in the one-carbon cycle, might be a specific regulator of retinoic acid receptors; these findings provide new insights into the functional linkage between nuclear folate metabolism and retinoic acid receptor signalling in neural tube defect pathology. © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
anencephaly;  methylenetetrahydrofolate dehydrogenase 1 (MTHFD1);  retinoic acid receptor signalling;  retinoid acid receptor γ (RARγ)

Document Type: Article
Publication Stage: Final
Source: Scopus

Prescription amphetamines in people with opioid use disorder and co-occurring psychostimulant use disorder initiating buprenorphine: an analysis of treatment retention and overdose risk
(2023) BMJ Mental Health, 26 (1), art. no. 26, . 

Tardelli, V.^a b , Xu, K.Y.^c , Bisaga, A.^d e , Levin, F.R.^d , Fidalgo, T.M.^a , Grucza, R.A.^f g

^a Department of Psychiatry, Universidade Federal de Sao Paulo, Sao Paulo, Brazil
^b Translational Addictions Research Lab, Centre for Addiction and Mental Health, Department of Psychiatr, University of Toronto, Toronto, ON, Canada
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychiatry, College of Physicians and Surgeons of Columbia University, New York City, NY, United States
^e Division of Substance Use Disorders, New York State Psychiatric Institute, New York City, NY, United States
^f Department of Family and Community Medicine, Saint Louis University, St. Louis, MO, United States
^g Department of Health and Outcomes Research, Saint Louis University, St. Louis, MO, United States

Abstract
Background Attention-deficit and hyperactivity disorder (ADHD) is frequently diagnosed in patients with substance use disorders (SUDs), including opioids. There remains concern about the safety and efficacy of prescription amphetamines (PAs) and their impact on effectiveness of opioid use disorder (OUD) treatment with buprenorphine. Objectives To assess the effect of PAs on OUD buprenorphine treatment retention and/or SUD-related emergency admission or drug-related poisonings. Methods We used a retrospective cohort design with a secondary analysis of data from Merative MarketScan Commercial and Multi-State Medicaid Databases from 1 January 2006 to 31 December 2016. Individuals included were aged 12-64 years, had an OUD diagnosis and were prescribed buprenorphine. Our analysis used multivariable Cox regression to evaluate the relationship between PA receipt and time to buprenorphine discontinuation. The second part focused on subsamples of buprenorphine initiators who had either (1) any SUD-related emergency admissions or (2) drug-related poisoning. These outcomes were modelled as a function of PA exposure using conditional logistic regression models as part of a within-person, case-crossover design. Findings Our sample had 90 269 patients with OUD (mean age 34.2 years (SD=11.3)) who initiated buprenorphine. Being prescribed a PA was associated with improved buprenorphine retention among individuals both with (adjusted HR (aHR) 0.91 (95% CI 0.86 to 0.97)) and without a concurrent psychostimulant use disorder (PSUD) (aHR 0.92 (95% CI 0.90 to 0.93)). Conclusions PA use was associated with improved buprenorphine retention in people with OUD with and without co-occurring PSUD. The risks of acute SUD-related events and drug-related poisonings associated with PA use did not differ when comparing PA-using days with days without PA use. Clinical implications Patients with OUD on buprenorphine should receive treatment with a PA when indicated. © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. Published by BMJ.

Author Keywords
adult psychiatry;  substance misuse

Funding details
National Institutes of HealthNIH
National Center for Advancing Translational SciencesNCATS
Institute of Clinical and Translational SciencesICTSUL1 TR002345
Saint Louis UniversitySLU

Document Type: Article
Publication Stage: Final
Source: Scopus

Thalamo-cortical and cerebello-cortical functional connectivity in development
(2023) Cerebral Cortex (New York, N.Y. : 1991), 33 (15), pp. 9250-9262. 

Badke D’Andrea, C.^a b c , Marek, S.^c , Van, A.N.^d e , Miller, R.L.^b d , Earl, E.A.^f , Stewart, S.B.^g , Dosenbach, N.U.F.^{c d e h i} , Schlaggar, B.L.^j , Laumann, T.O.^b , Fair, D.A.^k l m , Gordon, E.M.^c , Greene, D.J.^a

^a Department of Cognitive Science, University of California San Diego, La Jolla, CA, 92093, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^f Data Science and Sharing Team, National Institute of Mental Health, NIH, DHHS, Bethesda, United States
^g Department of Psychiatry, University of Colorado School of Medicine, Aurora, CO 80045, United States
^h Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
ⁱ Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO 63110, United States
^j Kennedy Krieger Institute, Baltimore, MD 21205, United States
^k Institute of Child Development, College of Education and Human Development, University of Minnesota, Minneapolis, United States
^l Department of Pediatrics, University of Minnesota Medical School, Minneapolis, United States
^m Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, United States

