“A single-cell guide to retinal development: Cell fate decisions of multipotent retinal progenitors in scRNA-seq” (2021) Developmental Biology
A single-cell guide to retinal development: Cell fate decisions of multipotent retinal progenitors in scRNA-seq
(2021) Developmental Biology, 478, pp. 41-58.
Shiau, F.a , Ruzycki, P.A.a , Clark, B.S.a b
a John F Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Recent advances in high throughput single-cell RNA sequencing (scRNA-seq) technology have enabled the simultaneous transcriptomic profiling of thousands of individual cells in a single experiment. To investigate the intrinsic process of retinal development, researchers have leveraged this technology to quantify gene expression in retinal cells across development, in multiple species, and from numerous important models of human disease. In this review, we summarize recent applications of scRNA-seq and discuss how these datasets have complemented and advanced our understanding of retinal progenitor cell competence, cell fate specification, and differentiation. Finally, we also highlight the outstanding questions in the field that advances in single-cell data generation and analysis will soon be able to answer. © 2021 The Authors
Author Keywords
Cell fate specification; Competence; Neurogenesis; Retinal development; Retinal progenitor cells; Review; scRNA-seq; Single-cell; Single-cell rna-sequencing
Funding details
National Institutes of HealthNIHR00EY027844
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
“Comparing stress prediction models using smartwatch physiological signals and participant self-reports” (2021) Computer Methods and Programs in Biomedicine
Comparing stress prediction models using smartwatch physiological signals and participant self-reports
(2021) Computer Methods and Programs in Biomedicine, 208, art. no. 106207, .
Dai, R.a , Lu, C.a , Yun, L.b , Lenze, E.c , Avidan, M.b , Kannampallil, T.b d
a Department of Computer Science, McKelvey School of Engineering, United States
b Department of Anesthesiology, United States
c Department of Psychiatry, United States
d Institute for Informatics, School of Medicine, Washington University in St. Louis, St Louis, MO, United States
Abstract
Recent advances in wearable technology have facilitated the non-obtrusive monitoring of physiological signals, creating opportunities to monitor and predict stress. Researchers have utilized machine learning methods using these physiological signals to develop stress prediction models. Many of these prediction models have utilized objective stressor tasks (e.g., a public speaking task or solving math problems). Alternatively, the subjective user responses with self-reports have also been used for measuring stress. In this paper, we describe a methodological approach (a) to compare the prediction performance of models developed using objective markers of stress using participant-reported subjective markers of stress from self-reports; and (b) to develop personalized stress models by accounting for inter-individual differences. Towards this end, we conducted a laboratory-based study with 32 healthy volunteers. Participants completed a series of stressor tasks—social, cognitive and physical—wearing an instrumented commercial smartwatch that collected physiological signals and participant responses using timed self-reports. After extensive data preprocessing using a combination of signal processing techniques, we developed two types of models: objective stress models using the stressor tasks as labels; and subjective stress models using participant responses to each task as the label for that stress task. We trained and tested several machine learning algorithms—support vector machine (SVM), random forest (RF), gradient boosted trees (GBT), AdaBoost, and Logistic Regression (LR)—and evaluated their performance. SVM had the best performance for the models using the objective stressor (i.e., stressor tasks) with an AUROC of 0.790 and an F-1 score of 0.623. SVM also had the highest performance for the models using the subjective stress (i.e., participant self-reports) with an AUROC of 0.719 and an F-1 score of 0.520. Model performance improved with a personalized threshold model to an AUROC of 0.751 and an F-1 score of 0.599. The performance of the stress models using an instrumented commercial smartwatch was comparable to similar models from other state-of-the-art laboratory-based studies. However, the subjective stress models had a lower performance, indicating the need for further research on the use of self-reports for stress-related studies. The improvement in performance with the personalized threshold-based models provide new directions for building stress prediction models. © 2021 Elsevier B.V.
Author Keywords
Objective stress; Personalized threshold; Smartwatch; Subjective stress
Funding details
Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
“Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory” (2021) Neurobiology of Learning and Memory
Acetylcholine from the nucleus basalis magnocellularis facilitates the retrieval of well-established memory
(2021) Neurobiology of Learning and Memory, 183, art. no. 107484, .
