WashU weekly Neuroscience publications: May 28, 2023

Effects of a virtual voice-based coach delivering problem-solving treatment on emotional distress and brain function: a pilot RCT in depression and anxiety
(2023) Translational Psychiatry, 13 (1), art. no. 166, . 

Kannampallil, T.^a b , Ajilore, O.A.^c , Lv, N.^d , Smyth, J.M.^e , Wittels, N.E.^d , Ronneberg, C.R.^d , Kumar, V.^d , Xiao, L.^f , Dosala, S.^d , Barve, A.^d , Zhang, A.^c , Tan, K.C.^d , Cao, K.K.^d , Patel, C.R.^d , Gerber, B.S.^g , Johnson, J.A.^e , Kringle, E.A.^d , Ma, J.^d

^a Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^b Institute for Informatics, Washington University School of Medicine, St Louis, MO, United States
^c Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, United States
^d Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
^e Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, United States
^f Department of Epidemiology and Population Health, Stanford University, Stanford, United States
^g Department of Population & Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, United States

Abstract
Consumer-based voice assistants have the ability to deliver evidence-based treatment, but their therapeutic potential is largely unknown. In a pilot trial of a virtual voice-based coach, Lumen, delivering problem-solving treatment, adults with mild-to-moderate depression and/or anxiety were randomized to the Lumen intervention (n = 42) or waitlist control (n = 21). The main outcomes included changes in neural measures of emotional reactivity and cognitive control, and Hospital Anxiety and Depression Scale [HADS] symptom scores over 16 weeks. Participants were 37.8 years (SD = 12.4), 68% women, 25% Black, 24% Latino, and 11% Asian. Activation of the right dlPFC (neural region of interest in cognitive control) decreased in the intervention group but increased in the control group, with an effect size meeting the prespecified threshold for a meaningful effect (Cohen’s d = 0.3). Between-group differences in the change in activation of the left dlPFC and bilateral amygdala were observed, but were of smaller magnitude (d = 0.2). Change in right dlPFC activation was also meaningfully associated (r ≥ 0.4) with changes in self-reported problem-solving ability and avoidance in the intervention. Lumen intervention also led to decreased HADS depression, anxiety, and overall psychological distress scores, with medium effect sizes (Cohen’s d = 0.49, 0.51, and 0.55, respectively), compared with the waitlist control group. This pilot trial showed promising effects of a novel digital mental health intervention on cognitive control using neuroimaging and depression and anxiety symptoms, providing foundational evidence for a future confirmatory study. © 2023, The Author(s).

Funding details
National Institute of Mental HealthNIMHR61MH119237

Document Type: Article
Publication Stage: Final
Source: Scopus

Resting-state MRI functional connectivity as a neural correlate of multidomain lifestyle adherence in older adults at risk for Alzheimer’s disease
(2023) Scientific Reports, 13 (1), art. no. 7487, . 

Ai, M.^a , Morris, T.P.^b , Zhang, J.^a , de la Colina, A.N.^c , Tremblay-Mercier, J.^d e , Villeneuve, S.^d e f , Whitfield-Gabrieli, S.^a , Kramer, A.F.^a g , Geddes, M.R.^c d h , Aisen, P.^h i , Anthal, E.^d e , Appleby, M.^d e , Bellec, P.^d h j , Benbouhoud, F.^e , Bohbot, V.^d e f , Brandt, J.^k , Breitner, J.C.S.^d e f , Brunelle, C.^d e , Chakravarty, M.^d e f , Cheewakriengkrai, L.^d e l , Collins, L.^d h m , Couture, D.^e , Craft, S.ⁿ , Dadar, M.^f h , Daoust, L.-A.^d , Das, S.^h o , Dauar-Tedeschi, M.^d e l , Dea, D.^d e , Desrochers, N.^d e , Dubuc, S.^e , Duclair, G.^d e , Dufour, M.^d e , Eisenberg, M.^p , El-Khoury, R.^d e , Etienne, P.^d e f , Evans, A.^d e m , Faubert, A.-M.^e , Ferdinand, F.^d e , Fonov, V.^m o , Fontaine, D.^d e , Francoeur, R.^d e , Frenette, J.^d e , Gagné, G.^d e , Gauthier, S.^{c d e f l} , Gervais, V.^d e , Giles, R.^d e , Gonneaud, J.^d e , Gordon, R.^d e , Greco, C.^d e , Hoge, R.^c d m , Hudon, L.^d , Ituria-Medina, Y.^c d m o , Kat, J.^d e m , Kazazian, C.^d e , Kligman, S.^d e , Kostopoulos, P.^m q , Labonté, A.^d e , Lafaille-Magnan, M.-E.^d e r , Lee, T.^d e , Leoutsakos, J.-M.^k , Leppert, I.^d e h , Madjar, C.^d e h , Mahar, L.^d e , Maltais, J.-R.^d e l , Mathieu, A.^e , Mathotaarachchi, S.^e l , Mayrand, G.^d e , McSweeney, M.^r , Meyer, P.-F.^d e r , Michaud, D.^e , Miron, J.^d e r , Morris, J.C.^s , Multhaup, G.^t , Münter, L.-M.^t , Nair, V.^e f l , Near, J.^e f , Newbold-Fox, H.^e , Nilsson, N.^d e r , Pagé, V.^e , Pascoal, T.A.^c d e l , Petkova, M.^d e h , Picard, C.^d e , Binette, A.P.^d e , Pogossova, G.^d e , Poirier, J.^d e f , Rajah, N.^d e q , Remz, J.^e , Rioux, P.^h , Rosa-Neto, P.^d e f l , Sager, M.A.^u , Saint-Fort, E.F.^e , Savard, M.^d e , Soucy, J.-P.^h o , Sperling, R.A.^v , Spreng, N.^h , St-Onge, F.^d e r , Tardif, C.^d e , Théroux, L.^d e , Thomas, R.G.^w , Toussaint, P.-J.^h o , Tuwaig, M.^d e , Vachon-Presseau, E.^e x , Vallée, I.^d e , Venugopalan, V.^d e , Wan, K.^d e , Wang, S.^e l r , for the PREVENT-AD Research Group^y

^a Department of Psychology, Northeastern University, Boston, MA, United States
^b Department of Physical Therapy, Movement and Rehabilitation Sciences, Northeastern University, Boston, MA, United States
^c Department of Neurology and Neurosurgery, Faculty of Medicine, McGill University, Montreal, QC, Canada
^d STOP-AD Centre, Centre for Studies on Prevention of Alzheimer’s Disease, Montreal, QC, Canada
^e Douglas Mental Health University Institute Research Centre, Affiliated with, McGill University, Montreal, QC, Canada
^f Department of Psychiatry, McGill University, Montreal, QC, Canada
^g Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana Champaign, Urbana-Champaign, IL, United States
^h Montreal Neurological Institute, Montreal, QC, Canada
ⁱ Alzheimer’s Therapeutic Research Institute at University of Southern California, San Diego, CA, United States
^j Université de Montréal, Montreal, QC, Canada
^k John Hopkins University, Baltimore, MD, United States
^l Research Centre for Studies in Aging, McGill University, Montreal, QC, Canada
^m Department of Biomedical Engineering, McGill University, Montreal, QC, Canada
ⁿ Wake Forest School of Medicine, Winston-Salem, NC, United States
^o McConnell Brain Imaging Center, McGill University, Montreal, QC, Canada
^p School of Population and Global Health, McGill University, Montreal, QC, Canada
^q Department of Psychology, McGill University, Montreal, QC, Canada
^r Neuroscience Department, McGill University, Montreal, QC, Canada
^s Washington University School of Medecine in St-Louis, St. Louis, MO, United States
^t Department of Pharmacology, McGill University, Montreal, QC, Canada
^u Wisconsin Alzheimer’s Institute, UW School of Medicine and Public Health, Milwaukee, WI, United States
^v Center for Alzheimer’s Research and Treatment Harvard Medical School, Boston, MA, United States
^w School of Medicine, University California, San Diego, La JollaCA, United States
^x Northwestern University, Chicago, IL, United States

Abstract
Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer’s disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need. The current study included 139 healthy older adults with familial risk for AD from the Prevent-AD longitudinal aging cohort. Self-reported exercise engagement, cognitive activity engagement, healthy diet adherence, and social activity engagement were included to examine potential phenotypes of an individual’s lifestyle adherence. Two adherence profiles were discovered using data-driven clustering methodology [i.e., Adherence to healthy lifestyle (AL) group and Non-adherence to healthy lifestyle group]. Resting-state functional connectivity matrices and grey matter brain features obtained from magnetic resonance imaging were used to classify the two groups using a support vector machine (SVM). The SVM classifier was 75% accurate in separating groups. The features that show consistently high importance to the classification model were functional connectivity mainly between nodes located in different prior-defined functional networks. Most nodes were located in the default mode network, dorsal attention network, and visual network. Our results provide preliminary evidence of neurobiological characteristics underlying multidomain healthy lifestyle choices. © 2023, The Author(s).

Funding details
NIG-17-08
Alzheimer’s AssociationAANIRG-397028
Canadian Institutes of Health ResearchIRSCPJT-148963
Natural Sciences and Engineering Research Council of CanadaNSERC
Alzheimer Society
Fonds de Recherche du Québec – SantéFRQS
Canada Research Chairs

Document Type: Article
Publication Stage: Final
Source: Scopus

Cognitive and neural bases of visual-context-guided decision-making
(2023) NeuroImage, 275, art. no. 120170, . 

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

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

Abstract
Humans adjust their behavioral strategies based on feedback, a process that may depend on intrinsic preferences and contextual factors such as visual salience. In this study, we hypothesized that decision-making based on visual salience is influenced by habitual and goal-directed processes, which can be evidenced by changes in attention and subjective valuation systems. To test this hypothesis, we conducted a series of studies to investigate the behavioral and neural mechanisms underlying visual salience-driven decision-making. We first established the baseline behavioral strategy without salience in Experiment 1 (n = 21). We then highlighted the utility or performance dimension of the chosen outcome using colors in Experiment 2 (n = 30). We demonstrated that the difference in staying frequency increased along the salient dimension, confirming a salience effect. Furthermore, the salience effect was abolished when directional information was removed in Experiment 3 (n = 28), suggesting that the salience effect is feedback-specific. To generalize our findings, we replicated the feedback-specific salience effects using eye-tracking and text emphasis. The fixation differences between the chosen and unchosen values were enhanced along the feedback-specific salient dimension in Experiment 4 (n = 48) but unchanged after removing feedback-specific information in Experiment 5 (n = 32). Moreover, the staying frequency was correlated with fixation properties, confirming that salience guides attention deployment. Lastly, our neuroimaging study (Experiment 6, n = 25) showed that the striatum subregions encoded salience-based outcome evaluation, while the vmPFC encoded salience-based behavioral adjustments. The connectivity of the vmPFC-ventral striatum accounted for individual differences in utility-driven, whereas the vmPFC-dmPFC for performance-driven behavioral adjustments. Together, our results provide a neurocognitive account of how task-irrelevant visual salience drives decision-making by involving attention and the frontal-striatal valuation systems. Public significance statement: Humans may use the current outcome to make behavior adjustments. How this occurs may depend on stable individual preferences and contextual factors, such as visual salience. Under the hypothesis that visual salience determines attention and subsequently modulates subjective valuation, we investigated the underlying behavioral and neural bases of visual-context-guided outcome evaluation and behavioral adjustments. Our findings suggest that the reward system is orchestrated by visual context and highlight the critical role of attention and the frontal-striatal neural circuit in visual-context-guided decision-making that may involve habitual and goal-directed processes. © 2023

Author Keywords
Attention;  Behavioral adjustment;  Outcome evaluation;  Striatum;  Subjective valuation;  Visual salience

Funding details
56045090
National Science FoundationNSFBCS-1945230
National Institutes of HealthNIHR01MH129426
Japan Society for the Promotion of ScienceKAKEN22K15626

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuroinflammation and white matter alterations in occupational manganese exposure assessed by diffusion basis spectrum imaging
(2023) NeuroToxicology, 97, pp. 25-33. 

Criswell, S.R.^a b , Nielsen, S.S.^b , Faust, I.M.^a b , Shimony, J.S.^b c , White, R.L., 3rd^b d , Lenox-Krug, J.^b , Racette, B.A.^a b e

^a Department of Neurology, Barrow Neurological Institute, 2910 N. 3rd Ave, Phoenix, AZ 85013, United States
^b Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^c Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S. Kingshighway Blvd, St. Louis, MO 63110, United States
^d John Cochran Division, St. Louis VA Medical Center, Neurology Section, 915 N. Grand Blvd, St. Louis, MO 63106, United States
^e School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 27 Andrews Rd, Parktown, 2193, South Africa

Abstract
Objective: To evaluate in-vivo neuroinflammation and white matter (WM) microstructural integrity in occupational manganese (Mn) exposure. Methods: We assessed brain inflammation using Diffusion Basis Spectrum Imaging (DBSI) in 26 Mn-exposed welders, 17 Mn-exposed workers, and 26 non-exposed participants. Cumulative Mn exposure was estimated from work histories and the Unified Parkinson’s Disease Rating Scale motor subsection 3 (UPDRS3) scores were completed by a movement specialist. Tract-based Spatial Statistics allowed for whole-brain voxel-wise WM analyses to compare WM DBSI-derived measures between the Mn-exposed and non-exposed groups. Exploratory grey matter region of interest (ROI) analyses examined the presence of similar alterations in the basal ganglia. We used voxelwise general linear modeling and linear regression to evaluate the association between cumulative Mn exposure, WM or basal ganglia DBSI metrics, and UPDRS3 scores, while adjusting for age. Results: Mn-exposed welders had higher DBSI-derived restricted fraction (DBSI-RF), higher DBSI-derived nonrestricted fraction (DBSI-NRF), and lower DBSI-derived fiber fraction (DBSI-FF) in multiple WM tracts (all p < 0.05) in comparison to less-exposed workers and non-exposed participants. Basal ganglia ROI analyses revealed higher average caudate DBSI-NRF and DBSI-derived radial diffusion (DBSI-RD) values in Mn-exposed welders relative to non-exposed participants (p < 0.05). Caudate DBSI-NRF was also associated with greater cumulative Mn exposure and higher UPRDS3 scores. Conclusions: Mn-exposed welders demonstrate greater DBSI-derived indicators of neuroinflammation-related cellularity (DBSI-RF), greater extracellular edema (DBSI-NRF), and lower apparent axonal density (DBSI-FF) in multiple WM tracts suggesting a neuroinflammatory component in the pathophysiology of Mn neurotoxicity. Caudate DBSI-NRF was positively associated with both cumulative Mn exposure and clinical parkinsonism, indicating a possible dose-dependent effect on extracellular edema with associated motor effects. © 2023 The Authors

Author Keywords
Biomarkers;  DBSI;  Manganese;  MRI;  Neurotoxicology

Funding details
National Institutes of HealthNIHICTS UL1RR024992, K01ES028295, K23ES021444, K24ES017765, P42ES004696, R01ES013743, R01ES021488–02S1, R01ES029524
American Parkinson Disease AssociationAPDA

Document Type: Article
Publication Stage: Final
Source: Scopus

Unsupervised high-frequency smartphone-based cognitive assessments are reliable, valid, and feasible in older adults at risk for Alzheimer’s disease
(2023) Journal of the International Neuropsychological Society: JINS, 29 (5), pp. 459-471. Cited 3 times.