Abstract
The thalamus is a critical relay center for neural pathways involving sensory, motor, and cognitive functions, including cortico-striato-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops. Despite the importance of these circuits, their development has been understudied. One way to investigate these pathways in human development in vivo is with functional connectivity MRI, yet few studies have examined thalamo-cortical and cerebello-cortical functional connectivity in development. Here, we used resting-state functional connectivity to measure functional connectivity in the thalamus and cerebellum with previously defined cortical functional networks in 2 separate data sets of children (7-12 years old) and adults (19-40 years old). In both data sets, we found stronger functional connectivity between the ventral thalamus and the somatomotor face cortical functional network in children compared with adults, extending previous cortico-striatal functional connectivity findings. In addition, there was more cortical network integration (i.e. strongest functional connectivity with multiple networks) in the thalamus in children than in adults. We found no developmental differences in cerebello-cortical functional connectivity. Together, these results suggest different maturation patterns in cortico-striato-thalamo-cortical and cortico-ponto-cerebellar-thalamo-cortical pathways. © The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
brain networks;  cerebellum;  functional MRI;  neurodevelopment;  thalamus

Document Type: Article
Publication Stage: Final
Source: Scopus

Deep Brain Stimulation of the Globus Pallidus Internus and Externus in Multiple System Atrophy
(2023) Movement Disorders, . 

Di Luca, D.G.^a b c d , Ramirez-Gomez, C.^a b , Germann, J.^e , Santyr, B.^e , Boutet, A.^f , Milosevic, L.^g h i j , Lang, A.E.^a i , Kalia, S.K.^e i j , Lozano, A.M.^e i j , Fasano, A.^a b i j

^a Edmond J. Safra Program in Parkinson’s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, ON, Canada
^b Division of Neurology, University of Toronto, Toronto, ON, Canada
^c Institute of Health Policy, Management and Evaluation, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Surgery, University of Toronto, Toronto, ON, Canada
^f Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
^g Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
^h Institute of Medical Sciences, University of Toronto, Toronto, ON, Canada
ⁱ Krembil Brain Institute, Toronto, ON, Canada
^j Center for Advancing Neurotechnological Innovation to Application, Toronto, ON, Canada

Abstract
Background: Multiple system atrophy with parkinsonism (MSA-P) is a progressive condition with no effective treatment. Objective: The aim of this study was to describe the safety and efficacy of deep brain stimulation (DBS) of globus pallidus pars interna and externa in a cohort of patients with MSA-P. Methods: Six patients were included. Changes in Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part III (MDS-UPDRS III), Parkinson’s Disease Questionnaire (PDQ-39) scores, and levodopa equivalent daily dose were compared before and after DBS. Electrode localization and volume tissue activation were calculated. Results: DBS surgery did not result in any major adverse events or intraoperative complications. Overall, no differences in MDS-UPDRS III scores were demonstrated (55.2 ± 17.6 preoperatively compared with 67.3 ± 19.2 at 1 year after surgery), although transient improvement in mobility and dyskinesia was reported in some subjects. Conclusions: Globus pallidus pars interna and externa DBS for patients with MSA-P did not result in major complications, although it did not provide significant clinical benefit as measured by MDS-UPDRS III. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Author Keywords
deep brain stimulation;  globus pallidus;  multiple system atrophy;  neuromodulation

Funding details
Medtronic
Multiple System Atrophy CoalitionMSA

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

Longitudinal Patterns of Brain Changes in a Community Sample in Relation to Aging and Cognitive Status
(2023) Journal of Alzheimer’s Disease: JAD, 94 (3), pp. 1035-1045. 