Soma, S.a b c , Suematsu, N.a d , Sato, A.Y.a e , Tsunoda, K.a , Bramian, A.b , Reddy, A.b , Takabatake, K.f , Karube, F.g h , Fujiyama, F.g h , Shimegi, S.a i
a Graduate School of Medicine, Osaka University, Osaka, 560-0043, Japan
b Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, CA 92697, United States
c Department of Molecular Cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan
d Center for Sciences Towards Symbiosis Among Human, Machine and Data, Kyoto Sangyo University, Kyoto, 603-8555, Japan
e Graduate School of Pharmaceutical Sciences, Nagoya University, Nagoya, 464-8601, Japan
f College of Arts & Sciences, Washington University in Saint Louis, Saint Louis, MO 63130, United States
g Graduate School of Brain Science, Doshisha University, Kyoto, 619-0225, Japan
h Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan
i Center for Education in Liberal Arts and Sciences, Osaka University, Toyonaka, Osaka 560-0043, Japan
Abstract
Retrieval deficit of long-term memory is a cardinal symptom of dementia and has been proposed to associate with abnormalities in the central cholinergic system. Difficulty in the retrieval of memory is experienced by healthy individuals and not limited to patients with neurological disorders that result in forgetfulness. The difficulty of retrieving memories is associated with various factors, such as how often the event was experienced or remembered, but it is unclear how the cholinergic system plays a role in the retrieval of memory formed by a daily routine (accumulated experience). To investigate this point, we trained rats moderately (for a week) or extensively (for a month) to detect a visual cue in a two-alternative forced-choice task. First, we confirmed the well-established memory in the extensively trained group was more resistant to the retrieval problem than recently acquired memory in the moderately trained group. Next, we tested the effect of a cholinesterase inhibitor, donepezil, on the retrieval of memory after a long no-task period in extensively trained rats. Pre-administration of donepezil improved performance and reduced the latency of task initiation compared to the saline-treated group. Finally, we lesioned cholinergic neurons of the nucleus basalis magnocellularis (NBM), which project to the entire neocortex, by injecting the cholinergic toxin 192 IgG-saporin. NBM-lesioned rats showed severely impaired task initiation and performance. These abilities recovered as the trials progressed, though they never reached the level observed in rats with intact NBM. These results suggest that acetylcholine released from the NBM contributes to the retrieval of well-established memory developed by a daily routine. © 2021 Elsevier Inc.
Author Keywords
192 IgG-saporin; Acetylcholine; Donepezil; Retrieval; Two-alternative forced-choice visual cue detection task; Well-established memory
Funding details
Japan Society for the Promotion of ScienceKAKEN16H01869, 20H03549, 20H04077, 20H05069, 20H05484, 20K15934, 20K20671, JP15J00807
Document Type: Article
Publication Stage: Final
Source: Scopus
“Black-White racial health disparities in inflammation and physical health: Cumulative stress, social isolation, and health behaviors” (2021) Psychoneuroendocrinology
Black-White racial health disparities in inflammation and physical health: Cumulative stress, social isolation, and health behaviors
(2021) Psychoneuroendocrinology, 131, art. no. 105251, .
McClendon, J.a b , Chang, K.c , J. Boudreaux, M.d , Oltmanns, T.F.e , Bogdan, R.e
a National Center for PTSD, VA Boston Healthcare System, Boston, MA, United States
b Boston University School of Medicine, Boston, MA, United States
c University of Rochester
d Hogan Assessment Systems, United States
e Washington University in St. Louis, St. Louis, MO, United States
Abstract
Black Americans have vastly increased odds and earlier onsets of stress- and age-related disease compared to White Americans. However, what contributes to these racial health disparities remains poorly understood. Using a sample of 1577 older adults (32.7% Black; ages 55–65 at baseline), we examined whether stress, health behaviors, social isolation, and inflammation are associated with racial disparities in self-reported physical health. A latent cumulative stress factor and unique stress-domain specific factors were modeled by applying bifactor confirmatory analysis to assessments across the lifespan (i.e., childhood maltreatment, trauma exposure, discrimination, stressful life events, and indices of socioeconomic status). Physical health, health behavior, and social isolation were assessed using self-report. Interleukin-6 (IL-6) and C-reactive protein (CRP) were assayed from morning fasting serum samples; a z-scored inflammation index was formed across these 2 cytokines. A parallel serial mediational model tested whether race (i.e., Black/White) is indirectly associated with health through the following 3 independent pathways: (1) cumulative stress to preventative health behaviors (e.g., healthy eating) to inflammation, (2) cumulative stress to risky health behaviors (e.g., substance use) to inflammation; and (3) cumulative stress to social isolation to inflammation. There were significant indirect effects between race and self-reported physical health through cumulative stress, preventative health behaviors, and inflammation (B = −0.02, 95% CI: −0.05, −0.01). Specifically, Black Americans were exposed to greater cumulative stress, which was associated with reduced engagement in preventative health behaviors, which was, in turn, associated with greater inflammation and reduced physical health. A unique SES factor also indirectly linked race to physical health through preventative health behaviors. Cumulative stress exposure and unique aspects of socioeconomic status are indirectly associated with Black-White racial health disparities through behavioral (i.e., preventative health behavior) and biological (i.e., inflammation) factors. Culturally responsive evidence-based interventions that enhance engagement in preventative health behaviors are needed to directly confront health disparities. Ultimately, large scale anti-racist public policies that reduce cumulative stress burden (e.g., a living wage, universal healthcare) may best attenuate racial health disparities. © 2021 Elsevier Ltd
Author Keywords
Disparities; Health; Inflammation; Race; Stress
Funding details
R01-AG045231, R01-AG052564, R01-AG061162, R01-DA046224, R01-HD083614, R21-AA027827, R34-DA050272, R56-AG059265
Klingenstein Third Generation FoundationKTGF
Document Type: Article
Publication Stage: Final
Source: Scopus
“Elucidating Neural Mechanisms of Poverty on Child Development Leads Back to Psychosocial Mechanisms” (2021) Biological Psychiatry
Elucidating Neural Mechanisms of Poverty on Child Development Leads Back to Psychosocial Mechanisms
(2021) Biological Psychiatry, 90 (3), pp. 141-142.
Luby, J.L.
Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
Document Type: Note
Publication Stage: Final
Source: Scopus
“Local and system mechanisms for action execution and observation in parietal and premotor cortices” (2021) Current Biology
Local and system mechanisms for action execution and observation in parietal and premotor cortices
(2021) Current Biology, 31 (13), pp. 2819-2830.e4.
Ferroni, C.G.a , Albertini, D.a , Lanzilotto, M.b , Livi, A.a c , Maranesi, M.a , Bonini, L.a
a Department of Medicine and Surgery, University of Parma, via Volturno 39, Parma, 43125, Italy
b Department of Psychology, University of Turin, via Verdi 10, Torino, 10124, Italy
c Department of Neuroscience, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
The action observation network (AON) includes a system of brain areas largely shared with action execution in both human and nonhuman primates. Yet temporal and tuning specificities of distinct areas and of physiologically identified neuronal classes in the encoding of self and others’ action remain unknown. We recorded the activity of 355 single units from three crucial nodes of the AON, the anterior intraparietal area (AIP), and premotor areas F5 and F6, while monkeys performed a Go/No-Go grasping task and observed an experimenter performing it. At the system level, during task execution, F6 displays a prevalence of suppressed neurons and signals whether an action has to be performed, whereas AIP and F5 share a prevalence of facilitated neurons and remarkable target selectivity; during task observation, F5 stands out for its unique prevalence of facilitated neurons and its stronger and earlier modulation than AIP and F6. By applying unsupervised clustering of spike waveforms, we found distinct cell classes unevenly distributed across areas, with different firing properties and carrying specific visuomotor signals. Broadly spiking neurons exhibited a balanced amount of facilitated and suppressed activity during action execution and observation, whereas narrower spiking neurons showed more mutually facilitated responses during the execution of one’s own and others’ action, particularly in areas AIP and F5. Our findings elucidate the time course of activity and firing properties of neurons in the AON during one’s own and others’ action, from the system level of anatomically distinct areas to the local level of physiologically distinct cell classes. © 2021 The Author(s)
Author Keywords
action organization; cell classes; mirror neuron; parietal cortex; premotor cortex; pyramidal neurons
Funding details
European Research CouncilERC678307
Ministero dell’Istruzione, dell’Università e della RicercaMIUR772953
Document Type: Article
Publication Stage: Final
Source: Scopus
“A locus coeruleus to dentate gyrus noradrenergic circuit modulates aversive contextual processing” (2021) Neuron
A locus coeruleus to dentate gyrus noradrenergic circuit modulates aversive contextual processing
(2021) Neuron, 109 (13), pp. 2116-2130.e6.
Seo, D.-O.a , Zhang, E.T.b c d , Piantadosi, S.C.c d , Marcus, D.J.c d , Motard, L.E.a , Kan, B.K.c d , Gomez, A.M.a , Nguyen, T.K.c d , Xia, L.e , Bruchas, M.R.a b c d e f
a Department of Anesthesiology, Division of Basic Research, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Bioengineering, University of Washington, Seattle, WA 98105, United States
c Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA 98195, United States
d Center for the Neurobiology of Addiction, Pain and Emotion, University of Washington, Seattle, WA 98195, United States
e Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States
f Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, WA 98195, United States
Abstract
Dysregulation in contextual processing is believed to affect several forms of psychopathology, such as post-traumatic stress disorder (PTSD). The dentate gyrus (DG), a subregion of the hippocampus, is thought to be an important brain region for disambiguating new experiences from prior experiences. Noradrenergic (NE) neurons in the locus coeruleus (LC) are more tonically active during stressful events and send dense projections to the DG, yet an understanding of their function in DG-dependent contextual discrimination has not been established. Here, we isolate a key function of the LC-NE-DG circuit in contextual aversive generalization using selective manipulations and in vivo single-cell calcium imaging. We report that activation of LC-NE neurons and terminal activity results in contextual generalization. We found that these effects required β-adrenergic-mediated modulation of hilar interneurons to ultimately promote aversive generalization, suggesting that disruption of noradrenergic tone may serve as an important avenue for treating stress-induced disorders. © 2021 Elsevier Inc.
Author Keywords
beta-adrenergic; calcium imaging; dentate gyrus; fear conditioning; hippocampus; learning and memory; locus coeruleus; neuromodulation; norepinephrine; optogenetics
Funding details
National Institutes of HealthNIH1U01 MH10913301, P30DA048736, R01 DA033396-04S1, R01MH112355
National Institute on Drug AbuseNIDA
Document Type: Article
Publication Stage: Final
Source: Scopus
“Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice” (2021) Proceedings of the National Academy of Sciences of the United States of America
Acute Trem2 reduction triggers increased microglial phagocytosis, slowing amyloid deposition in mice
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (27), art. no. e2100356118, .