Nicosia, J.^a , Aschenbrenner, A.J.^a , Balota, D.A.^b , Sliwinski, M.J.^c , Tahan, M.^a , Adams, S.^a , Stout, S.S.^a , Wilks, H.^a , Gordon, B.A.^b d , Benzinger, T.L.S.^d , Fagan, A.M.^a , Xiong, C.^a e , Bateman, R.J.^a , Morris, J.C.^a , Hassenstab, J.^a b

^a Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^b Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Human Development and Family Studies, Pennsylvania State University, University ParkPA, United States
^d Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
^e Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE: Smartphones have the potential for capturing subtle changes in cognition that characterize preclinical Alzheimer’s disease (AD) in older adults. The Ambulatory Research in Cognition (ARC) smartphone application is based on principles from ecological momentary assessment (EMA) and administers brief tests of associative memory, processing speed, and working memory up to 4 times per day over 7 consecutive days. ARC was designed to be administered unsupervised using participants’ personal devices in their everyday environments. METHODS: We evaluated the reliability and validity of ARC in a sample of 268 cognitively normal older adults (ages 65-97 years) and 22 individuals with very mild dementia (ages 61-88 years). Participants completed at least one 7-day cycle of ARC testing and conventional cognitive assessments; most also completed cerebrospinal fluid, amyloid and tau positron emission tomography, and structural magnetic resonance imaging studies. RESULTS: First, ARC tasks were reliable as between-person reliability across the 7-day cycle and test-retest reliabilities at 6-month and 1-year follow-ups all exceeded 0.85. Second, ARC demonstrated construct validity as evidenced by correlations with conventional cognitive measures (r = 0.53 between composite scores). Third, ARC measures correlated with AD biomarker burden at baseline to a similar degree as conventional cognitive measures. Finally, the intensive 7-day cycle indicated that ARC was feasible (86.50% approached chose to enroll), well tolerated (80.42% adherence, 4.83% dropout), and was rated favorably by older adult participants. CONCLUSIONS: Overall, the results suggest that ARC is reliable and valid and represents a feasible tool for assessing cognitive changes associated with the earliest stages of AD.

Author Keywords
digital biomarkers;  ecological momentary assessment;  mobile testing;  preclinical Alzheimer’s disease

Document Type: Article
Publication Stage: Final
Source: Scopus

Resting-state cortical hubs in youth organize into four categories
(2023) Cell Reports, 42 (5), art. no. 112521, . 

Demeter, D.V.^a , Gordon, E.M.^b , Nugiel, T.^c , Garza, A.^d , Larguinho, T.L.^d , Church, J.A.^d

^a Department of Cognitive Science, University of California San Diego, La Jolla, CA 92093, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
^d Department of Psychology, The University of Texas at Austin, Austin, TX 78712, United States

Abstract
During childhood, neural systems supporting high-level cognitive processes undergo periods of rapid growth and refinement, which rely on the successful coordination of activation across the brain. Some coordination occurs via cortical hubs—brain regions that coactivate with functional networks other than their own. Adult cortical hubs map into three distinct profiles, but less is known about hub categories during development, when critical improvement in cognition occurs. We identify four distinct hub categories in a large youth sample (n = 567, ages 8.5–17.2), each exhibiting more diverse connectivity profiles than adults. Youth hubs integrating control-sensory processing split into two distinct categories (visual control and auditory/motor control), whereas adult hubs unite under one. This split suggests a need for segregating sensory stimuli while functional networks are experiencing rapid development. Functional coactivation strength for youth control-processing hubs are associated with task performance, suggesting a specialized role in routing sensory information to and from the brain’s control system. © 2023 The Author(s)

Author Keywords
cortical hubs;  CP: Neuroscience;  executive functions;  fMRI;  functional connectivity;  resting state

Funding details
20141031a
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA051016, U01DA051018, U01DA051037, U01DA051038, U01DA051039, U24DA041123, U24DA041147
National Institute of Mental HealthNIMH
Brain and Behavior Research FoundationBBRF
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDR21 HD081437

Document Type: Article
Publication Stage: Final
Source: Scopus

Mechanically manipulating glymphatic transport by ultrasound combined with microbubbles
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (21), pp. e2212933120. 

Ye, D.^a , Chen, S.^a , Liu, Y.^a , Weixel, C.^a , Hu, Z.^a , Yuan, J.^a , Chen, H.^a b c d

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

Abstract
The glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transport is believed to be driven by the perivascular pumping effect created by the pulsation of the arterial wall caused by the cardiac cycle. Ultrasound sonication of circulating microbubbles (MBs) in the cerebral vasculature induces volumetric expansion and contraction of MBs that push and pull on the vessel wall to generate a MB pumping effect. The objective of this study was to evaluate whether glymphatic transport can be mechanically manipulated by focused ultrasound (FUS) sonication of MBs. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as fluid tracers, followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected MBs. Intracisternal magna injection, the conventional technique used in studying glymphatic transport, was employed to provide a comparative reference. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space (PVS) along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the PVS into the interstitial space. This study revealed that ultrasound combined with circulating MBs could mechanically enhance glymphatic transport in the brain.

Author Keywords
cerebral blood vessels;  focused ultrasound;  glymphatic;  intranasal;  mechanics

Document Type: Article
Publication Stage: Final
Source: Scopus

Modulating fast skeletal muscle contraction protects skeletal muscle in animal models of Duchenne muscular dystrophy
(2023) The Journal of Clinical Investigation, 133 (10), . 

Russell, A.J.^a , DuVall, M.^a , Barthel, B.^a , Qian, Y.^a , Peter, A.K.^a , Newell-Stamper, B.L.^a , Hunt, K.^a , Lehman, S.^a , Madden, M.^a , Schlachter, S.^a , Robertson, B.^a , Van Deusen, A.^a , Rodriguez, H.M.^b , Vera, C.^c , Su, Y.^d , Claflin, D.R.^e , Brooks, S.V.^d , Nghiem, P.^f , Rutledge, A.^f , Juehne, T.I.^g , Yu, J.^g , Barton, E.R.^h , Luo, Y.E.^h , Patsalos, A.ⁱ , Nagy, L.ⁱ , Sweeney, H.L.^j , Leinwand, L.A.^c , Koch, K.^a

^a BioFrontiers Institute, University of Colorado, Boulder, CO, United States
^b Palo Alto, CA, United States
^c Department of Molecular, Cellular, Developmental Biology and BioFrontiers Institute, University of Colorado, Boulder, CO, United States
^d Molecular and Integrative Physiology and
^e Department of Surgery, Section of Plastic Surgery, University of Michigan, Ann Arbor, MI, United States
^f Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College StationTX, United States
^g Genome Technology Access Center, Department of Genetics, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA
^h Department of Applied Physiology and Kinesiology and Myology Institute, University of Florida College of Health and Human Performance, Gainesville, FL, United States
ⁱ Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States
^j Department of Pharmacology and Therapeutics and Myology Institute, University of Florida College of Medicine, Gainesville, FL, United States

Abstract
Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

Author Keywords
Muscle Biology;  Neuromuscular disease;  Skeletal muscle;  Therapeutics

Document Type: Article
Publication Stage: Final
Source: Scopus

TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma
(2023) Science Advances, 9 (19), p. eade3559. 

Sun, R.^a , Han, R.^a , McCornack, C.^a , Khan, S.^a , Tabor, G.T.^b , Chen, Y.^b c , Hou, J.^c , Jiang, H.^d , Schoch, K.M.^b e , Mao, D.D.^a , Cleary, R.^a , Yang, A.^a , Liu, Q.^d , Luo, J.^f g , Petti, A.^a h i , Miller, T.M.^b e , Ulrich, J.D.^b e , Holtzman, D.M.^b e j , Kim, A.H.^{a b h i k}

^a Department of Neurological Surgery, Washington University School of MedicineMO, United States
^b Department of Neurology, Washington University School of MedicineMO, United States
^c Department of Pathology and Immunology, Washington University School of MedicineMO, United States
^d Department of Anesthesiology, Washington University School of MedicineMO, United States
^e Hope Center for Neurological Disorders, Washington University in St. LouisMO, United States
^f Department of Surgery, Washington University School of MedicineMO, United States
^g Division of Biostatistics, Washington University School of MedicineMO, United States
^h Department of Genetics, Washington University School of MedicineMO, United States
ⁱ Brain Tumor Center, Siteman Cancer Center, Washington University School of MedicineMO, United States
^j Center for Science and Engineering of Living Systems, Washington University in St. LouisMO, United States
^k Department of Developmental Biology, Washington University School of MedicineMO, United States

Abstract
Triggering receptor expressed on myeloid cells 2 (TREM2) plays important roles in brain microglial function in neurodegenerative diseases, but the role of TREM2 in the GBM TME has not been examined. Here, we found that TREM2 is highly expressed in myeloid subsets, including macrophages and microglia in human and mouse GBM tumors and that high TREM2 expression correlates with poor prognosis in patients with GBM. TREM2 loss of function in human macrophages and mouse myeloid cells increased interferon-γ-induced immunoactivation, proinflammatory polarization, and tumoricidal capacity. In orthotopic mouse GBM models, mice with chronic and acute Trem2 loss of function exhibited decreased tumor growth and increased survival. Trem2 inhibition reprogrammed myeloid phenotypes and increased programmed cell death protein 1 (PD-1)+CD8+ T cells in the TME. Last, Trem2 deficiency enhanced the effectiveness of anti-PD-1 treatment, which may represent a therapeutic strategy for patients with GBM.

Document Type: Article
Publication Stage: Final
Source: Scopus

Two forms of asynchronous release with distinctive spatiotemporal dynamics in central synapses
(2023) eLife, 12, . 

Malagon, G., Myeong, J., Klyachko, V.A.

Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, United States

Abstract
Asynchronous release is a ubiquitous form of neurotransmitter release that persists for tens to hundreds of milliseconds after an action potential. How asynchronous release is organized and regulated at the synaptic active zone (AZ) remains debatable. Using nanoscale-precision imaging of individual release events in rat hippocampal synapses, we observed two spatially distinct subpopulations of asynchronous events, ~75% of which occurred inside the AZ and with a bias towards the AZ center, while ~25% occurred outside of the functionally defined AZ, that is, ectopically. The two asynchronous event subpopulations also differed from each other in temporal properties, with ectopic events occurring at significantly longer time intervals from synchronous events than the asynchronous events inside the AZ. Both forms of asynchronous release did not, to a large extent, utilize the same release sites as synchronous events. The two asynchronous event subpopulations also differ from synchronous events in some aspects of exo-endocytosis coupling, particularly in the contribution from the fast calcium-dependent endocytosis. These results identify two subpopulations of asynchronous release events with distinctive organization and spatiotemporal dynamics. © 2023, Malagon, Myeong et al.

Author Keywords
active zone;  asynchronous release;  neuroscience;  neurotransmitter release;  presynaptic organization;  rat;  synaptic terminals

Document Type: Article
Publication Stage: Final
Source: Scopus

Neighborhood Deprivation and Association with Neonatal Intensive Care Unit Mortality and Morbidity for Extremely Premature Infants
(2023) JAMA Network Open, 6 (5), p. E2311761. Cited 1 time.

Sullivan, B.A.^a , Doshi, A.^b , Chernyavskiy, P.^c , Husain, A.^d , Binai, A.^d , Sahni, R.^e , Fairchild, K.D.^e , Moorman, J.R.^f , Travers, C.P.^g , Vesoulis, Z.A.^d

^a Division of Neonatology, Department of Pediatrics, University of Virginia, School of Medicine, Charlottesville, United States
^b University of Virginia, School of Medicine, Charlottesville, United States
^c Department of Public Health Sciences, University of Virginia, School of Medicine, Charlottesville, United States
^d Division of Newborn Medicine, Department of Pediatrics, Washington University in St Louis, St Louis, MO, United States
^e Division of Neonatology, Department of Pediatrics, Columbia University Vagelos, College of Physicians and Surgeons, New York, NY, United States
^f Division of Cardiology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, United States
^g Division of Neonatology, Department of Pediatrics, University of Alabama at Birmingham, United States

Abstract
Importance: Socioeconomic status affects pregnancy and neurodevelopment, but its association with hospital outcomes among premature infants is unknown. The Area Deprivation Index (ADI) is a validated measure of neighborhood disadvantage that uses US Census Bureau data on income, educational level, employment, and housing quality. Objective: To determine whether ADI is associated with neonatal intensive care unit (NICU) mortality and morbidity in extremely premature infants. Design, Setting, and Participants: This retrospective cohort study was performed at 4 level IV NICUs in the US Northeast, Mid-Atlantic, Midwest, and South regions. Non-Hispanic White and Black infants with gestational age of less than 29 weeks and born between January 1, 2012, and December 31, 2020, were included in the analysis. Addresses were converted to census blocks, identified by Federal Information Processing Series codes, to link residences to national ADI percentiles. Exposures: ADI, race, birth weight, sex, and outborn status. Main Outcomes and Measures: In the primary outcome, the association between ADI and NICU mortality was analyzed using bayesian logistic regression adjusted for race, birth weight, outborn status, and sex. Risk factors were considered significant if the 95% credible intervals excluded zero. In the secondary outcome, the association between ADI and NICU morbidities, including late-onset sepsis, necrotizing enterocolitis (NEC), and severe intraventricular hemorrhage (IVH), were also analyzed. Results: A total of 2765 infants with a mean (SD) gestational age of 25.6 (1.7) weeks and mean (SD) birth weight of 805 (241) g were included in the analysis. Of these, 1391 (50.3%) were boys, 1325 (47.9%) reported Black maternal race, 498 (18.0%) died before NICU discharge, 692 (25.0%) developed sepsis or NEC, and 353 (12.8%) had severe IVH. In univariate analysis, higher median ADI was found among Black compared with White infants (77 [IQR, 45-93] vs 57 [IQR, 32-77]; P <.001), those who died before NICU discharge vs survived (71 [IQR, 45-89] vs 64 [IQR, 36-86]), those with late-onset sepsis or NEC vs those without (68 [IQR, 41-88] vs 64 [IQR, 35-86]), and those with severe IVH vs those without (69 [IQR, 44-90] vs 64 [IQR, 36-86]). In a multivariable bayesian logistic regression model, lower birth weight, higher ADI, and male sex were risk factors for mortality (95% credible intervals excluded zero), while Black race and outborn status were not. The ADI was also identified as a risk factor for sepsis or NEC and severe IVH. Conclusions and Relevance: The findings of this cohort study of extremely preterm infants admitted to 4 NICUs in different US geographic regions suggest that ADI was a risk factor for mortality and morbidity after adjusting for multiple covariates.. © 2023 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Mitigating the Associations of Kidney Dysfunction with Blood Biomarkers of Alzheimer Disease by Using Phosphorylated Tau to Total Tau Ratios
(2023) JAMA Neurology, 80 (5), pp. 516-522. 