Chwa, W.J.^a b , Lopez, O.L.^c , Longstreth, W.T.^d , Dai, W.^e , Raji, C.A.^b

^a Saint Louis University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^d Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, United States
^e Department of Computer Science, State University of New York at Binghamton, Binghamton, NY, United States

Abstract
BACKGROUND: Aging and Alzheimer’s disease (AD) are characterized by widespread cortical and subcortical atrophy. Though atrophy patterns between aging and AD overlap considerably, regional differences between these two conditions may exist. Few studies, however, have investigated these patterns in large community samples. OBJECTIVE: Elaborate longitudinal changes in brain morphometry in relation to aging and cognitive status in a well-characterized community cohort. METHODS: Clinical and neuroimaging data were compiled from 72 participants from the Cardiovascular Health Study-Cognition Study, a community cohort of healthy aging and probable AD participants. Two time points were identified for each participant with a mean follow-up time of 5.36 years. MRI post-processing, morphometric measurements, and statistical analyses were performed using FreeSurfer, Version 7.1.1. RESULTS: Cortical volume was significantly decreased in the bilateral superior frontal, bilateral inferior parietal, and left superior parietal regions, among others. Cortical thickness was significantly reduced in the bilateral superior frontal and left inferior parietal regions, among others. Overall gray and white matter volumes and hippocampal subfields also demonstrated significant reductions. Cortical volume atrophy trajectories between cognitively stable and cognitively declined participants were significantly different in the right postcentral region. CONCLUSION: Observed volume reductions were consistent with previous studies investigating morphometric brain changes. Patterns of brain atrophy between AD and aging may be different in magnitude but exhibit widespread spatial overlap. These findings help characterize patterns of brain atrophy that may reflect the general population. Larger studies may more definitively establish population norms of aging and AD-related neuroimaging changes.

Author Keywords
Aging;  Alzheimer’s disease;  cognition;  cognitive dysfunction;  neuroimaging

Document Type: Article
Publication Stage: Final
Source: Scopus

Effect of exercise engagement and cardiovascular risk on neuronal injury
(2023) Alzheimer’s and Dementia, . 

Stojanovic, M.^a b , Schindler, S.E.^b c , Morris, J.C.^b c , Head, D.^a c d

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^c Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
INTRODUCTION: Neuronal health as a potential underlying mechanism of the beneficial effects of exercise has been understudied in humans. Furthermore, there has been limited consideration of potential moderators (e.g., cardiovascular health) on the effects of exercise. METHODS: Clinically normal middle-aged and older adults completed a validated questionnaire about exercise engagement over a 10-year period (n = 75; age 63 ± 8 years). A composite estimate of neuronal injury was formulated that included cerebrospinal fluid-based measures of visinin-like protein-1, neurogranin, synaptosomal-associated protein 25, and neurofilament light chain. Cardiovascular risk was estimated using the Framingham Risk Score. RESULTS: Cross-sectional analyses showed that greater exercise engagement was associated with less neuronal injury in the group with lower cardiovascular risk (p = 0.008), but not the group with higher cardiovascular risk (p = 0.209). DISCUSSION: Cardiovascular risk is an important moderator to consider when examining the effects of exercise on cognitive and neural health, and may be relevant to personalized exercise recommendations. Highlights: We examined the association between exercise engagement and neuronal injury. Vascular risk moderated the association between exercise and neuronal injury. Cardiovascular risk may be relevant to personalized exercise recommendations. © 2023 the Alzheimer’s Association.

Author Keywords
cardiovascular risk;  NfL;  Ng;  SNAP-25;  VILIP-1

Funding details
National Institutes of HealthNIHK23AG053426, P01AG003991, P01AG026276, P30AG066444, R01AG070941, U19AG024904, U19AG032438

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

Advancing specificity in delirium: The delirium subtyping initiative
(2023) Alzheimer’s and Dementia, . 

Bowman, E.M.L.^a b , Brummel, N.E.^c , Caplan, G.A.^d , Cunningham, C.^e , Evered, L.A.^f g h , Fiest, K.M.^{i j k l m} , Girard, T.D.ⁿ , Jackson, T.A.^o , LaHue, S.C.^p q r , Lindroth, H.L.^s t , Maclullich, A.M.J.^u , McAuley, D.F.^b , Oh, E.S.^v , Oldham, M.A.^w , Page, V.J.^x , Pandharipande, P.P.^y , Potter, K.M.ⁿ , Sinha, P.^z , Slooter, A.J.C.^aa ab , Sweeney, A.M.^a , Tieges, Z.^u ac , Van Dellen, E.^aa ab , Wilcox, M.E.^ad , Zetterberg, H.^{ae af ag ah ai aj} , Cunningham, E.L.^a