Schoch, K.M.a , Ezerskiy, L.A.a , Morhaus, M.M.a , Bannon, R.N.a , Sauerbeck, A.D.a , Shabsovich, M.a , Jafar-Nejad, P.b , Rigo, F.b , Miller, T.M.a
a Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO 63110, United States
b Ionis Pharmaceuticals, Carlsbad, CA 92010, United States
Abstract
Heterozygous genetic variants within the TREM2 gene show a strong association with increased Alzheimer’s disease (AD) risk. Amyloid beta-depositing mouse models haploinsufficient or null for Trem2 have identified important relationships among TREM2, microglia, and AD pathology; however, results are challenging to interpret in the context of varying microglial phenotypes and disease progression. We hypothesized that acute Trem2 reduction may alter amyloid pathology and microglial responses independent of genetic Trem2 deletion in mouse models. We developed antisense oligonucleotides (ASOs) that potently but transiently lower Trem2 messenger RNA throughout the brain and administered them to APP/PS1 mice at varying stages of plaque pathology. Late-stage ASO-mediated Trem2 knockdown significantly reduced plaque deposition and attenuated microglial association around plaque deposits when evaluated 1 mo after ASO injection. Changes in microglial gene signatures 1 wk after ASO administration and phagocytosis measured in ASO-treated cells together indicate that microglia may be activated with short-term Trem2 reduction. These results suggest a time- and/or dose-dependent role for TREM2 in mediating plaque deposition and microglial responses in which loss of TREM2 function may be beneficial for microglial activation and plaque removal in an acute context. © 2021 National Academy of Sciences. All rights reserved.
Author Keywords
Alzheimer’s disease; Amyloid; Antisense oligonucleotide; Microglia; Trem2
Funding details
CDI-CORE-2015-505, CDI-CORE-2019-813
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR01NS078398
Washington University in St. LouisWUSTL
Foundation for Barnes-Jewish Hospital3770, 4642
University of WashingtonUWS10 RR027552
Hope Center for Neurological Disorders
Document Type: Article
Publication Stage: Final
Source: Scopus
“Treatment strategies for hydrocephalus related to Dandy-Walker syndrome: Evaluating procedure selection and success within the Hydrocephalus Clinical Research Network” (2021) Journal of Neurosurgery: Pediatrics
Treatment strategies for hydrocephalus related to Dandy-Walker syndrome: Evaluating procedure selection and success within the Hydrocephalus Clinical Research Network
(2021) Journal of Neurosurgery: Pediatrics, 28 (1), pp. 93-101.
Yengo-Kahn, A.M.a b , Wellons, J.C., IIIa b , Hankinson, T.C.c , Hauptman, J.S.d , Jackson, E.M.e , Jensen, H.f , Krieger, M.D.g , Kulkarni, A.V.h , Limbrick, D.D., Jr.i , McDonald, P.J.j , Naftel, R.P.a b , Pindrik, J.A.k , Pollack, I.F.l , Reeder, R.f , Riva-Cambrin, J.m , Rozzelle, C.J.n , Tamber, M.S.j , Whitehead, W.E.o , Kestle, J.R.W.p , Networkq
a Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, TN, United States
b Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, TN, United States
c Department of Neurosurgery, Children’s Hospital Colorado, Colorado Springs, CO, United States
d Department of Neurosurgery, Seattle Children’s Hospital, University of Washington, Seattle, WA, United States
e Department of Neurosurgery, The Johns Hopkins Hospital, Johns Hopkins University, Baltimore, MD, United States
f Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
g Department of Neurosurgery, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA, United States
h Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada
i Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
j Division of Neurosurgery, British Columbia Children’s Hospital, The University of British Columbia, Vancouver, BC, Canada
k Department of Neurosurgery, The Ohio State University College of Medicine, Columbus, OH, United States
l Department of Neurosurgery, UPMC Children’s Hospital of Pittsburgh, University of PittsburghPA, United States
m Division of Neurosurgery Alberta Children’s Hospital, University of CalgaryAB, Canada
n Division of Neurosurgery, Children’s of Alabama, University of Alabama, Birmingham, AL, United States
o Department of Neurosurgery, Texas Children’s Hospital, Houston, TX, United States
p Department of Neurosurgery, University of Utah, Salt Lake City, UT, United States
Abstract
Objective: Treating Dandy-Walker syndrome-related hydrocephalus (DWSH) involves either a CSF shunt-based or endoscopic third ventriculostomy (ETV)-based procedure. However, comparative investigations are lacking. This study aimed to compare shunt-based and ETV-based treatment strategies utilizing archival data from the Hydrocephalus Clinical Research Network (HCRN) registry. Methods: A retrospective review of prospectively collected and maintained data on children with DWSH, available from the HCRN registry (14 sites, 2008-2018), was performed. The primary outcome was revision-free survival of the initial surgical intervention. The primary exposure was either shunt-based (i.e., cystoperitoneal shunt [CPS], ventriculoperitoneal shunt [VPS], and/or dual-compartment) or ETV-based (i.e., ETV alone or with choroid plexus cauterization [CPC]) initial surgical treatment. Primary analysis included multivariable Cox proportional hazards models. Results: Of 8400 HCRN patients, 151 (1.8%) had DWSH. Among these, the 102 patients who underwent shunt placement (79 VPSs, 16 CPSs, 3 other, and 4 multiple proximal catheter) were younger (6.6 vs 18.8 months, p < 0.001) and more frequently had 1 or more comorbidities (37.3% vs 14.3%, p = 0.005) than the 49 ETV-treated children (28 ETVCPC). Fifty percent of the shunt-based and 51% of the ETV-based treatments failed. Notably, 100% (4/4) of the dualcompartment shunts failed. Adjusting for age, baseline ventricular size, and comorbidities, ETV-based treatment was not significantly associated with earlier failure compared with shunt-based treatment (HR for failure 1.32, 95% CI 0.77-2.26; p = 0.321). Complication rates were low: 4.9% and 6.1% (p = 0.715) for shunt- and ETV-based procedures, respectively. There was no difference in survival between ETV-CPC- and ETV-based treatment when adjusting for age (HR for failure 0.86, 95% CI 0.29-2.55, p = 0.783). Conclusions: In this North American, multicenter, prospective database review, shunt-based and ETV-based primary treatment strategies of DWSH appear similarly durable. Pediatric neurosurgeons can reasonably consider ETV-based initial treatment given the similar durability and the low complication rate. However, given the observational nature of this study, the treating surgeon might need to consider subgroups that were too small for a separate analysis. Very young children with comorbidities were more commonly treated with shunts, and older children with fewer comorbidities were offered ETV-based treatment. Future studies may determine preoperative characteristics associated with ETV treatment success in this population. © 2021 AANS.