Janelidze, S.^a , Barthélemy, N.R.^b c , He, Y.^b c , Bateman, R.J.^b c , Hansson, O.^a d

^a Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
^b Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
^c The Tracy Family SILQ Center, St Louis, MO, United States
^d Skåne University Hospital, Malmö, Sweden

Abstract
Importance: Chronic kidney disease (CKD) has been associated with increased plasma concentrations of phosphorylated tau (p-tau) 217 and p-tau181, which potentially decreases their usefulness in the diagnostic workup of Alzheimer disease (AD). Objective: To investigate associations of CKD with plasma ratios of p-tau217 and p-tau181 to the corresponding unphosphorylated peptides in AD. Design, Setting, and Participants: This cross-sectional study included patients with mild cognitive impairment (cohort 1; enrollment in 2000-2005) and replication in cohort 2 from the Swedish BioFINDER-2 study, including both cognitively unimpaired individuals and those with cognitive impairment (enrollment in 2017-2022). All participants were from 2 memory clinics in Sweden and had plasma tau assessments and CKD status established within 6 months of plasma collection. Exposures: P-tau217 and p-tau181, unphosphorylated peptides (Tau212-221 and Tau181-190), and the ratios (pT217/T217 and pT181/T181) as well as estimated glomerular filtration rate (eGFR) as an indicator of CKD. Main Outcomes and Measures: Associations between plasma-soluble p-tau and CKD. Results: A total of 141 participants from cohort 1 (mean [SD] age, 72.2 [7.7] years; 82 [58.2%] women) and 332 participants from cohort 2 (172 with cognitive impairment and 160 cognitively unimpaired individuals; mean [SD] age, 69.8 [9.4] years; 169 [50.9%] women) were included. Higher eGFR was associated with increased levels of plasma p-tau217, p-tau181, Tau212-221, and Tau181-190 in individuals with cognitive impairment (cohort 1: R range, -0.24 to -0.59; P <.004; cohort 2: R range, -0.18 to -0.53; P <.02) and cognitively unimpaired individuals (cohort 2: R range, -0.44 to -0.50; P <.001). However, eGFR did not correlate with the pT217/T217 ratio in patients with cognitive impairment (cohort 1: R, -0.11; P =.19; cohort 2: R, -0.02; P =.78), and the correlations with pT217/T217 ratio were significantly attenuated in cognitively unimpaired individuals (difference: R, -0.14 [95% CI, -0.22 to -0.007]; P =.001). For p-tau217 and pT217/T217, the mean fold increases in amyloid-β positive (Aβ+) compared with Aβ- groups ranged from 2.31 (95% CI, 1.86-2.77) to 4.61 (95% CI, 3.39-5.83) in participants with cognitive impairment and from 1.26 (95% CI, 0.98-1.55) to 1.27 (95% CI, 0.94-1.59) in cognitively unimpaired individuals and were clearly higher than the mean fold increases in those with CKD compared with those without CKD, ranging from 0.05 (95% CI, -0.28 to 0.38) to 0.72 (95% CI, 0.25-1.19) in participants with cognitive impairment and from 0.09 (95% CI, -0.08 to 0.26) to 0.36 (95% CI, 0.19-0.52) in cognitively unimpaired individuals. Conclusions and Relevance: In this study, CKD was associated with increased plasma levels of soluble tau, but for p-tau217 the associations were considerably lower than the association with Aβ positivity. Importantly, the ratios, and especially pT217/T217, were less associated with CKD than p-tau forms alone and therefore are likely to more accurately reflect AD-related pathological changes.. © 2023 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of Sex with Neurobehavioral Markers of Executive Function in 2-Year-Olds at High and Low Likelihood of Autism
(2023) JAMA Network Open, 6 (5), p. E2311543. 

St. John, T.^a b , Estes, A.M.^a b , Hazlett, H.C.^c d , Marrus, N.^e , Burrows, C.A.^f , Donovan, K.^g , Torres Gomez, S.^h , Grzadzinski, R.L.^c d , Parish-Morris, J.ⁱ , Smith, R.^c , Styner, M.^c d , Garic, D.^c d , Pandey, J.ⁱ , Lee, C.M.^f , Schultz, R.T.ⁱ , Botteron, K.N.^e , Zwaigenbaum, L.^j , Piven, J.^c d , Dager, S.R.^k

^a Department of Speech and Hearing Science, University of Washington, Seattle, United States
^b University of Washington Autism Center, University of Washington, Seattle, United States
^c Carolina Institute for Developmental Disabilities, Carrboro, NC, United States
^d Department of Psychiatry, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, United States
^e Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^f Department of Pediatrics, University of Minnesota, Minneapolis, United States
^g Department of Biostatistics, University of Pennsylvania, Philadelphia, United States
^h McGill Centre for Integrative Neuroscience, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
ⁱ Center for Autism Research, Children’s Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, Philadelphia, United States
^j Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
^k Department of Radiology, University of Washington Medical Center, Seattle, United States

Abstract
Importance: Children with autism and their siblings exhibit executive function (EF) deficits early in development, but associations between EF and biological sex or early brain alterations in this population are largely unexplored. Objective: To investigate the interaction of sex, autism likelihood group, and structural magnetic resonance imaging alterations on EF in 2-year-old children at high familial likelihood (HL) and low familial likelihood (LL) of autism, based on having an older sibling with autism or no family history of autism in first-degree relatives. Design, Setting, and Participants: This prospective cohort study assessed 165 toddlers at HL (n = 110) and LL (n = 55) of autism at 4 university-based research centers. Data were collected from January 1, 2007, to December 31, 2013, and analyzed between August 2021 and June 2022 as part of the Infant Brain Imaging Study. Main Outcomes and Measures: Direct assessments of EF and acquired structural magnetic resonance imaging were performed to determine frontal lobe, parietal lobe, and total cerebral brain volume. Results: A total of 165 toddlers (mean [SD] age, 24.61 [0.95] months; 90 [54%] male, 137 [83%] White) at HL for autism (n = 110; 17 diagnosed with ASD) and LL for autism (n = 55) were studied. The toddlers at HL for autism scored lower than the toddlers at LL for autism on EF tests regardless of sex (mean [SE] B = -8.77 [4.21]; 95% CI, -17.09 to -0.45; η2p= 0.03). With the exclusion of toddlers with autism, no group (HL vs LL) difference in EF was found in boys (mean [SE] difference, -7.18 [4.26]; 95% CI, 1.24-15.59), but EF was lower in HL girls than LL girls (mean [SE] difference, -9.75 [4.34]; 95% CI, -18.32 to -1.18). Brain-behavior associations were examined, controlling for overall cerebral volume and developmental level. Sex differences in EF-frontal (B [SE] = 16.51 [7.43]; 95% CI, 1.36-31.67; η2p= 0.14) and EF-parietal (B [SE] = 17.68 [6.99]; 95% CI, 3.43-31.94; η2p= 0.17) associations were found in the LL group but not the HL group (EF-frontal: B [SE] = -1.36 [3.87]; 95% CI, -9.07 to 6.35; η2p= 0.00; EF-parietal: B [SE] = -2.81 [4.09]; 95% CI, -10.96 to 5.34; η2p= 0.01). Autism likelihood group differences in EF-frontal (B [SE] = -9.93 [4.88]; 95% CI, -19.73 to -0.12; η2p= 0.08) and EF-parietal (B [SE] = -15.44 [5.18]; 95% CI, -25.86 to -5.02; η2p= 0.16) associations were found in girls not boys (EF-frontal: B [SE] = 6.51 [5.88]; 95% CI, -5.26 to 18.27; η2p= 0.02; EF-parietal: B [SE] = 4.18 [5.48]; 95% CI, -6.78 to 15.15; η2p= 0.01). Conclusions and Relevance: This cohort study of toddlers at HL and LL of autism suggests that there is an association between sex and EF and that brain-behavior associations in EF may be altered in children at HL of autism. Furthermore, EF deficits may aggregate in families, particularly in girls.. © 2023 American Medical Association. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Diminished Auditory Cortex Dynamic Range and its Clinical Correlates in First Episode Psychosis
(2023) Schizophrenia Bulletin, 49 (3), pp. 679-687. 

Sklar, A.L.^a , Ren, X.^a b , Chlpka, L.^a c , Curtis, M.^a d , Coffman, B.A.^a , Salisbury, D.F.^a

^a Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^b Laureate Institute for Brain Research, Tulsa, OK, United States
^c College of Medicine, Northeast Ohio Medical UniversityOH, United States
^d Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
BACKGROUND AND HYPOTHESIS: There is growing appreciation for the contribution of sensory disruptions to disease morbidity in psychosis. The present study examined auditory cortex (AC) dynamic range: the scaling of neurophysiological responses to stimulus intensity, among individuals with a schizophrenia spectrum illness (FESz) and its relationship to clinical outcomes at disease onset. STUDY DESIGN: Magnetoencephalography (MEG) was recorded from 35 FESz and 40 healthy controls (HC) during binaural presentation of tones at three intensities (75 dB, 80 dB, and 85 dB). MRIs were obtained to enhance cortical localization of MEG sensor-level activity. All participants completed the MATRICS cognitive battery (MCCB) and Global Functioning: Role and Social scales (GFR/GFS). Patients were administered the Positive and Negative Syndrome Scale (PANSS). STUDY RESULTS: FESz exhibited reduced AC response relative to HC. Enhancement of AC activity to tones of increasing intensity was blunted in FESz relative to HC. Reduced dynamic range (85-75 dB AC response) was associated with lower GFS (r = .58) and GFR (r = .45) scores, worse MCCB performance (r = .45), and increased PANSS Negative symptom subscale scores (r = -.55) among FESz, relationships not observed with AC responses to individual tones. CONCLUSION: Beyond an impaired AC response to pure tones, FESz exhibit reduced dynamic range relative to HC. This impairment was correlated with markers of disease morbidity including poorer community functioning as well as cognitive and negative symptoms. The relationship with impaired social functioning may reflect the role of AC dynamic range in decoding the emotional content of language and highlights its importance to future therapeutic sensory remediation protocols. © The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
auditory processing;  first episode psychosis;  magnetoencephalography;  psychometric function;  social functioning;  sound intensity

Document Type: Article
Publication Stage: Final
Source: Scopus

Insular and Striatal Correlates of Uncertain Risky Reward Pursuit in Schizophrenia
(2023) Schizophrenia Bulletin, 49 (3), pp. 726-737. 

Purcell, J.R.^a b c , Brown, J.W.^a b , Tullar, R.L.^a , Bloomer, B.F.^a , Kim, D.-J.^a , Moussa-Tooks, A.B.^a b d , Dolan-Bennett, K.^a e , Bangert, B.M.^b f , Wisner, K.M.^a b , Lundin, N.B.^a b g , O’Donnell, B.F.^a b , Hetrick, W.P.^a b

^a Department of Psychological & Brain Sciences, Indiana University, Bloomington, IN, United States
^b Program in Neuroscience, Indiana University, Bloomington, IN, United States
^c Department of Psychiatry, Brain Health Institute, Rutgers University, Piscataway, NJ, United States
^d Department of Psychiatry and Behavioral Sciences, Vanderbilt University School of Medicine, Nashville, TN, United States
^e Department of Psychological and Brain Science, Washington University, St. LouiseMO, United States
^f College of Medicine, University of Cincinnati, Cincinnati, OH, United States
^g Department of Psychiatry and Behavioral Health, Ohio State University, Columbus, OH, United States

Abstract
BACKGROUND AND HYPOTHESIS: Risk-taking in specific contexts can be beneficial, leading to rewarding outcomes. Schizophrenia is associated with disadvantageous decision-making, as subjects pursue uncertain risky rewards less than controls. However, it is unclear whether this behavior is associated with more risk sensitivity or less reward incentivization. Matching on demographics and intelligence quotient (IQ), we determined whether risk-taking was more associated with brain activation in regions affiliated with risk evaluation or reward processing. STUDY DESIGN: Subjects (30 schizophrenia/schizoaffective disorder, 30 controls) completed a modified, fMRI Balloon Analogue Risk Task. Brain activation was modeled during decisions to pursue risky rewards and parametrically modeled according to risk level. STUDY RESULTS: The schizophrenia group exhibited less risky-reward pursuit despite previous adverse outcomes (Average Explosions; F(1,59) = 4.06, P = .048) but the comparable point at which risk-taking was volitionally discontinued (Adjusted Pumps; F(1,59) = 2.65, P = .11). Less activation was found in schizophrenia via whole brain and region of interest (ROI) analyses in the right (F(1,59) = 14.91, P < 0.001) and left (F(1,59) = 16.34, P < 0.001) nucleus accumbens (NAcc) during decisions to pursue rewards relative to riskiness. Risk-taking correlated with IQ in schizophrenia, but not controls. Path analyses of average ROI activation revealed less statistically determined influence of anterior insula upon dorsal anterior cingulate bilaterally (left: χ2 = 12.73, P < .001; right: χ2 = 9.54, P = .002) during risky reward pursuit in schizophrenia. CONCLUSIONS: NAcc activation in schizophrenia varied less according to the relative riskiness of uncertain rewards compared to controls, suggesting aberrations in reward processing. The lack of activation differences in other regions suggests similar risk evaluation. Less insular influence on the anterior cingulate may relate to attenuated salience attribution or inability for risk-related brain region collaboration to sufficiently perceive situational risk. © The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
cingulate;  decision-making;  fMRI;  nucleus accumbens;  Psychosis;  risk-taking;  schizoaffective disorder

Funding details
Novartis
Macula Foundation

Document Type: Article
Publication Stage: Final
Source: Scopus

Assessment of Neuroanatomical Endophenotypes of Autism Spectrum Disorder and Association with Characteristics of Individuals with Schizophrenia and the General Population
(2023) JAMA Psychiatry, 80 (5), pp. 498-507. 