^a Centre for Public Health, Queen’s University Belfast, Block B, Institute of Clinical Sciences, Royal Victoria Hospital Site, Belfast, United Kingdom
^b Centre for Experimental Medicine, Queen’s University Belfast, Wellcome-Wolfson Institute for Experimental Medicine, Belfast, United Kingdom
^c The Ohio State University College of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Columbus, OH, United States
^d Department of Geriatric Medicine, Prince of Wales Hospital, Sydney, Australia University of New South Wales, Sydney, Australia
^e School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
^f Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States
^g Department of Critical Care, University of Melbourne, Melbourne, Australia
^h Department of Anaesthesia & Acute Pain Medicine, St. Vincent’s Hospital, Melbourne, Australia
ⁱ Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
^j Department of Critical Care Medicine, University of Calgary and Alberta Health Services, Calgary, AB, Canada
^k O’Brien Institute for Public Health, University of Calgary, Calgary, AB, Canada
^l Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
^m Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
ⁿ Clinical Research, Investigation, and Systems Modeling of Acute Illness (CRISMA) Center, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^o Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom
^p Department of Neurology, School of Medicine, University of California, San Francisco, CA, United States
^q Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA, United States
^r Buck Institute for Research on Aging, Novato, CA, United States
^s Department of Nursing, Mayo Clinic, Rochester, MN, United States
^t Center for Aging Research, Regenstrief Institute, School of Medicine, Indiana University, Indianapolis, IN, United States
^u Edinburgh Delirium Research Group, Ageing and Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom
^v Departments of Medicine, Psychiatry and Behavioral Sciences and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^w Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, United States
^x Department of Anaesthetics, Watford General Hospital, Watford, United Kingdom
^y Departments of Anesthesiology and Surgery, Division of Anesthesiology Critical Care Medicine and Critical Illness, Brain Dysfunction, and Survivorship Center, Vanderbilt University Medical Center, Nashville, TN, United States
^z Division of Clinical and Translational Research, Washington University School of Medicine, St. Louis, MO, United States
^aa Departments of Psychiatry and Intensive Care Medicine and UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
^ab Department of Neurology, UZ Brussel and Vrije Universiteit Brussel, Brussels, Belgium
^ac School of Computing, Engineering and Built Environment, Glasgow Caledonian University, Glasgow, United Kingdom
^ad Department of Critical Care Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
^ae Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
^af Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^ag Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
^ah UK Dementia Research Institute at UCL, London, United Kingdom
^ai Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong
^aj Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin–Madison, Madison, WI, United States

Abstract
BACKGROUND: Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long-term outcomes. Recording and analyzing all delirium equally could be hindering the field’s understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology. METHODS: The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts. RESULTS: Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium-spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations. DISCUSSION: The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes. Highlights: Delirium features must be clearly defined, standardized, and operationalized. Large datasets incorporating both clinical and biomarker variables should be analyzed together. Delirium screening should incorporate communication and reasoning. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
acute encephalopathy;  biomarkers;  clinical features;  cognitive change;  delirium;  endotype;  subphenotype;  subtype

Funding details
P30 AG044281
National Institutes of HealthNIHR01AG057725, R01AG076525
National Institute on AgingNIAR03AG074035
Larry L. Hillblom FoundationLLHFA137420
National Heart and Lung InstituteNHLIT32HL007820
Research Institute for Aging, University of WaterlooRIAK23AG076662

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

An economic model and evidence of the evolution of human intelligence in the Middle Pleistocene: Climate change and assortative mating
(2023) PloS One, 18 (8), p. e0287964. 

Petersen, B.C.

Department of Economics, Washington University, St. Louis, MO, United States

Abstract
A main objective of this paper is to provide the first model of how climate change, working through sexual selection, could have led to dramatic increases in hominin brain size, and presumably intelligence, in the Middle Pleistocene. The model is built using core elements from the field of family economics, including assortative mating and specialization and complementarities between mates. The main assumptions are that family public goods (e.g., conversation, shelter, fire) were particularly cognitively intensive to produce and became increasingly important for child survival during glacial phases. Intermediate climates (e.g., not the depths of severe glacial phases) create the largest gains from specialization, encouraging negative assortative mating. In contrast, severe glacial phases encourage positive assortative mating because of the rising importance of family public goods. One testable hypothesis is that absence of severe glacial phases should have led to stasis in brain size. Two other testable hypotheses are that severe glacial phases should have led to speciation events, as well as increases in brain size. The evidence shows that there was a million-year stasis in cranial size prior to the start of the severe glacial phases. This stasis is broken by a speciation event (Homo heidelbergensis), with the oldest fossil evidence dated near the close of the first severe glacial phase. In the next 300 kyr, there are two additional severe glacial phases, accompanied by considerable increases in cranial capacity. The last speciation event is Homo sapiens, with the earliest fossils dated near the end of the last of these two glacial phases. Copyright: © 2023 Bruce C. Petersen. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Document Type: Article
Publication Stage: Final
Source: Scopus