Author Keywords
Dandy-Walker; Endoscopic third ventriculostomy; ETV; Hydrocephalus clinical research network; Posterior fossa cyst
Funding details
National Institute of Neurological Disorders and StrokeNINDS1RC1NS068943-01, 1U01NS107486-01A1
Gerber Foundation1692-3638
Patient-Centered Outcomes Research InstitutePCORICER-1403-13857
Hydrocephalus AssociationHA
Document Type: Article
Publication Stage: Final
Source: Scopus
“Nanoparticulate matter exposure results in white matter damage and an inflammatory microglial response in an experimental murine model” (2021) PLoS ONE
Nanoparticulate matter exposure results in white matter damage and an inflammatory microglial response in an experimental murine model
(2021) PLoS ONE, 16 (7 July), art. no. e0253766, .
Connor, M.a , Lamorie-Foote, K.b , Liu, Q.b , Shkirkova, K.b , Baertsch, H.b , Sioutas, C.c , Morgan, T.E.d , Finch, C.E.d , Mack, W.J.b e
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, United States
c Department of Civil and Environmental Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, United States
d Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States
e Department of Neurological Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
Abstract
Exposure to ambient air pollution has been associated with white matter damage and neurocognitive decline. However, the mechanisms of this injury are not well understood and remain largely uncharacterized in experimental models. Prior studies have shown that exposure to particulate matter (PM), a sub-fraction of air pollution, results in neuroinflammation, specifically the upregulation of inflammatory microglia. This study examines white matter and axonal injury, and characterizes microglial reactivity in the corpus callosum of mice exposed to 10 weeks (150 hours) of PM. Nanoscale particulate matter (nPM, aerodynamic diameter ≤200 nm) consisting primarily of traffic-related emissions was collected from an urban area in Los Angeles. Male C57BL/6J mice were exposed to either re-aerosolized nPM or filtered air for 5 hours/day, 3 days/week, for 10 weeks (150 hours; n = 18/group). Microglia were characterized by immunohistochemical double staining of ionized calcium-binding protein-1 (Iba-1) with inducible nitric oxide synthase (iNOS) to identify proinflammatory cells, and Iba-1 with arginase-1 (Arg) to identify anti-inflammatory/ homeostatic cells. Myelin injury was assessed by degraded myelin basic protein (dMBP). Oligodendrocyte cell counts were evaluated by oligodendrocyte transcription factor 2 (Olig2). Axonal injury was assessed by axonal neurofilament marker SMI-312. iNOS-expressing microglia were significantly increased in the corpus callosum of mice exposed to nPM when compared to those exposed to filtered air (2.2 fold increase; p<0.05). This was accompanied by an increase in dMBP (1.4 fold increase; p<0.05) immunofluorescent density, a decrease in oligodendrocyte cell counts (1.16 fold decrease; p<0.05), and a decrease in neurofilament SMI-312 (1.13 fold decrease; p<0.05) immunofluorescent density. Exposure to nPM results in increased inflammatory microglia, white matter injury, and axonal degradation in the corpus callosum of adult male mice. iNOS-expressing microglia release cytokines and reactive oxygen/ nitrogen species which may further contribute to the white matter damage observed in this model. © 2021 Connor et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIA01AG055367
National Institute of Environmental Health SciencesNIEHS01ES024936
Charles Edison FundCEF
Document Type: Article
Publication Stage: Final
Source: Scopus
“The Stroke Neuro-Imaging Phenotype Repository: An Open Data Science Platform for Stroke Research” (2021) Frontiers in Neuroinformatics
The Stroke Neuro-Imaging Phenotype Repository: An Open Data Science Platform for Stroke Research
(2021) Frontiers in Neuroinformatics, 15, art. no. 597708, .