Hwang, G.^a , Wen, J.^a b , Sotardi, S.^c , Brodkin, E.S.^d , Chand, G.B.^a e , Dwyer, D.B.^f , Erus, G.^a , Doshi, J.^a , Singhal, P.^g , Srinivasan, D.^a , Varol, E.^a h , Sotiras, A.^a e , Dazzan, P.ⁱ , Kahn, R.S.^j , Schnack, H.G.^k , Zanetti, M.V.^l m , Meisenzahl, E.ⁿ , Busatto, G.F.^l , Crespo-Facorro, B.^o , Pantelis, C.^p , Wood, S.J.^q r s , Zhuo, C.^t u , Shinohara, R.T.^a v , Shou, H.^a v , Fan, Y.^a , Di Martino, A.^w , Koutsouleris, N.^f , Gur, R.E.^d , Gur, R.C.^d , Satterthwaite, T.D.^a d , Wolf, D.H.^a d , Davatzikos, C.^a

^a AI2D Center for Data Science for Integrated Diagnostics, Center for Biomedical Image Computing and Analytics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^b Laboratory of AI and Biomedical Science (LABS), Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, University of Southern California, Marina del Rey, United States
^c Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^d Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^e Department of Radiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^f Department of Psychiatry and Psychotherapy, Ludwig-Maximilian University, Munich, Germany
^g Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^h Department of Statistics, Zuckerman Institute, Columbia University, New York, NY, United States
ⁱ Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
^j Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^k Department of Psychiatry, University Medical Center Utrecht, Utrecht, Netherlands
^l Institute of Psychiatry, Faculty of Medicine, University of São Paulo, São Paulo, Brazil
^m Hospital Sírio-Libanês, São Paulo, Brazil
ⁿ LVR-Klinikum Düsseldorf, Kliniken der Heinrich-Heine-Universität, Düsseldorf, Germany
^o University Hospital Virgen Del Rocio, Department of Psychiatry, School of Medicine, IBiS-CIBERSAM, University of Sevilla, Seville, Spain
^p Melbourne Neuropsychiatry Centre, Department of Psychiatry, University of Melbourne and Melbourne Health, Carlton South, VIC, Australia
^q Orygen, Melbourne, VIC, Australia
^r Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia
^s School of Psychology, University of Birmingham, Edgbaston, United Kingdom
^t Department of Psychiatric, Neuroimaging-Genetics and Co-morbidity Laboratory, Tianjin Anding Hospital, Tianjin, China
^u Department of Psychiatry, Tianjin Medical University, Tianjin, China
^v Penn Statistics in Imaging and Visualization Center, Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^w Phyllis Green and Randolph Cowen Institute for Pediatric Neuroscience, New York University Child Study Center, New York, United States

Abstract
Importance: Autism spectrum disorder (ASD) is associated with significant clinical, neuroanatomical, and genetic heterogeneity that limits precision diagnostics and treatment. Objective: To assess distinct neuroanatomical dimensions of ASD using novel semisupervised machine learning methods and to test whether the dimensions can serve as endophenotypes also in non-ASD populations. Design, Setting, and Participants: This cross-sectional study used imaging data from the publicly available Autism Brain Imaging Data Exchange (ABIDE) repositories as the discovery cohort. The ABIDE sample included individuals diagnosed with ASD aged between 16 and 64 years and age- and sex-match typically developing individuals. Validation cohorts included individuals with schizophrenia from the Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging (PHENOM) consortium and individuals from the UK Biobank to represent the general population. The multisite discovery cohort included 16 internationally distributed imaging sites. Analyses were performed between March 2021 and March 2022. Main Outcomes and Measures: The trained semisupervised heterogeneity through discriminative analysis models were tested for reproducibility using extensive cross-validations. It was then applied to individuals from the PHENOM and the UK Biobank. It was hypothesized that neuroanatomical dimensions of ASD would display distinct clinical and genetic profiles and would be prominent also in non-ASD populations. Results: Heterogeneity through discriminative analysis models trained on T1-weighted brain magnetic resonance images of 307 individuals with ASD (mean [SD] age, 25.4 [9.8] years; 273 [88.9%] male) and 362 typically developing control individuals (mean [SD] age, 25.8 [8.9] years; 309 [85.4%] male) revealed that a 3-dimensional scheme was optimal to capture the ASD neuroanatomy. The first dimension (A1: aginglike) was associated with smaller brain volume, lower cognitive function, and aging-related genetic variants (FOXO3; Z = 4.65; P = 1.62 × 10-6). The second dimension (A2: schizophrenialike) was characterized by enlarged subcortical volumes, antipsychotic medication use (Cohen d = 0.65; false discovery rate-adjusted P =.048), partially overlapping genetic, neuroanatomical characteristics to schizophrenia (n = 307), and significant genetic heritability estimates in the general population (n = 14786; mean [SD] h2, 0.71 [0.04]; P < 1 × 10-4). The third dimension (A3: typical ASD) was distinguished by enlarged cortical volumes, high nonverbal cognitive performance, and biological pathways implicating brain development and abnormal apoptosis (mean [SD] β, 0.83 [0.02]; P = 4.22 × 10-6). Conclusions and Relevance: This cross-sectional study discovered 3-dimensional endophenotypic representation that may elucidate the heterogeneous neurobiological underpinnings of ASD to support precision diagnostics. The significant correspondence between A2 and schizophrenia indicates a possibility of identifying common biological mechanisms across the 2 mental health diagnoses.. © 2023 American Medical Association. All rights reserved.

Funding details
National Institutes of HealthNIHR01MH112070, R01MH123550
BrightFocus FoundationBFF
National Natural Science Foundation of ChinaNSFC
Federación Española de Enfermedades RarasFEDER
Ministerio de Economía y CompetitividadMINECO
Instituto de Salud Carlos IIIISCIII
European Regional Development FundERDF
Fundación Marqués de ValdecillaFMV

Document Type: Article
Publication Stage: Final
Source: Scopus

Integrative Imaging Informatics for Cancer Research: Workflow Automation for Neuro-Oncology (I3CR-WANO)
(2023) JCO Clinical Cancer Informatics, 7, p. e2200177. 

Chakrabarty, S.^a , Abidi, S.A.^b , Mousa, M.^b , Mokkarala, M.^b , Hren, I.^c , Yadav, D.^d , Kelsey, M.^b , LaMontagne, P.^b , Wood, J.^d , Adams, M.^d , Su, Y.^d , Thorpe, S.^d , Chung, C.^d , Sotiras, A.^b e , Marcus, D.S.^b

^a Department of Electrical and Systems Engineering, Washington University in St Louis, St Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
^c Department of Computer Science & Engineering, Washington University in St Louis, St Louis, MO, United States
^d Division of Radiation Oncology, Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States
^e Institute for Informatics, Washington University School of Medicine, St Louis, MO, United States

Abstract
PURPOSE: Efforts to use growing volumes of clinical imaging data to generate tumor evaluations continue to require significant manual data wrangling, owing to data heterogeneity. Here, we propose an artificial intelligence-based solution for the aggregation and processing of multisequence neuro-oncology MRI data to extract quantitative tumor measurements. MATERIALS AND METHODS: Our end-to-end framework (1) classifies MRI sequences using an ensemble classifier, (2) preprocesses the data in a reproducible manner, (3) delineates tumor tissue subtypes using convolutional neural networks, and (4) extracts diverse radiomic features. Moreover, it is robust to missing sequences and adopts an expert-in-the-loop approach in which the segmentation results may be manually refined by radiologists. After the implementation of the framework in Docker containers, it was applied to two retrospective glioma data sets collected from the Washington University School of Medicine (WUSM; n = 384) and The University of Texas MD Anderson Cancer Center (MDA; n = 30), comprising preoperative MRI scans from patients with pathologically confirmed gliomas. RESULTS: The scan-type classifier yielded an accuracy of >99%, correctly identifying sequences from 380 of 384 and 30 of 30 sessions from the WUSM and MDA data sets, respectively. Segmentation performance was quantified using the Dice Similarity Coefficient between the predicted and expert-refined tumor masks. The mean Dice scores were 0.882 (±0.244) and 0.977 (±0.04) for whole-tumor segmentation for WUSM and MDA, respectively. CONCLUSION: This streamlined framework automatically curated, processed, and segmented raw MRI data of patients with varying grades of gliomas, enabling the curation of large-scale neuro-oncology data sets and demonstrating high potential for integration as an assistive tool in clinical practice.

Document Type: Article
Publication Stage: Final
Source: Scopus

Measuring the cognitive effort associated with task switching in routine EHR-based tasks
(2023) Journal of Biomedical Informatics, 141, p. 104349. 

Bartek, B.^a , Lou, S.S.^b , Kannampallil, T.^c

^a Institute for Informatics, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^b Institute for Informatics, School of Medicine, Washington University in St Louis, St Louis, MO, United States; Department of Anesthesiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States
^c Institute for Informatics, School of Medicine, Washington University in St Louis, St Louis, MO, United States; Department of Anesthesiology, School of Medicine, Washington University in St Louis, St Louis, MO, United States; Department of Computer Science and Engineering, McKelvey School of Engineering, Washington University in St Louis, St Louis, MO, United States

Abstract
OBJECTIVE: Clinical work involves performing overlapping, time-sensitive tasks that frequently require clinicians to switch their attention between multiple tasks. We developed a methodological approach using EHR-based audit logs to determine switch costs-the cognitive burden associated with task switching-and assessed its magnitude during routine EHR-based clinical tasks. METHOD: Physician trainees (N = 75) participated in a longitudinal study where they provided access to their EHR-based audit logs. Physicians’ audit log actions were used to create a taxonomy of EHR tasks. These tasks were transformed into task sequences and the time spent on each task in a sequence was computed. Within these task sequences, instances of task switching (i.e., switching from one task to the next) and non-switching were identified. The primary outcome of interest was the time spent on a post-switch task. Using a mixed-effects regression model, we compared the durations of post-switch and non-switch tasks. RESULTS: 2,781,679 audit log events over 117,822 sessions from 75 physicians were analyzed. Physicians spent most time on chart review (Median (IQR) = 5,439 (2,492-8,336) seconds), note review (1,936 (827-3,321) seconds), and navigating the EHR interface (1,048 (365.5-2,006) seconds) daily. Post task switch activity times were greater for documentation (Median increase = 5 s), order entry (Median increase = 3 s) and results review (Median increase = 3 s). Mixed-effects regression showed that time spent on tasks were longer following a task switch (β = 0.03; 95% CIlower = 0.027, CIupper = 0.034), with greater post-swtich task times for imaging, order entry, note review, handoff, note entry, chart review and best practice advisory tasks. DISCUSSION: Increased task switching time-an indicator of the cognitive burden associated with switching between tasks-is prevalent in routine EHR-based tasks. We discuss the cumulative impact of incremental switch costs have on overall EHR workload, wellness, and error rates. Relying on theoretical cognitive foundations, we suggest pragmatic design considerations for mitigating the effects of cognitive burden associated with task switching. Copyright © 2023 Elsevier Inc. All rights reserved.

Author Keywords
Cognitive burden;  Cognitive science;  EHR audit logs;  Switch costs;  Task switching

Document Type: Article
Publication Stage: Final
Source: Scopus

Spike timing-dependent plasticity alters electrosensory neuron synaptic strength in vitro but does not consistently predict changes in sensory tuning in vivo
(2023) Journal of Neurophysiology, 129 (5), pp. 1127-1144. 

Lube, A.J., Ma, X., Carlson, B.A.

Department of Biology, Washington University in St. Louis, St. Louis, MO, United States

Abstract
How do sensory systems optimize detection of behaviorally relevant stimuli when the sensory environment is constantly changing? We addressed the role of spike timing-dependent plasticity (STDP) in driving changes in synaptic strength in a sensory pathway and whether those changes in synaptic strength could alter sensory tuning. It is challenging to precisely control temporal patterns of synaptic activity in vivo and replicate those patterns in vitro in behaviorally relevant ways. This makes it difficult to make connections between STDP-induced changes in synaptic physiology and plasticity in sensory systems. Using the mormyrid species Brevimyrus niger and Brienomyrus brachyistius, which produce electric organ discharges for electrolocation and communication, we can precisely control the timing of synaptic input in vivo and replicate these same temporal patterns of synaptic input in vitro. In central electrosensory neurons in the electric communication pathway, using whole cell intracellular recordings in vitro, we paired presynaptic input with postsynaptic spiking at different delays. Using whole cell intracellular recordings in awake, behaving fish, we paired sensory stimulation with postsynaptic spiking using the same delays. We found that Hebbian STDP predictably alters sensory tuning in vitro and is mediated by NMDA receptors. However, the change in synaptic responses induced by sensory stimulation in vivo did not adhere to the direction predicted by the STDP observed in vitro. Further analysis suggests that this difference is influenced by polysynaptic activity, including inhibitory interneurons. Our findings suggest that STDP rules operating at identified synapses may not drive predictable changes in sensory responses at the circuit level.NEW & NOTEWORTHY We replicated behaviorally relevant temporal patterns of synaptic activity in vitro and used the same patterns during sensory stimulation in vivo. There was a Hebbian spike timing-dependent plasticity (STDP) pattern in vitro, but sensory responses in vivo did not shift according to STDP predictions. Analysis suggests that this disparity is influenced by differences in polysynaptic activity, including inhibitory interneurons. These results suggest that STDP rules at synapses in vitro do not necessarily apply to circuits in vivo.

Author Keywords
Hebbian plasticity;  sensory processing;  synaptic plasticity;  temporal coding;  weakly electric fish

Document Type: Article
Publication Stage: Final
Source: Scopus

MYT1L is required for suppressing earlier neuronal development programs in the adult mouse brain
(2023) Genome Research, 33 (4), pp. 541-556. 

Chen, J.^a b , Fuhler, N.A.^b c , Noguchi, K.K.^b c , Dougherty, J.D.^b c d

^a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO 63108, United States
^d Department of Genetics, Washington University School of Medicine, St. Louis, Missouri 63110, USA;

Abstract
In vitro studies indicate the neurodevelopmental disorder gene myelin transcription factor 1-like (MYT1L) suppresses non-neuronal lineage genes during fibroblast-to-neuron direct differentiation. However, MYT1L’s molecular and cellular functions in the adult mammalian brain have not been fully characterized. Here, we found that MYT1L loss leads to up-regulated deep layer (DL) gene expression, corresponding to an increased ratio of DL/UL neurons in the adult mouse cortex. To define potential mechanisms, we conducted Cleavage Under Targets & Release Using Nuclease (CUT&RUN) to map MYT1L binding targets and epigenetic changes following MYT1L loss in mouse developing cortex and adult prefrontal cortex (PFC). We found MYT1L mainly binds to open chromatin, but with different transcription factor co-occupancies between promoters and enhancers. Likewise, multiomic data set integration revealed that, at promoters, MYT1L loss does not change chromatin accessibility but increases H3K4me3 and H3K27ac, activating both a subset of earlier neuronal development genes as well as Bcl11b, a key regulator for DL neuron development. Meanwhile, we discovered that MYT1L normally represses the activity of neurogenic enhancers associated with neuronal migration and neuronal projection development by closing chromatin structures and promoting removal of active histone marks. Further, we showed that MYT1L interacts with HDAC2 and transcriptional repressor SIN3B in vivo, providing potential mechanisms underlying repressive effects on histone acetylation and gene expression. Overall, our findings provide a comprehensive map of MYT1L binding in vivo and mechanistic insights into how MYT1L loss leads to aberrant activation of earlier neuronal development programs in the adult mouse brain. © 2023 Chen et al.; Published by Cold Spring Harbor Laboratory Press.

Document Type: Article
Publication Stage: Final
Source: Scopus

Maternal Immune Activation Induces Cortical Catecholaminergic Hypofunction and Cognitive Impairments in Offspring
(2023) Journal of Neuroimmune Pharmacology, . 