Mohammadian Foroushani, H.a , Dhar, R.b , Chen, Y.c , Gurney, J.d , Hamzehloo, A.b , Lee, J.-M.c , Marcus, D.S.d
a Department of Electrical and System Engineering, School of Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Division of Neurocritical Care, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Division of Cerebrovascular Disease, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Stroke is one of the leading causes of death and disability worldwide. Reducing this disease burden through drug discovery and evaluation of stroke patient outcomes requires broader characterization of stroke pathophysiology, yet the underlying biologic and genetic factors contributing to outcomes are largely unknown. Remedying this critical knowledge gap requires deeper phenotyping, including large-scale integration of demographic, clinical, genomic, and imaging features. Such big data approaches will be facilitated by developing and running processing pipelines to extract stroke-related phenotypes at large scale. Millions of stroke patients undergo routine brain imaging each year, capturing a rich set of data on stroke-related injury and outcomes. The Stroke Neuroimaging Phenotype Repository (SNIPR) was developed as a multi-center centralized imaging repository of clinical computed tomography (CT) and magnetic resonance imaging (MRI) scans from stroke patients worldwide, based on the open source XNAT imaging informatics platform. The aims of this repository are to: (i) store, manage, process, and facilitate sharing of high-value stroke imaging data sets, (ii) implement containerized automated computational methods to extract image characteristics and disease-specific features from contributed images, (iii) facilitate integration of imaging, genomic, and clinical data to perform large-scale analysis of complications after stroke; and (iv) develop SNIPR as a collaborative platform aimed at both data scientists and clinical investigators. Currently, SNIPR hosts research projects encompassing ischemic and hemorrhagic stroke, with data from 2,246 subjects, and 6,149 imaging sessions from Washington University’s clinical image archive as well as contributions from collaborators in different countries, including Finland, Poland, and Spain. Moreover, we have extended the XNAT data model to include relevant clinical features, including subject demographics, stroke severity (NIH Stroke Scale), stroke subtype (using TOAST classification), and outcome [modified Rankin Scale (mRS)]. Image processing pipelines are deployed on SNIPR using containerized modules, which facilitate replicability at a large scale. The first such pipeline identifies axial brain CT scans from DICOM header data and image data using a meta deep learning scan classifier, registers serial scans to an atlas, segments tissue compartments, and calculates CSF volume. The resulting volume can be used to quantify the progression of cerebral edema after ischemic stroke. SNIPR thus enables the development and validation of pipelines to automatically extract imaging phenotypes and couple them with clinical data with the overarching aim of enabling a broad understanding of stroke progression and outcomes. © Copyright © 2021 Mohammadian Foroushani, Dhar, Chen, Gurney, Hamzehloo, Lee and Marcus.
Author Keywords
big data; containerized pipeline; deep learning; informatics; phenotype repository; stroke neuroimaging; XNAT
Funding details
National Institute of Neurological Disorders and StrokeNINDSK23 NS099440, P30 NS098577, R01 EB009352, R01 NS085419
Document Type: Article
Publication Stage: Final
Source: Scopus
“Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy” (2021) Frontiers in Oncology
Irradiation-Modulated Murine Brain Microenvironment Enhances GL261-Tumor Growth and Inhibits Anti-PD-L1 Immunotherapy
(2021) Frontiers in Oncology, 11, art. no. 693146, .
Garbow, J.R.a b , Johanns, T.M.b c , Ge, X.a , Engelbach, J.A.a , Yuan, L.d , Dahiya, S.e , Tsien, C.I.f i , Gao, F.g , Rich, K.M.d , Ackerman, J.J.H.a b c h
a Department of Radiology, Washington University, Saint Louis, MO, United States
b Alvin J. Siteman Cancer Center, Washington University, Saint Louis, MO, United States
c Department of Internal Medicine, Washington University, Saint Louis, MO, United States
d Department of Neurosurgery, Washington University, Saint Louis, MO, United States
e Division of Neuropathology, Department of Pathology and Immunology, Washington University, Saint Louis, MO, United States
f Department of Radiation Oncology, Washington University, Saint Louis, MO, United States
g Department of Surgery, Washington University, Saint Louis, MO, United States
h Department of Chemistry, Washington University, Saint Louis, MO, United States
i †Christina I. Tsien, Department of Radiation Oncology, Johns Hopkins Medicine, Baltimore, MD, United States
Abstract
Purpose: Clinical evidence suggests radiation induces changes in the brain microenvironment that affect subsequent response to treatment. This study investigates the effect of previous radiation, delivered six weeks prior to orthotopic tumor implantation, on subsequent tumor growth and therapeutic response to anti-PD-L1 therapy in an intracranial mouse model, termed the Radiation Induced Immunosuppressive Microenvironment (RI2M) model. Method and Materials: C57Bl/6 mice received focal (hemispheric) single-fraction, 30-Gy radiation using the Leksell GammaKnife® Perfexion™, a dose that does not produce frank/gross radiation necrosis. Non-irradiated GL261 glioblastoma tumor cells were implanted six weeks later into the irradiated hemisphere. Lesion volume was measured longitudinally by in vivo MRI. In a separate experiment, tumors were implanted into either previously irradiated (30 Gy) or non-irradiated mouse brain, mice were treated with anti-PD-L1 antibody, and Kaplan-Meier survival curves were constructed. Mouse brains were assessed by conventional hematoxylin and eosin (H&E) staining, IBA-1 staining, which detects activated microglia and macrophages, and fluorescence-activated cell sorting (FACS) analysis. Results: Tumors in previously irradiated brain display aggressive, invasive growth, characterized by viable tumor and large regions of hemorrhage and necrosis. Mice challenged intracranially with GL261 six weeks after prior intracranial irradiation are unresponsive to anti-PD-L1 therapy. K-M curves demonstrate a statistically significant difference in survival for tumor-bearing mice treated with anti-PD-L1 antibody between RI2M vs. non-irradiated mice. The most prominent immunologic change in the post-irradiated brain parenchyma is an increased frequency of activated microglia. Conclusions: The RI2M model focuses on the persisting (weeks-to-months) impact of radiation applied to normal, control-state brain on the growth characteristics and immunotherapy response of subsequently implanted tumor. GL261 tumors growing in the RI2M grew markedly more aggressively, with tumor cells admixed with regions of hemorrhage and necrosis, and showed a dramatic loss of response to anti-PD-L1 therapy compared to tumors in non-irradiated brain. IHC and FACS analyses demonstrate increased frequency of activated microglia, which correlates with loss of sensitivity to checkpoint immunotherapy. Given that standard-of-care for primary brain tumor following resection includes concurrent radiation and chemotherapy, these striking observations strongly motivate detailed assessment of the late effects of the RI2M on tumor growth and therapeutic efficacy. © Copyright © 2021 Garbow, Johanns, Ge, Engelbach, Yuan, Dahiya, Tsien, Gao, Rich and Ackerman.