Perez-Palomar, B.^{a b c d e} , Erdozain, A.M.^a b , Erkizia-Santamaría, I.^a , Ortega, J.E.^a b c , Meana, J.J.^a b c

^a Department of Pharmacology, University of the Basque Country UPV/EHU, Leioa, Bizkaia, E-48940, Spain
^b Centro de Investigación Biomédica en Red de Salud Mental CIBERSAM, ISCIII, Leioa, Spain
^c Biocruces Bizkaia Health Research Institute, Bizkaia, Spain
^d Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63110, United States
^e Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy in St. Louis, St. Louis, MO 63110, United States

Abstract
Background: Impairment of specific cognitive domains in schizophrenia has been associated with prefrontal cortex (PFC) catecholaminergic deficits. Among other factors, prenatal exposure to infections represents an environmental risk factor for schizophrenia development in adulthood. However, it remains largely unknown whether the prenatal infection-induced changes in the brain may be associated with concrete switches in a particular neurochemical circuit, and therefore, if they could alter behavioral functions. Methods: In vitro and in vivo neurochemical evaluation of the PFC catecholaminergic systems was performed in offspring from mice undergoing maternal immune activation (MIA). The cognitive status was also evaluated. Prenatal viral infection was mimicked by polyriboinosinic-polyribocytidylic acid (poly(I:C)) administration to pregnant dams (7.5 mg/kg i.p., gestational day 9.5) and consequences were evaluated in adult offspring. Results: MIA-treated offspring showed disrupted recognition memory in the novel object recognition task (t = 2.30, p = 0.031). This poly(I:C)-based group displayed decreased extracellular dopamine (DA) concentrations compared to controls (t = 3.17, p = 0.0068). Potassium-evoked release of DA and noradrenaline (NA) were impaired in the poly(I:C) group (DA: Ft[10,90] = 43.33, p &lt; 0.0001; Ftr[1,90] = 1.224, p = 0.2972; Fi[10,90] = 5.916, p &lt; 0.0001; n = 11); (NA: Ft[10,90] = 36.27, p &lt; 0.0001; Ftr[1,90] = 1.841, p = 0.208; Fi[10,90] = 8.686, p &lt; 0.0001; n = 11). In the same way, amphetamine‐evoked release of DA and NA were also impaired in the poly(I:C) group (DA: Ft[8,328] = 22.01, p &lt; 0.0001; Ftr[1,328] = 4.507, p = 0.040; Fi[8,328] = 2.319, p = 0.020; n = 43); (NA: Ft[8,328] = 52.07; p &lt; 0.0001; Ftr[1,328] = 4.322; p = 0.044; Fi[8,398] = 5.727; p &lt; 0.0001; n = 43). This catecholamine imbalance was accompanied by increased dopamine D1 and D2 receptor expression (t = 2.64, p = 0.011 and t = 3.55, p = 0.0009; respectively), whereas tyrosine hydroxylase, DA and NA tissue content, DA and NA transporter (DAT/NET) expression and function were unaltered. Conclusions: MIA induces in offspring a presynaptic catecholaminergic hypofunction in PFC with cognitive impairment. This poly(I:C)-based model reproduces catecholamine phenotypes reported in schizophrenia and represents an opportunity for the study of cognitive impairment associated to this disorder. © 2023, The Author(s).

Author Keywords
Cognitive Impairment;  D1 Receptors;  D2 Receptors;  Dopamine;  Maternal Immune Activation;  Microdialysis;  Noradrenaline

Funding details
Janssen Pharmaceuticals
Eusko JaurlaritzaIT-1211-19, IT1512-22
Ministerio de Educación, Cultura y DeporteMECD
Ministerio de Ciencia e InnovaciónMICINN
European Regional Development FundERDF
Agencia Estatal de InvestigaciónAEI

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

A motor association area in the depths of the central sulcus
(2023) Nature Neuroscience, . 

Jensen, M.A.^a b , Huang, H.^a , Valencia, G.O.^c , Klassen, B.T.^d , van den Boom, M.A.^b c , Kaufmann, T.J.^e , Schalk, G.^b f g , Brunner, P.^h , Worrell, G.A.^c d , Hermes, D.^c , Miller, K.J.^b c

^a Medical Scientist Training Program, Mayo Clinic, Rochester, MN, United States
^b Neurosurgery, Mayo Clinic, Rochester, MN, United States
^c Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States
^d Neurology, Mayo Clinic, Rochester, MN, United States
^e Radiology, Mayo Clinic, Rochester, MN, United States
^f Chen Frontier Lab for Applied Neurotechnology, Tianqiao and Chrissy Chen Institute, Shanghai, China
^g Neurosurgery, Fudan University/Huashan Hospital, Shanghai, China
^h Neurosurgery, Washington University School of Medicine, St Louis, MO, United States

Abstract
Cells in the precentral gyrus directly send signals to the periphery to generate movement and are principally organized as a topological map of the body. We find that movement-induced electrophysiological responses from depth electrodes extend this map three-dimensionally throughout the gyrus. Unexpectedly, this organization is interrupted by a previously undescribed motor association area in the depths of the midlateral aspect of the central sulcus. This ‘Rolandic motor association’ (RMA) area is active during movements of different body parts from both sides of the body and may be important for coordinating complex behaviors. © 2023, The Author(s).

Funding details
National Institutes of HealthNIHP41-EB018783, R01-EB026439, U01-NS108916, U01-NS128612, U24-NS109103
Brain Research FoundationBRF
National Center for Advancing Translational SciencesNCATSCTSA KL2 TR002379

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

Design and feasibility of an Alzheimer’s disease blood test study in a diverse community-based population
(2023) Alzheimer’s and Dementia, . 

Li, M.^a b , Li, Y.^a b , Schindler, S.E.^a c d , Yen, D.^a , Sutcliffe, S.^e , Babulal, G.M.^a , Benzinger, T.L.S.^d f , Lenze, E.J.^g , Bateman, R.J.^a b c d

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b The Tracy Family Stable Isotope Labeling Quantitation Center for Neurodegenerative Biology, Washington University School of Medicine, St. Louis, MO, United States
^c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^d Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Surgery – Public Health Sciences, Washington University School of Medicine, St. Louis, MO, United States
^f Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
INTRODUCTION: Alzheimer’s disease (AD) blood tests are likely to become increasingly important in clinical practice, but they need to be evaluated in diverse groups before use in the general population. METHODS: This study enrolled a community-based sample of older adults in the St. Louis, Missouri, USA area. Participants completed a blood draw, Eight-Item Informant Interview to Differentiate Aging and Dementia (AD8®), Montreal Cognitive Assessment (MoCA), and survey about their perceptions of the blood test. A subset of participants completed additional blood collection, amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), and Clinical Dementia Rating (CDR®). RESULTS: Of the 859 participants enrolled in this ongoing study, 20.6% self-identified as Black or African American. The AD8 and MoCA correlated moderately with the CDR. The blood test was well accepted by the cohort, but it was perceived more positively by White and highly educated individuals. DISCUSSION: Studying an AD blood test in a diverse population is feasible and may accelerate accurate diagnosis and implementation of effective treatments. HIGHLIGHTS: A diverse group of older adults was recruited to evaluate a blood amyloid test. The enrollment rate was high and the blood test was well accepted by participants. Cognitive impairment screens have moderate performance in a diverse population. Alzheimer’s disease blood tests are likely to be feasible for use in real-world settings. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  amyloid PET;  blood test;  blood-based biomarkers;  clinical trial enrollment;  cognitive impairment;  dementia;  recruitment

Funding details
National Institutes of HealthNIHR56AG061900
National Center for Advancing Translational SciencesNCATS
Foundation for Barnes-Jewish HospitalFBJH
Institute of Clinical and Translational SciencesICTSUL1TR002345
GHR FoundationGHR

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

Generation of iPSC-derived human forebrain organoids assembling bilateral eye primordia
(2023) Nature Protocols, . 

Gabriel, E.^a , Albanna, W.^b c , Pasquini, G.^d , Ramani, A.^a , Josipovic, N.^e f , Mariappan, A.^a , Riparbelli, M.G.^g , Callaini, G.^g , Karch, C.M.^h , Goureau, O.ⁱ , Papantonis, A.^e f , Busskamp, V.^d , Schneider, T.^b , Gopalakrishnan, J.^a

^a Institute of Human Genetics, University Hospital, Heinrich-Heine-University, Düsseldorf, Germany
^b Institute for Neurophysiology, University of Cologne, Cologne, Germany
^c Department of Neurosurgery, RWTH Aachen University, Aachen, Germany
^d Department of Ophthalmology, Medical Faculty, University of Bonn, Bonn, Germany
^e Institute of Pathology, University Medicine Göttingen, Georg-August University Göttingen, Göttingen, Germany
^f Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
^g Department of Life Sciences and Medical Biotechnology University of Siena, Siena, Italy
^h Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Institut de la Vision, Sorbonne Université, INSERM, CNRS, Paris, France

Abstract
Induced pluripotent stem cell-derived brain organoids enable the developmental complexities of the human brain to be deconstructed. During embryogenesis, optic vesicles (OVs), the eye primordium attached to the forebrain, develop from diencephalon. However, most 3D culturing methods generate either brain or retinal organoids individually. Here we describe a protocol to generate organoids with both forebrain entities, which we call OV-containing brain organoids (OVB organoids). In this protocol, we first induce neural differentiation (days 0–5) and collect neurospheres, which we culture in a neurosphere medium to initiate their patterning and further self-assembly (days 5–10). Then, upon transfer to spinner flasks containing OVB medium (days 10–30), neurospheres develop into forebrain organoids with one or two pigmented dots restricted to one pole, displaying forebrain entities of ventral and dorsal cortical progenitors and preoptic areas. Further long-term culture results in photosensitive OVB organoids constituting complementary cell types of OVs, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections and electrically active neuronal networks. OVB organoids provide a system to help dissect interorgan interactions between the OVs as sensory organs and the brain as a processing unit, and can help model early eye patterning defects, including congenital retinal dystrophy. To conduct the protocol, experience in sterile cell culture and maintenance of human induced pluripotent stem cells is essential; theoretical knowledge of brain development is advantageous. Furthermore, specialized expertise in 3D organoid culture and imaging for the analysis is needed. © 2023, Springer Nature Limited.

Funding details
Deutsche ForschungsgemeinschaftDFGEXC-2151-390873048-Cluster, SPP2127-BU 2974/4-1
Volkswagen FoundationA110720
Fritz Thyssen Stiftung
Rheinische Friedrich-Wilhelms-Universität BonnUni Bonn

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

Twelve Weeks of Intermittent Caloric Restriction Diet Mitigates Neuroinflammation in Midlife Individuals with Multiple Sclerosis: A Pilot Study with Implications for Prevention of Alzheimer’s Disease
(2023) Journal of Alzheimer’s Disease: JAD, 93 (1), pp. 263-273. 

Rahmani, F.^a , Ghezzi, L.^b , Tosti, V.^b , Liu, J.^a c , Song, S.-K.^d e , Wu, A.T.^d e , Rajamanickam, J.^a , Obert, K.A.^b , Benzinger, T.L.S.^a f , Mittendorfer, B.^g , Piccio, L.^b e h i , Raji, C.A.^a f

^a Mallinckrodt Institute of Radiology, Division of Neuroradiology, 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 Department of Surgery, Division of Public Health Sciences, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Physics, Washington University in St. Louis, St. Louis, MO, United States
^e Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
^f Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St Louis, St. Louis, MO, United States
^g Department of Medicine, Division of Geriatrics and Nutritional Science, Washington University in St. Louis, St. Louis, MO, United States
^h Brain and Mind Centre, School of Medical Sciences, University of Sydney, NSW, Australia
ⁱ Charles Perkin Centre, University of Sydney NSW, Australia

Abstract
BACKGROUND: Multiple sclerosis (MS) is a prototype neuroinflammatory disorder with increasingly recognized role for neurodegeneration. Most first-line treatments cannot prevent the progression of neurodegeneration and the resultant disability. Interventions can improve symptoms of MS and might provide insights into the underlying pathology. OBJECTIVE: To investigate the effect of intermittent caloric restriction on neuroimaging markers of MS. METHODS: We randomized ten participants with relapsing remitting MS to either a 12-week intermittent calorie restriction (iCR) diet (n = 5) or control (n = 5). Cortical thickness and volumes were measured through FreeSurfer, cortical perfusion was measured by arterial spin labeling and neuroinflammation through diffusion basis spectrum imaging. RESULTS: After 12 weeks of iCR, brain volume increased in the left superior and inferior parietal gyri (p: 0.050 and 0.049, respectively) and the banks of the superior temporal sulcus (p: 0.01). Similarly in the iCR group, cortical thickness improved in the bilateral medial orbitofrontal gyri (p: 0.04 and 0.05 in right and left, respectively), the left superior temporal gyrus (p: 0.03), and the frontal pole (p: 0.008) among others. Cerebral perfusion decreased in the bilateral fusiform gyri (p: 0.047 and 0.02 in right and left, respectively) and increased in the bilateral deep anterior white matter (p: 0.03 and 0.013 in right and left, respectively). Neuroinflammation, demonstrated through hindered and restricted water fractions (HF and RF), decreased in the left optic tract (HF p: 0.02), and the right extreme capsule (RF p: 0.007 and HF p: 0.003). CONCLUSION: These pilot data suggest therapeutic effects of iCR in improving cortical volume and thickness and mitigating neuroinflammation in midlife adults with MS.

Author Keywords
Alzheimer’s disease;  arterial spin labeling;  caloric restriction;  diffusion basis spectrum imaging;  multiple sclerosis;  neuroinflammation;  prevention;  relative cerebral blood flow

Document Type: Article
Publication Stage: Final
Source: Scopus

Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG)
(2023) Journal of Neuromuscular Diseases, 10 (3), pp. 389-404. 

Finkel, R.S.^a b , Darras, B.T.^c , Mendell, J.R.^d e , Day, J.W.^f , Kuntz, N.L.^g , Connolly, A.M.^d e h , Zaidman, C.M.ⁱ , Crawford, T.O.^j , Butterfield, R.J.^k , Shieh, P.B.^l , Tennekoon, G.^m , Brandsema, J.F.^m , Iannaccone, S.T.ⁿ , Shoffner, J.^o p , Kavanagh, S.^o , Macek, T.A.^o , Tauscher-Wisniewski, S.^o

^a Center for Experimental Neurotherapeutics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Division of Neurology, Nemours Children’s Hospital, Orlando, FL, United States
^c Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^d Center for Gene Therapy, Nationwide Children’s Hospital, Columbus, OH, United States
^e Department of Pediatrics and Department of Neurology, Ohio State University, Columbus, OH, United States
^f Department of Neurology, Stanford University Medical Center, Stanford, CA, United States
^g Division of Neurology, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, United States
^h Division of Neurology, Nationwide Children’s Hospital, Columbus, OH, United States
ⁱ Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^k Department of Pediatrics, University of Utah Health, Salt Lake City, UT, United States
^l Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
^m Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁿ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
^o Bannockburn, IL, United States
^p Richmond, CA, United States

Abstract
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing. OBJECTIVE: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients. METHODS: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls. RESULTS: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01). CONCLUSIONS: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Author Keywords
Adeno-associated virus;  clinical trial;  gene therapy;  Hammersmith Functional Motor Scale Expanded;  intrathecal administration;  motor milestones;  neurodegenerative disorders;  onasemnogene abeparvovec;  spinal muscular atrophy;  vector genomes

Document Type: Article
Publication Stage: Final
Source: Scopus

Distress related to psychotic experiences: Enhancing the world health organization composite international diagnostic interview psychosis screen
(2023) International Journal of Methods in Psychiatric Research, . 