Author Keywords
checkpoint inhibitors; immunotherapy; microenvironment; microglia; MRI; radiation; tumor
Funding details
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
“Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine” (2021) Frontiers in Neuroscience
Using Monozygotic Twins to Dissect Common Genes in Posttraumatic Stress Disorder and Migraine
(2021) Frontiers in Neuroscience, 15, art. no. 678350, .
Bainomugisa, C.K.a , Sutherland, H.G.a b , Parker, R.c , Mcrae, A.F.d , Haupt, L.M.a b , Griffiths, L.R.a b , Heath, A.e , Nelson, E.C.e , Wright, M.J.f g , Hickie, I.B.h , Martin, N.G.c , Nyholt, D.R.a , Mehta, D.a
a Centre for Genomics and Personalised Health, School of Biomedical Science, Faculty of Health, Queensland University of Technology, Kelvin Grove, QLD, Australia
b Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Institute of Health and Biomedical Innovation, Kelvin Grove, QLD, Australia
c QIMR Berghofer Medical Research Institute, Royal Brisbane Hospital, Herston, QLD, Australia
d Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
e Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
f Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
g Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
h Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia
Abstract
Epigenetic mechanisms have been associated with genes involved in Posttraumatic stress disorder (PTSD). PTSD often co-occurs with other health conditions such as depression, cardiovascular disorder and respiratory illnesses. PTSD and migraine have previously been reported to be symptomatically positively correlated with each other, but little is known about the genes involved. The aim of this study was to understand the comorbidity between PTSD and migraine using a monozygotic twin disease discordant study design in six pairs of monozygotic twins discordant for PTSD and 15 pairs of monozygotic twins discordant for migraine. DNA from peripheral blood was run on Illumina EPIC arrays and analyzed. Multiple testing correction was performed using the Bonferroni method and 10% false discovery rate (FDR). We validated 11 candidate genes previously associated with PTSD including DOCK2, DICER1, and ADCYAP1. In the epigenome-wide scan, seven novel CpGs were significantly associated with PTSD within/near IL37, WNT3, ADNP2, HTT, SLFN11, and NQO2, with all CpGs except the IL37 CpG hypermethylated in PTSD. These results were significantly enriched for genes whose DNA methylation was previously associated with migraine (p-value = 0.036). At 10% FDR, 132 CpGs in 99 genes associated with PTSD were also associated with migraine in the migraine twin samples. Genes associated with PTSD were overrepresented in vascular smooth muscle, axon guidance and oxytocin signaling pathways, while genes associated with both PTSD and migraine were enriched for AMPK signaling and longevity regulating pathways. In conclusion, these results suggest that common genes and pathways are likely involved in PTSD and migraine, explaining at least in part the co-morbidity between the two disorders. © Copyright © 2021 Bainomugisa, Sutherland, Parker, Mcrae, Haupt, Griffiths, Heath, Nelson, Wright, Hickie, Martin, Nyholt and Mehta.
Author Keywords
DNA methylation; genes; migraine; posttraumatic stress disorder; twins
Funding details
National Institutes of HealthNIHAA011998_5978, AA07728, AA10249, AA13321, AA13326, AA13446
National Health and Medical Research CouncilNHMRCAPP1069141
Queensland University of TechnologyQUT
Document Type: Article
Publication Stage: Final
Source: Scopus
“Sleep drive reconfigures wake-promoting clock circuitry to regulate adaptive behavior” (2021) PLoS Biology
Sleep drive reconfigures wake-promoting clock circuitry to regulate adaptive behavior
(2021) PLoS Biology, 19 (6), art. no. 3001324, .
Klose, M.K., Shaw, P.J.
Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Circadian rhythms help animals synchronize motivated behaviors to match environmental demands. Recent evidence indicates that clock neurons influence the timing of behavior by differentially altering the activity of a distributed network of downstream neurons. Downstream circuits can be remodeled by Hebbian plasticity, synaptic scaling, and, under some circumstances, activity-dependent addition of cell surface receptors; the role of this receptor respecification phenomena is not well studied. We demonstrate that high sleep pressure quickly reprograms the wake-promoting large ventrolateral clock neurons to express the pigment dispersing factor receptor (PDFR). The addition of this signaling input into the circuit is associated with increased waking and early mating success. The respecification of PDFR in both young and adult large ventrolateral neurons requires 2 dopamine (DA) receptors and activation of the transcriptional regulator nejire (cAMPAU : PleasenotethatCREB bindingproteinhasbeenchangedtoCREBthroughoutthearticletoenforceconsistency:response element-binding protein [CREB]). These data identify receptor respecification as an important mechanism to sculpt circuit function to match sleep levels with demand. © 2021 Public Library of Science. All rights reserved.