Oh, H.^a , Karcher, N.R.^b , Soffer-Dudek, N.^c , Koyanagi, A.^d , Besecker, M.^a , DeVylder, J.E.^e

^a Suzanne Dworak Peck School of Social Work, University of Southern California, Los Angeles, CA, United States
^b Washington University, St. Louis, MO, United States
^c Department of Psychology, Ben-Gurion University of the Negev, Beer-Sheva, Israel
^d Parc Sanitari Sant Joan de Deu, Sant Boi de Llobregat, Spain
^e Fordham University Graduate School of Social Service, New York, NY, United States

Abstract
Background: The abbreviated version of the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI) psychosis screen tends to yield high prevalence in online samples. Psychotic Experiences (PE) may not necessarily indicate current or imminent psychopathology; however, distressing PE appear to be more clinically informative. Methods: We analyzed data collected from an online survey administered to a Qualtrics panel (N = 2522 adults). Using multivariable logistic regression, we examined the association between PE (with and without associated distress) and several mental health outcomes, adjusting for age, gender, and race/ethnicity. Results: Individuals with distressing PE had greater odds of most mental health outcomes when compared with individuals with non-distressing PE. This was true for being in mental health treatment, loneliness, probable mental illness, suicidal ideation, and suicide attempt, adjusting for age, gender, race/ethnicity, and education level. The only exception was for hazardous alcohol use, for which there was no significant association with distressing PE. Conclusion: As screening for PE gains traction in public health and preventive medicine, using an abbreviated version of the WHO CIDI psychosis screen may be clinically informative, especially when eliciting the distressful nature of PE. © 2023 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.

Author Keywords
CIDI;  distress;  psychosis;  psychotic experiences;  WHO

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

CSF-Based Volumetric Imaging Biomarkers Highlight Incidence and Risk Factors for Cerebral Edema After Ischemic Stroke
(2023) Neurocritical Care, .

Bui, Q.^a , Kumar, A.^a , Chen, Y.^a , Hamzehloo, A.^a , Heitsch, L.^b , Slowik, A.^c , Strbian, D.^d , Lee, J.-M.^a , Dhar, R.^a

^a Department of Neurology, Washington University School of Medicine, 660 S Euclid Avenue, Campus Box 8111, St. Louis, MO, United States
^b Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Jagiellonian University Medical College, Krakow, Poland
^d Department of Neurology, Helsinki University Hospital, Helsinki, Finland

Abstract
Background: Cerebral edema has primarily been studied using midline shift or clinical deterioration as end points, which only captures the severe and delayed manifestations of a process affecting many patients with stroke. Quantitative imaging biomarkers that measure edema severity across the entire spectrum could improve its early detection, as well as identify relevant mediators of this important stroke complication. Methods: We applied an automated image analysis pipeline to measure the displacement of cerebrospinal fluid (ΔCSF) and the ratio of lesional versus contralateral hemispheric cerebrospinal fluid (CSF) volume (CSF ratio) in a cohort of 935 patients with hemispheric stroke with follow-up computed tomography scans taken a median of 26 h (interquartile range 24–31) after stroke onset. We determined diagnostic thresholds based on comparison to those without any visible edema. We modeled baseline clinical and radiographic variables against each edema biomarker and assessed how each biomarker was associated with stroke outcome (modified Rankin Scale at 90 days). Results: The displacement of CSF and CSF ratio were correlated with midline shift (r = 0.52 and − 0.74, p < 0.0001) but exhibited broader ranges. A ΔCSF of greater than 14% or a CSF ratio below 0.90 identified those with visible edema: more than half of the patients with stroke met these criteria, compared with only 14% who had midline shift at 24 h. Predictors of edema across all biomarkers included a higher National Institutes of Health Stroke Scale score, a lower Alberta Stroke Program Early CT score, and lower baseline CSF volume. A history of hypertension and diabetes (but not acute hyperglycemia) predicted greater ΔCSF but not midline shift. Both ΔCSF and a lower CSF ratio were associated with worse outcome, adjusting for age, National Institutes of Health Stroke Scale score, and Alberta Stroke Program Early CT score (odds ratio 1.7, 95% confidence interval 1.3–2.2 per 21% ΔCSF). Conclusions: Cerebral edema can be measured in a majority of patients with stroke on follow-up computed tomography using volumetric biomarkers evaluating CSF shifts, including in many without visible midline shift. Edema formation is influenced by clinical and radiographic stroke severity but also by chronic vascular risk factors and contributes to worse stroke outcomes. © 2023, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.

Author Keywords
Biomarkers;  Brain edema;  Computed tomography;  Imaging;  Stroke

Funding details
National Institutes of HealthNIHK23NS099440, K23NS099487, R01NS085419, R01NS121218, U24NS107230
Biogen

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

Epileptic spasms in CDKL5 deficiency disorder: Delayed treatment and poor response to first-line therapies
(2023) Epilepsia, .

Olson, H.E.^a , Demarest, S.^b , Pestana-Knight, E.^c , Moosa, A.N.^c , Zhang, X.^c , Pérez-Pérez, J.R.^c , Weisenberg, J.^d , O’Connor Prange, E.^e , Marsh, E.D.^e , Rajaraman, R.R.^f , Suter, B.^g , Katyayan, A.^g , Haviland, I.^a , Daniels, C.^a , Zhang, B.^h , Greene, C.^a , DeLeo, M.^a , Swanson, L.^a , Love-Nichols, J.^a , Benke, T.^b , Harini, C.^a , Poduri, A.^a

^a Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
^b Department of Pediatrics, School of Medicine, Children’s Hospital Colorado, University of Colorado, Aurora, CO, United States
^c Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
^d Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Division of Child Neurology, Children’s Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^f Division of Pediatric Neurology, David Geffen School of Medicine and UCLA Mattel Children’s Hospital, Los Angeles, CA, United States
^g Department of Pediatrics and Neurology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Houston, TX, United States
^h Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Objective: We aimed to assess the treatment response of infantile-onset epileptic spasms (ES) in CDKL5 deficiency disorder (CDD) vs other etiologies. Methods: We evaluated patients with ES from the CDKL5 Centers of Excellence and the National Infantile Spasms Consortium (NISC), with onset from 2 months to 2 years, treated with adrenocorticotropic hormone (ACTH), oral corticosteroids, vigabatrin, and/or the ketogenic diet. We excluded children with tuberous sclerosis complex, trisomy 21, or unknown etiology with normal development because of known differential treatment responses. We compared the two cohorts for time to treatment and ES remission at 14 days and 3 months. Results: We evaluated 59 individuals with CDD (79% female, median ES onset 6 months) and 232 individuals from the NISC database (46% female, median onset 7 months). In the CDD cohort, seizures prior to ES were common (88%), and hypsarrhythmia and its variants were present at ES onset in 34%. Initial treatment with ACTH, oral corticosteroids, or vigabatrin started within 1 month of ES onset in 27 of 59 (46%) of the CDD cohort and 182 of 232 (78%) of the NISC cohort (p <.0001). Fourteen-day clinical remission of ES was lower for the CDD group (26%, 7/27) than for the NISC cohort (58%, 106/182, p =.0002). Sustained ES remission at 3 months occurred in 1 of 27 (4%) of CDD patients vs 96 of 182 (53%) of the NISC cohort (p <.0001). Comparable results were observed with longer lead time (≥1 month) or prior treatment. Ketogenic diet, used within 3 months of ES onset, resulted in ES remission at 1 month, sustained at 3 months, in at least 2 of 13 (15%) individuals with CDD. Significance: Compared to the broad group of infants with ES, children with ES in the setting of CDD often experience longer lead time to treatment and respond poorly to standard treatments. Development of alternative treatments for ES in CDD is needed. © 2023 International League Against Epilepsy.

Author Keywords
adrenocorticotropic hormone;  CDD;  hypsarrhythmia;  National Infantile Spasms Consortium;  prednisolone;  vigabatrin

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSK23 NS107646‐05
International Rett Syndrome FoundationIRSF
HHT Foundation International
ACADIA PharmaceuticalsACADIA
Rett Syndrome Research TrustRSRT
Orphan Disease Center, Perelman School of Medicine, University of PennsylvaniaODC
Eagles Autism FoundationEAF
International Foundation for CDKL5 ResearchIFCR

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

Jansen-de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families
(2023) American Journal of Medical Genetics, Part A, . 

Wojcik, M.H.^a b c , Srivastava, S.^d , Agrawal, P.B.^c e , Balci, T.B.^f , Callewaert, B.^g , Calvo, P.L.^h , Carli, D.ⁱ , Caudle, M.^f , Colaiacovo, S.^f , Cross, L.^j , Demetriou, K.^k , Drazba, K.^l , Dutra-Clarke, M.^m , Edwards, M.ⁿ , Genetti, C.A.^b c , Grange, D.K.^o , Hickey, S.E.^p , Isidor, B.^q , Küry, S.^r , Lachman, H.M.^s , Lavillaureix, A.^t , Lyons, M.J.^l , Marcelis, C.^u , Marco, E.J.^v , Martinez-Agosto, J.A.^w , Nowak, C.^b , Pizzol, A.^h , Planes, M.^x , Prijoles, E.J.^l , Riberi, E.ⁱ , Rush, E.T.^y z aa , Russell, B.E.^w , Sachdev, R.^k ab , Schmalz, B.^p , Shears, D.^ac , Stevenson, D.A.^ad , Wilson, K.^ac , Jansen, S.^ae , de Vries, B.B.A.^ae , Curry, C.J.^af

^a Division of Newborn Medicine, Department of Pediatrics and Harvard Medical School, Boston Children’s Hospital, Boston, MA, United States
^b Division of Genetics and Genomics, Department of Pediatrics and Harvard Medical School, Boston Children’s Hospital, Boston, MA, United States
^c Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, United States
^d Department of Neurology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States
^e Division of Neonatology, Department of Pediatrics, Miller School of Medicine, University of Miami and Holtz Children’s Hospital, Jackson Health System, Miami, FL, United States
^f Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada
^g Center for Medical Genetics, Pediatrics Department, Ghent University Hospital, Ghent, Belgium
^h Pediatric Gastroenterology Unit, Regina Margherita Children’s Hospital, Azienda Ospedaliera-Universitaria Città della Salute e della Scienza, Turin, Italy
ⁱ Department of Public Health and Pediatrics, University of Torino, Torino, Italy
^j Clinical Genetics, Children’s Mercy Hospital, Kansas City, MO, United States
^k Centre for Clinical Genetics, Sydney Children’s Hospital, Sydney, NSW, Australia
^l Greenwood Genetic Center, Greenwood, SC, United States
^m Division of Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
ⁿ Paediatrics, School of Medicine, Western Sydney University, Hunter Genetics, Newcastle, NSW, Australia
^o Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^p Department of Pediatrics, The Ohio State University College of Medicine, Division of Genetic & Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
^q Department of Medical Genetics, Nantes Hospital, Nantes, France
^r Nantes Université, CHU Nantes, Service de Génétique Médicale, Nantes, France; Nantes Université, CHU Nantes, CNRS, INSERM, L’institut du thorax, Nantes, France
^s Departments of Behavioral Science, Medicine, and Psychiatry, Albert Einstein College of Medicine, Bronx, NY, United States
^t Service de Génétique Clinique, Centre de Référence Maladies Rares CLAD-Ouest, ERN ITHACA, CHU Rennes, Hôpital Sud, Rennes, France
^u Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
^v Cortica Healthcare, Marin Center, San Rafael, CA, United States
^w Division of Genetics, Departments of Pediatrics and Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, United States
^x Service de Génétique Clinique, University Hospital Morvan, Brest, France
^y UKMC School of Medicine, University of Missouri Kansas City, Kansas City, MO, United States
^z Division of Genetics, Children’s Mercy Kansas City, Kansas City, MO, United States
^aa Department of Internal Medicine, University of Kansas School of Medicine, Kansas City, MO, United States
^ab School of Women’s and Children’s Health, University of New South Wales, Sydney, NSW, Australia
^ac Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
^ad Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, CA, United States
^ae Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, Netherlands
^af Genetic Medicine, Department of Pediatrics, University of California San Francisco/Fresno, Fresno, CA, United States

Abstract
Jansen-de Vries syndrome (JdVS) is a neurodevelopmental condition attributed to pathogenic variants in Exons 5 and 6 of PPM1D. As the full phenotypic spectrum and natural history remain to be defined, we describe a large cohort of children and adults with JdVS. This is a retrospective cohort study of 37 individuals from 34 families with disease-causing variants in PPM1D leading to JdVS. Clinical data were provided by treating physicians and/or families. Of the 37 individuals, 27 were male and 10 female, with median age 8.75 years (range 8 months to 62 years). Four families document autosomal dominant transmission, and 32/34 probands were diagnosed via exome sequencing. The facial gestalt, including a broad forehead and broad mouth with a thin and tented upper lip, was most recognizable between 18 and 48 months of age. Common manifestations included global developmental delay (35/36, 97%), hypotonia (25/34, 74%), short stature (14/33, 42%), constipation (22/31, 71%), and cyclic vomiting (6/35, 17%). Distinctive personality traits include a hypersocial affect (21/31, 68%) and moderate-to-severe anxiety (18/28, 64%). In conclusion, JdVS is a clinically recognizable neurodevelopmental syndrome with a characteristic personality and distinctive facial features. The association of pathogenic variants in PPM1D with cyclic vomiting bears not only medical attention but also further pathogenic and mechanistic evaluation. © 2023 Wiley Periodicals LLC.

Author Keywords
cyclic vomiting;  developmental delay;  hypersocial personality;  Jansen-de Vries syndrome;  PPM1D

Funding details
912‐12‐109
K23 HD102589
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR21 MH131740
National Institute of Neurological Disorders and StrokeNINDSK23 NS119666
Albert Einstein College of Medicine, Yeshiva UniversityAECOM
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP30 HD071593

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

Neonatal subarachnoid hemorrhage disrupts multiple aspects of cerebellar development
(2023) Frontiers in Molecular Neuroscience, 16, art. no. 1161086, . 

Butler, D.F.^a e , Skibo, J.^b , Traudt, C.M.^c , Millen, K.J.^b d

^a Division of Pediatric Critical Care, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
^b Center for Integrative Brain Research, Seattle Children’s Research Institute, Seattle, WA, United States
^c Salem Health Hospitals and Clinics, Salem, OR, United States
^d Department of Pediatrics, University of Washington Medical School, Seattle, WA, United States
^e Division of Critical Care Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Over the past decade, survival rates for extremely low gestational age neonates (ELGANs; <28 weeks gestation) has markedly improved. Unfortunately, a significant proportion of ELGANs will suffer from neurodevelopmental dysfunction. Cerebellar hemorrhagic injury (CHI) has been increasingly recognized in the ELGANs population and may contribute to neurologic dysfunction; however, the underlying mechanisms are poorly understood. To address this gap in knowledge, we developed a novel model of early isolated posterior fossa subarachnoid hemorrhage (SAH) in neonatal mice and investigated both acute and long-term effects. Following SAH on postnatal day 6 (P6), we found significant decreased levels of proliferation with the external granular layer (EGL), thinning of the EGL, decreased Purkinje cell (PC) density, and increased Bergmann glial (BG) fiber crossings at P8. At P42, CHI resulted in decreased PC density, decreased molecular layer interneuron (MLI) density, and increased BG fiber crossings. Results from both Rotarod and inverted screen assays did not demonstrate significant effects on motor strength or learning at P35–38. Treatment with the anti-inflammatory drug Ketoprofen did not significantly alter our findings after CHI, suggesting that treatment of neuro-inflammation does not provide significant neuroprotection post CHI. Further studies are required to fully elucidate the mechanisms through which CHI disrupts cerebellar developmental programming in order to develop therapeutic strategies for neuroprotection in ELGANs. Copyright © 2023 Butler, Skibo, Traudt and Millen.

Author Keywords
cerebellar development;  cerebellar granule cells;  cerebellar hemorrhage;  preterm brain injury;  Purkinje cells

Funding details
National Institutes of HealthNIHR37NS095733

Document Type: Article
Publication Stage: Final
Source: Scopus

Setting boundaries: Development of neural and behavioral event cognition in early childhood
(2023) Developmental Science, . 

Benear, S.L.^a , Popal, H.S.^b , Zheng, Y.^c , Tanrıverdi, B.^b , Murty, V.P.^b , Perlman, S.B.^d , Olson, I.R.^b , Newcombe, N.S.^b

^a Department of Psychology, New York University, New York, NY, United States
^b Department of Psychology and Neuroscience, Temple University, Philadelphia, PA, United States
^c Department of Psychology, Northwestern University, Evanston, IL, United States
^d Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
The ongoing stream of sensory experience is so complex and ever-changing that we tend to parse this experience at “event boundaries,” which structures and strengthens memory. Memory processes undergo profound change across early childhood. Whether young children also divide their ongoing processing along event boundaries, and if those boundaries relate to memory, could provide important insight into the development of memory systems. In Study 1, 4–7-year-old children and adults segmented a cartoon, and we tested their memory. Children’s event boundaries were more variable than adults’ and differed in location and consistency of agreement. Older children’s event segmentation was more adult-like than younger children’s, and children who segmented events more like adults had better memory for those events. In Study 2, we asked whether these developmental differences in event segmentation had their roots in distinct neural representations. A separate group of 4–8-year-old children watched the same cartoon while undergoing an fMRI scan. In the right hippocampus, greater pattern dissimilarity across event boundaries compared to within events was evident for both child and adult behavioral boundaries, suggesting children and adults share similar event cognition. However, the boundaries identified by a data-driven Hidden Markov Model found that a different brain region—the left and right angular gyrus—aligned only with event boundaries defined by children. Overall, these data suggest that children’s event cognition is reasonably well-developed by age 4 but continues to become more adult-like across early childhood. RESEARCH HIGHLIGHTS: Adults naturally break their experience into events, which structures and strengthens memory, but less is known about children’s event perception and memory. Study 1 had adults and children segment and remember events from an animated show, and Study 2 compared those segmentations to other children’s fMRI data. Children show better recognition and temporal order memory and more adult-like event segmentation with age, and children who segment more like adults have better memory. Children’s and adults’ behavioral boundaries mapped onto pattern similarity differences in hippocampus, and children’s behavioral boundaries matched a data-driven model’s boundaries in angular gyrus. © 2023 John Wiley & Sons Ltd.

Author Keywords
cognitive development;  event cognition;  event segmentation;  Hidden Markov model;  memory development;  representational similarity analysis

Funding details
National Science FoundationNSF1625061
National Institutes of HealthNIHR01 HD099165, R01 MH124266, R21 HD098509
Army Research LaboratoryARLW911NF‐16‐2‐0189
Temple UniversityTU

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

Establishing the Reliability, Validity, and Prognostic Utility of the Momentary Pain Catastrophizing Scale for Use in Ecological Momentary Assessment Research
(2023) Journal of Pain, . 

Frumkin, M.R.^a , Greenberg, J.K.^b , Boyd, P.^c , Javeed, S.^b , Shayo, B.^c , Shin, J.^a , Wilson, E.A.^c , Zhang, J.K.^b , Sullivan, M.J.L.^d , Haroutounian, S.^c , Rodebaugh, T.L.^a

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, Missouri, United States
^b Department of Neurosurgery, Washington University School of Medicine, St. Louis, Missouri, United States
^c Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri, United States
^d Department of Psychology, McGill University, Montreal, QC, Canada

Abstract
Despite the marked increase in ecological momentary assessment research, few reliable and valid measures of momentary experiences have been established. The goal of this preregistered study was to establish the reliability, validity, and prognostic utility of the momentary Pain Catastrophizing Scale (mPCS), a 3-item measure developed to assess situational pain catastrophizing. Participants in 2 studies of postsurgical pain outcomes completed the mPCS 3 to 5 times per day prior to surgery (N = 494, T = 20,271 total assessments). The mPCS showed good psychometric properties, including multilevel reliability and factor invariance across time. Participant-level average mPCS was strongly positively correlated with dispositional pain catastrophizing as assessed by the Pain Catastrophizing Scale (r = .55 and .69 in study 1 and study 2, respectively). To establish prognostic utility, we then examined whether the mPCS improved prediction of postsurgical pain outcomes above and beyond one-time assessment of dispositional pain catastrophizing. Indeed, greater variability in momentary pain catastrophizing prior to surgery was uniquely associated with increased pain immediately after surgery (b = .58, P = .005), after controlling for preoperative pain levels and dispositional pain catastrophizing. Greater average mPCS score prior to surgery was also uniquely associated with lesser day-to-day improvement in postsurgical pain (b = .01, P = .003), whereas dispositional pain catastrophizing was not (b = −.007, P = .099). These results show that the mPCS is a reliable and valid tool for ecological momentary assessment research and highlight its potential utility over and above retrospective measures of pain catastrophizing. Perspective: This article presents the psychometric properties and prognostic utility of a new measure to assess momentary pain catastrophizing. This brief, 3-item measure will allow researchers and clinicians to assess fluctuations in pain catastrophizing during individuals’ daily lives, as well as dynamic relationships between catastrophizing, pain, and related factors. © 2023 United States Association for the Study of Pain, Inc.

Author Keywords
Catastrophizing;  ecological momentary assessment;  measurement;  postsurgical pain;  psychosocial

Funding details
U.S. Department of DefenseDODW81XWH2110736
National Institute of Mental HealthNIMHMH124291
Cervical Spine Research SocietyCSRS
Scoliosis Research SocietySRS
Foundation for Barnes-Jewish HospitalFBJH
University of WashingtonUW
Canada Research Chairs
Institut de Recherche Robert-Sauvé en Santé et en Sécurité du TravailIRSST

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

Identifying the neural correlates of anticipatory postural control: A novel fMRI paradigm
(2023) Human Brain Mapping, . 

Smith, J.A.^a , Tain, R.^b , Sharp, K.G.^c d , Glynn, L.M.^e , Van Dillen, L.R.^f , Henslee, K.^a , Jacobs, J.V.^g , Cramer, S.C.^h i

^a Department of Physical Therapy, Chapman University, Orange, CA, United States
^b University of California, Campus Center for Neuroimaging, Irvine, CA, United States
^c Department of Dance, School of Arts, University of California, Irvine, CA, United States
^d Department of Physical Medicine and Rehabilitation, University of California, Irvine, CA, United States
^e Department of Psychology, Chapman University, Orange, CA, United States
^f Program in Physical Therapy, Orthopaedic Surgery, Washington University School of Medicine in St. Louis, St. Louis, WA, United States
^g Rehabilitation and Movement Science, University of Vermont, Burlington, VT, United States
^h Department of Neurology, University of California, Los Angeles, CA, United States
ⁱ California Rehabilitation Institute, Los Angeles, CA, United States

Abstract
Altered postural control in the trunk/hip musculature is a characteristic of multiple neurological and musculoskeletal conditions. Previously it was not possible to determine if altered cortical and subcortical sensorimotor brain activation underlies impairments in postural control. This study used a novel fMRI-compatible paradigm to identify the brain activation associated with postural control in the trunk and hip musculature. BOLD fMRI imaging was conducted as participants performed two versions of a lower limb task involving lifting the left leg to touch the foot to a target. For the supported leg raise (SLR) the leg is raised from the knee while the thigh remains supported. For the unsupported leg raise (ULR) the leg is raised from the hip, requiring postural muscle activation in the abdominal/hip extensor musculature. Significant brain activation during the SLR task occurred predominantly in the right primary and secondary sensorimotor cortical regions. Brain activation during the ULR task occurred bilaterally in the primary and secondary sensorimotor cortical regions, as well as cerebellum and putamen. In comparison with the SLR, the ULR was associated with significantly greater activation in the right premotor/SMA, left primary motor and cingulate cortices, primary somatosensory cortex, supramarginal gyrus/parietal operculum, superior parietal lobule, cerebellar vermis, and cerebellar hemispheres. Cortical and subcortical regions activated during the ULR, but not during the SLR, were consistent with the planning, and execution of a task involving multisegmental, bilateral postural control. Future studies using this paradigm will determine mechanisms underlying impaired postural control in patients with neurological and musculoskeletal dysfunction. © 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.

Author Keywords
functional MRI;  movement;  neuroimaging;  postural control;  sensorimotor;  trunk

Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDK01 HD092612

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

Deficits in doors P300 amplitude during adolescence associated with preschool-onset depression
(2023) Psychophysiology, . 

Santopetro, N.J.^a , Barch, D.^b , Luby, J.L.^c , Hennefield, L.^c , Gilbert, K.E.^c , Whalen, D.J.^c , Hajcak, G.^a

^a Department of Psychology, Florida State University, Tallahassee, FL, United States
^b Department of Psychological & Brain Sciences, Washington University in St. Louis, St Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St. Louis, St Louis, MO, United States

Abstract
The psychophysiological underpinnings of preschool-onset depression (PO-MDD) remain underexplored. Moreover, there is currently a limited understanding of the potential impact that PO-MDD might have on neurobiological functions later in development such as general cognitive domains and reward processing. Thus, the current study sought to examine potential neurophysiological differences, measured via electroencephalography (EEG), in adolescents with and without a history of PO-MDD. Participants and their caregivers (N = 138) from a large longitudinal study completed semi-structured clinical interviews at a baseline visit (ages 3–7) to determine PO-MDD status. At a follow-up visit approximately 11 years later, adolescents (ages 13–19) completed the doors gambling task while EEG was recorded to measure event-related potentials (ERPs) elicited by both the doors and feedback stimuli, to index cognitive and reward processing functions (i.e., doors-P300, gain/loss feedback-P300, and RewP). Adolescents with a history of PO-MDD exhibited significantly smaller doors-P300 compared with adolescents with no history of PO-MDD, whereas there were no group differences in gain/loss feedback-P300 or RewP. Additionally, reduced doors-P300 was independently associated with lower baseline income-to-needs ratio, older age, and female gender. The current study suggests that reduced doors-P300 amplitude during adolescence might reflect impaired neurophysiological development related to PO-MDD. Thus, the P300 derived from the doors stimuli might be a valuable neural measure to further our understanding of potential neurophysiological differences associated with early-onset childhood depression. © 2023 Society for Psychophysiological Research.

Author Keywords
adolescence;  EEG;  ERP;  P300;  PO-MDD

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

Symmetric data-driven fusion of diffusion tensor MRI: Age differences in white matter
(2023) Frontiers in Neurology, 14, art. no. 1094313, . 

Mendez Colmenares, A.^a b , Hefner, M.B.^a , Calhoun, V.D.^c , Salerno, E.A.^d , Fanning, J.^e , Gothe, N.P.^f , McAuley, E.^f g , Kramer, A.F.^g h , Burzynska, A.Z.^a b i

^a BRAiN Laboratory, Department of Human Development and Family Studies, Colorado State University, Fort Collins, CO, United States
^b Molecular, Cellular and Integrative Neurosciences, Colorado State University, Fort Collins, CO, United States
^c Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State, Georgia Tech, Emory, Atlanta, GA, United States
^d Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e Department of Health and Exercise Sciences, Wake Forest University, Winston-Salem, NC, United States
^f Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, United States
^g Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, United States
^h Department of Psychology, Northeastern University, Boston, MA, United States
ⁱ Department of Human Development and Family Studies, Colorado State University, Fort Collins, CO, United States

Abstract
In the past 20 years, white matter (WM) microstructure has been studied predominantly using diffusion tensor imaging (DTI). Decreases in fractional anisotropy (FA) and increases in mean (MD) and radial diffusivity (RD) have been consistently reported in healthy aging and neurodegenerative diseases. To date, DTI parameters have been studied individually (e.g., only FA) and separately (i.e., without using the joint information across them). This approach gives limited insights into WM pathology, increases the number of multiple comparisons, and yields inconsistent correlations with cognition. To take full advantage of the information in a DTI dataset, we present the first application of symmetric fusion to study healthy aging WM. This data-driven approach allows simultaneous examination of age differences in all four DTI parameters. We used multiset canonical correlation analysis with joint independent component analysis (mCCA + jICA) in cognitively healthy adults (age 20–33, n = 51 and age 60–79, n = 170). Four-way mCCA + jICA yielded one high-stability modality-shared component with co-variant patterns of age differences in RD and AD in the corpus callosum, internal capsule, and prefrontal WM. The mixing coefficients (or loading parameters) showed correlations with processing speed and fluid abilities that were not detected by unimodal analyses. In sum, mCCA + jICA allows data-driven identification of cognitively relevant multimodal components within the WM. The presented method should be further extended to clinical samples and other MR techniques (e.g., myelin water imaging) to test the potential of mCCA+jICA to discriminate between different WM disease etiologies and improve the diagnostic classification of WM diseases. Copyright © 2023 Mendez Colmenares, Hefner, Calhoun, Salerno, Fanning, Gothe, McAuley, Kramer and Burzynska.

Author Keywords
aging;  diffusion MRI;  fusion;  multimodal;  white matter

Funding details
National Science FoundationNSF2112455
National Institutes of HealthNIHR01MH118695, R37 AG025667
National Institute on AgingNIA
Colorado State UniversityCSU1R21AG068939-01A1
Abbott Nutrition

Document Type: Article
Publication Stage: Final
Source: Scopus

Relationships Between Hourly Cognitive Variability and Risk of Alzheimer’s Disease Revealed With Mixed-Effects Location Scale Models
(2023) Neuropsychology, . 

Aschenbrenner, A.J.^a , Hassenstab, J.^a b , Morris, J.C.^a , Cruchaga, C.^c , Jackson, J.J.^b

^a Department of Neurology, School of Medicine, Washington University, St. Louis, United States
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, United States
^c Department of Psychiatry, School of Medicine, Washington University, St. Louis, United States

Abstract
Objective: Observational studies on aging and Alzheimer’s disease (AD) typically focus on mean-level changes in cognitive performance over relatively long periods of time (years or decades). Additionally, some studies have examined how trial-level fluctuations in speeded reaction time are related to both age and AD. The aim of the current project was to describe patterns of variability across repeated days of testing as a function of AD risk in cognitively normal older adults. Method: The current project examined the performance of the Ambulatory Research in Cognition (ARC) smartphone application, a highfrequency remote cognitive assessment paradigm, that administers brief tests of episodic memory, spatial working memory, and processing speed. Bayesian mixed-effects location scale models were used to explore differences in mean cognitive performance and intraindividual variability across 28 repeated sessions over a 1-week assessment interval as function of age and genetic risk of AD, specifically the presence of at least one apolipoprotein E (APOE) ε4 allele. Results: Mean performance on processing speed and working memory was negatively related to age and APOE status.More importantly, e4 carriers exhibited increased session-level variability on a test of processing speed compared to noncarriers. Age and education did not consistently relate to cognitive variability, contrary to expectations. Conclusion: Preclinical AD risk, defined as possessing at least one APOE ε4 allele, is not only associated with meanlevel performance differences, but also with increases in variability across repeated testing occasions particularly on a test of processing speed. Thus, cognitive variability may serve as an additional and important indicator of AD risk © 2023 American Psychological Association

Author Keywords
Alzheimer’s disease;  apolipoprotein E;  cognition;  measurement burst;  variability

Funding details
R01 AG057840
National Institute on AgingNIAK01 AG071847, P01-AG003991, P01-AG026276, P30 AG066444

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

Sound and light levels in intensive care units in a large urban hospital in the United States
(2023) Chronobiology International, . 

Leone, M.J.^a b , Dashti, H.S.^c d e f , Coughlin, B.^a , Tesh, R.A.^a b , Quadri, S.A.^a b , Bucklin, A.A.^a b , Adra, N.^a b , Krishnamurthy, P.V.^a b , Ye, E.M.^a b , Hemmige, A.^a b , Rajan, S.^a b , Panneerselvam, E.^a b , Higgins, J.^a b , Ayub, M.A.^a b g , Ganglberger, W.^a b h i , Paixao, L.^a b j , Houle, T.T.^h k , Thompson, B.T.^g , Johnson-Akeju, O.^d , Saxena, R.^c d e f , Cash, S.S.^a b , Thomas, R.J.^b l , Westover, M.B.^a b k

^a Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^b Clinical Data Animation Center, Massachusetts General Hospital, Boston, MA, United States
^c Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, United States
^d Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, United States
^e Brain Data Science Platform, Broad Institute, Cambridge, MA, United States
^f Division of Sleep Medicine, Harvard Medical School, Boston, MA, United States
^g Division of Pulmonary and Critical Care, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^h Sleep & Health Zurich, University of Zurich, Zurich, Switzerland
ⁱ Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, United States
^j Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^k Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
^l Department of Medicine, Division of Pulmonary, Critical Care & Sleep, Beth Israel Deaconess Medical Center, Boston, MA, United States

Abstract
Intensive care units (ICUs) may disrupt sleep. Quantitative ICU studies of concurrent and continuous sound and light levels and timings remain sparse in part due to the lack of ICU equipment that monitors sound and light. Here, we describe sound and light levels across three adult ICUs in a large urban United States tertiary care hospital using a novel sensor. The novel sound and light sensor is composed of a Gravity Sound Level Meter for sound level measurements and an Adafruit TSL2561 digital luminosity sensor for light levels. Sound and light levels were continuously monitored in the room of 136 patients (mean age = 67.0 (8.7) years, 44.9% female) enrolled in the Investigation of Sleep in the Intensive Care Unit study (ICU-SLEEP; Clinicaltrials.gov: #NCT03355053), at the Massachusetts General Hospital. The hours of available sound and light data ranged from 24.0 to 72.2 hours. Average sound and light levels oscillated throughout the day and night. On average, the loudest hour was 17:00 and the quietest hour was 02:00. Average light levels were brightest at 09:00 and dimmest at 04:00. For all participants, average nightly sound levels exceeded the WHO guideline of < 35 decibels. Similarly, mean nightly light levels varied across participants (minimum: 1.00 lux, maximum: 577.05 lux). Sound and light events were more frequent between 08:00 and 20:00 than between 20:00 and 08:00 and were largely similar on weekdays and weekend days. Peaks in distinct alarm frequencies (Alarm 1) occurred at 01:00, 06:00, and at 20:00. Alarms at other frequencies (Alarm 2) were relatively consistent throughout the day and night, with a small peak at 20:00. In conclusion, we present a sound and light data collection method and results from a cohort of critically ill patients, demonstrating excess sound and light levels across multiple ICUs in a large tertiary care hospital in the United States. ClinicalTrials.gov, #NCT03355053. Registered 28 November 2017, https://clinicaltrials.gov/ct2/show/NCT03355053. © 2023 Taylor & Francis Group, LLC.

Author Keywords
critical illness;  devices;  Intensive care units;  light;  sound;  urban hospitals

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

Dissociating Proactive and Reactive Control in Older Adults
(2023) Psychology and Aging, . 

Ball, B.H.^a , Peper, P.^a , Bugg, J.M.^b

^a Department of Psychology, University of Texas, Arlington, United States
^b Department of Psychological and Brain Sciences, Washington University, Saint Louis, United States

Abstract
The DualMechanisms of Control framework predicts that age-related declines should be most prominent for tasks that require proactive control, while tasks requiring reactive control should show minimal age differences in performance. However, results from traditional paradigms are inconclusive as to whether these two processes are independent, making it difficult to understand how these processes change with age. The present study manipulated the proportion congruency in a list-wide (Experiments 1 and 2) or item-specific (Experiment 1) fashion to independently assess proactive and reactive control, respectively. In the list-wide task, older adults were unable to proactively bias attention away from word processing based on list-level expectancies. Proactive control deficits replicated across multiple task paradigms, with different Stroop stimuli (picture-word, integrated color-word, separated color-word), and different behavioral indices (Stroop interference, secondary prospective memory). In contrast, older adults were successfully able to reactively filter theword dimension based on item-specific expectancies. These findings provide unambiguous support that aging is associated with declines in proactive, but not reactive, control. © 2023 American Psychological Association

Author Keywords
attention;  cognitive control;  inhibition;  prospective memory

Funding details
National Institute on AgingNIAT32AG000030-40
National Institute of General Medical SciencesNIGMSR16GM146705

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

Ancestral, Pregnancy, and Negative Early-Life Risks Shape Children’s Brain (Dis)similarity to Schizophrenia
(2023) Biological Psychiatry, . 

Kochunov, P.^a , Ma, Y.^a , Hatch, K.S.^a , Gao, S.^a , Acheson, A.^b , Jahanshad, N.^c , Thompson, P.M.^c , Adhikari, B.M.^a , Bruce, H.^a , Van der vaart, A.^a , Chiappelli, J.^a , Du, X.^a , Sotiras, A.^d , Kvarta, M.D.^a , Ma, T.^e , Chen, S.^a , Hong, L.E.^a

^a Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, United States
^b Department of Psychiatry, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^c Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of University of the Sunshine Coast, Marina del Rey, California, United States
^d Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States
^e Department of Epidemiology and Biostatistics, University of Maryland, College ParkMaryland, United States

Abstract
Background: Familial, obstetric, and early-life environmental risks for schizophrenia spectrum disorder (SSD) alter normal cerebral development, leading to the formation of characteristic brain deficit patterns prior to onset of symptoms. We hypothesized that the insidious effects of these risks may increase brain similarity to adult SSD deficit patterns in prepubescent children. Methods: We used data collected by the Adolescent Brain Cognitive Development (ABCD) Study (N = 8940, age = 9.9 ± 0.1 years, 4307/4633 female/male), including 727 (age = 9.9 ± 0.1 years, 351/376 female/male) children with family history of SSD, to evaluate unfavorable cerebral effects of ancestral SSD history, pre/perinatal environment, and negative early-life environment. We used a regional vulnerability index to measure the alignment of a child’s cerebral patterns with the adult SSD pattern derived from a large meta-analysis of case-control differences. Results: In children with a family history of SSD, the regional vulnerability index captured significantly more variance in ancestral history than traditional whole-brain and regional brain measurements. In children with and without family history of SSD, the regional vulnerability index also captured more variance associated with negative pre/perinatal environment and early-life experiences than traditional brain measurements. Conclusions: In summary, in a cohort in which most children will not develop SSD, familial, pre/perinatal, and early developmental risks can alter brain patterns in the direction observed in adult patients with SSD. Individual similarity to adult SSD patterns may provide an early biomarker of the effects of genetic and developmental risks on the brain prior to psychotic or prodromal symptom onset. © 2023 Society of Biological Psychiatry

Author Keywords
Adolescence;  Big data;  Brain development;  Imaging;  Individual prediction;  Schizophrenia

Funding details
National Institutes of HealthNIHP50MH103222, R01AG095874, R01EB015611, R01MH112180, R01MH116147, R01MH116948, R01MH117601, R01MH123163, S10OD023696, U01MH108148
Biogen

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

Entrectinib in children and young adults with solid or p y g,, aberrations (STARTRK-NG)
(2022) Neuro-Oncology, 24 (10), pp. 1776-1789. Cited 13 times.

Desai, A.V.^a , Robinson, G.W.^b , Gauvain, K.^c , Basu, E.M.^d , Macy, M.E.^e , Maese, L.^f , Whipple, N.S.^g , Sabnis, A.J.^h , Foster, J.H.ⁱ , Shusterman, S.^j , Yoon, J.^k , Weiss, B.D.^l , Abdelbaki, M.S.^m , Armstrong, A.E.ⁿ , Cash, T.^o , Pratilas, C.A.^p , Corradini, N.^q , Marshall, L.V.^r , Farid-Kapadia, M.^s , Chohan, S.^t , Devlin, C.^u , Meneses-Lorente, G.^v , Cardenas, A.^w , Hutchinson, K.E.^x , Bergthold, G.^y , Caron, H.^z , Maneval, E.C.^aa , Gajjar, A.^b , Fox, E.^ab

^a Department of Pediatrics, Section of Hematology/Oncology/Stem CellTransplantation, University of Chicago Medical Center, Chicago, IL, United States
^b Division of Neuro-Oncology, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^c Pediatric Neuro-Oncology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pediatrics, Memorial Sloan Kettering Cancer Center, NewYork, NY, United States
^e Pediatric Hematology-Oncology, Children’s Hospital Colorado, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
^f Department of Pediatrics, Division of Hematology/Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, United States
^g Pediatric Hematology-Oncology, University of Utah, Salt Lake City, UT, United States
^h Division of Pediatric Oncology, Department of Pediatrics, University of California, San Francisco, CA, United States
ⁱ Department of Pediatrics, Hematology-Oncology, Texas Children’s Hospital, Houston, TX, United States
^j Pediatric Hematology and Oncology, Dana Farber Cancer Institute, Children’s Cancer and Blood Disorders Center, Boston, MA, United States
^k Department of Pediatrics, University of California San Diego, San Diego, CA, United States
^l Department of Pediatrics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
^m Division of Hematology and Oncology, Nationwide Children’s Hospital, Columbus, OH, United States
ⁿ Division of Pediatric Hematology/ Oncology, Washington University School of Medicine, St. Louis, MO, United States
^o Pediatric Hematology/ Oncology, Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, United States
^p Department of Oncology, Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^q Department of Pediatric Hematology and Oncology, Institute of Pediatric Hematology and Oncology (IHOPe), Léon Bérard Cancer Centre, Lyon, France
^r Children and Young People’s Unit, Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom
^s Biometrics Department, F. Hoffmann-La Roche Ltd., Mississauga, ON, Canada
^t PDD Data and Statistical Sciences, F. Hoffmann-La Roche Ltd., Mississauga, ON, Canada
^u Pharma Development Oncology and Hematology, Roche Products Ltd., Welwyn Garden City, United Kingdom
^v Pharma Research and Early Development, Roche Products Ltd., Welwyn Garden City, United Kingdom
^w Clinical Safety, Genentech, Inc., South San Francisco, CA, United States
^x Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, United States
^y Product Development Oncology, F. Hoffmann-La Roche Ltd, Basel, Switzerland
^z Clinical Development, Ignyta, Inc., San Diego, CA, United States
^aa Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^ab Pediatric Hematology/Oncology/Stem CellTransplantation, MSCE, 5841 South Maryland Ave. MC4060, Chicago, IL 60637, United States

Abstract
Background. Entrectinib is a TRKA/B/C, ROS1, ALK tyrosine kinase inhibitor approved for the treatment of adults and children aged ≥12 years with NTRK fusion-positive solid tumors and adults with ROS1 fusion-positive non–small-cell lung cancer. We report an analysis of the STARTRK-NG trial, investigating the recommended phase 2 dose (RP2D) and activity of entrectinib in pediatric patients with solid tumors including primary central nervous system tumors. Methods. STARTRK-NG (NCT02650401) is a phase 1/2 trial. Phase 1, dose-escalation of oral, once-daily entrectinib, enrolled patients aged <22 years with solid tumors with/without target NTRK1/2/3, ROS1, or ALK fusions. Phase 2, basket trial at the RP2D, enrolled patients with intracranial or extracranial solid tumors harboring target fusions or neuroblastoma. Primary endpoints: phase 1, RP2D based on toxicity; phase 2, objective response rate (ORR) in patients harboring target fusions. Safety-evaluable patients: ≥1 dose of entrectinib; response-evaluable patients: measurable/evaluable baseline disease and ≥1 dose at RP2D. Results. At data cutoff, 43 patients, median age of 7 years, were response-evaluable. In phase 1, 4 patients experienced dose-limiting toxicities. The most common treatment-related adverse event was weight gain (48.8%). Nine patients experienced bone fractures (20.9%). In patients with fusion-positive tumors, ORR was 57.7% (95% CI 36.9-76.7), median duration of response was not reached, and median (interquartile range) duration of treatment was 10.6 months (4.2-18.4). Conclusions. Entrectinib resulted in rapid and durable responses in pediatric patients with solid tumors harboring NTRK1/2/3 or ROS1 fusions. © The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Author Keywords
CNS tumors;  entrectinib;  pediatric;  recommended phase 2 dose;  solid tumors

Funding details
F. Hoffmann-La RocheNCT02650401

Document Type: Article
Publication Stage: Final
Source: Scopus

Endogenous recapitulation of Alzheimer’s disease neuropathology through human 3D direct neuronal reprogramming
(2023) bioRxiv 2023.05.24.542155

Zhao Sun, Ji-Sun Kwon, Yudong Ren, Shawei Chen, Kitra Cates, Xinguo Lu, Courtney K. Walker, Hande Karahan, Sanja Sviben, James A J Fitzpatrick, Clarissa Valdez, Henry Houlden, Celeste M. Karch, Randall J. Bateman, Chihiro Sato, Steven J. Mennerick, Marc I. Diamond, Jungsu Kim, Rudolph E. Tanzi, David M. Holtzman, Andrew S. Yoo

Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-β (Aβ) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular Aβ deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with β- or γ-secretase inhibitors in LOAD patient-derived neurons and spheroids before Aβ deposit formation significantly lowered Aβ deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed Aβ deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between Aβ accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration.

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