Document Type: Article
Publication Stage: Final
Source: Scopus
“Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder” (2021) Psychological Medicine
Investigation of convergent and divergent genetic influences underlying schizophrenia and alcohol use disorder
(2021) Psychological Medicine, pp. 1-9.
Johnson, E.C.a , Kapoor, M.b , Hatoum, A.S.a , Zhou, H.c d , Polimanti, R.c d , Wendt, F.R.c d , Walters, R.K.e f , Lai, D.g , Kember, R.L.h i , Hartz, S.a , Meyers, J.L.j k , Peterson, R.E.l , Ripke, S.e f m , Bigdeli, T.B.j , Fanous, A.H.j , Pato, C.N.j , Pato, M.T.j , Goate, A.M.b , Kranzler, H.R.h i , O’Donovan, M.C.n , Walters, J.T.R.n , Gelernter, J.c d o p , Edenberg, H.J.g q , Agrawal, A.a
a Department of Psychiatry, Washington University, School of Medicine, Saint Louis, MO, United States
b Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
c Department of Psychiatry, Division of Human Genetics, Yale University, School of Medicine, New Haven, CT, United States
d Department of Psychiatry, Veterans Affairs Connecticut Healthcare System, West Haven, CT, United States
e Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
f Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, United States
g Department of Medical and Molecular Genetics, Indiana University, School of Medicine, Indianapolis, IN, United States
h Department of Psychiatry, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, United States
i VISN 4 MIRECC, Crescenz VAMC, Philadelphia, PA, United States
j Department of Psychiatry and Behavioral Sciences, SUNY Downstate, Health Sciences University, Brooklyn, NY, United States
k Henri Begleiter Neurodynamics Laboratory, SUNY Downstate, Health Sciences University, Brooklyn, NY, United States
l Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, United States
m Department of Psychiatry and Psychotherapy, Charité – Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
n Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, School of Medicine, Cardiff, United Kingdom
o Department of Genetics, Yale University, School of Medicine, New Haven, CT, United States
p Department of Neuroscience, Yale University, School of Medicine, New Haven, CT, United States
q Department of Biochemistry and Molecular Biology, Indiana University, School of Medicine, Indianapolis, IN, United States
Abstract
Background Alcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and large-scale genome-wide association studies (GWAS) have identified significant genetic correlations between these disorders. Methods We used the largest published GWAS for AUD (total cases = 77 822) and SCZ (total cases = 46 827) to identify genetic variants that influence both disorders (with either the same or opposite direction of effect) and those that are disorder specific. Results We identified 55 independent genome-wide significant single nucleotide polymorphisms with the same direction of effect on AUD and SCZ, 8 with robust effects in opposite directions, and 98 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). Conclusions Our findings provide further evidence that SCZ shares meaningful genetic overlap with AUD. Copyright © The Author(s), 2021. Published by Cambridge University Press.
Author Keywords
Alcohol; genetic overlap; genome wide association study; pleiotropy; schizophrenia
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Associations between long-term psychosis risk, probabilistic category learning, and attenuated psychotic symptoms with cortical surface morphometry” (2021) Brain Imaging and Behavior
Associations between long-term psychosis risk, probabilistic category learning, and attenuated psychotic symptoms with cortical surface morphometry
(2021) Brain Imaging and Behavior, .
Hua, J.P.Y.a b , Karcher, N.R.a c , Straub, K.T.a , Kerns, J.G.a
a Department of Psychological Sciences, University of Missouri, Columbia, MO 65211, United States
b Department of Mental Health, San Francisco VA Medical Center, San Francisco, CA 94121, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Neuroimaging studies have consistently found structural cortical abnormalities in individuals with schizophrenia, especially in structural hubs. However, it is unclear what abnormalities predate psychosis onset and whether abnormalities are related to behavioral performance and symptoms associated with psychosis risk. Using surface-based morphometry, we examined cortical volume, gyrification, and thickness in a psychosis risk group at long-term risk for developing a psychotic disorder (n = 18; i.e., extreme positive schizotypy plus interview-rated attenuated psychotic symptoms [APS]) and control group (n = 19). Overall, the psychosis risk group exhibited cortical abnormalities in multiple structural hub regions, with abnormalities associated with poorer probabilistic category learning, a behavioral measure strongly associated with psychosis risk. For instance, the psychosis risk group had hypogyria in a right posterior midcingulate cortical hub and left superior parietal cortical hub, as well as decreased volume in a right pericalcarine hub. Morphometric measures in all of these regions were also associated with poorer probabilistic category learning. In addition to decreased right pericalcarine volume, the psychosis risk group exhibited a number of other structural abnormalities in visual network structural hub regions, consistent with previous evidence of visual perception deficits in psychosis risk. Further, severity of APS hallucinations, delusional ideation, and suspiciousness/persecutory ideas were associated with gyrification abnormalities, with all domains associated with hypogyria of the right lateral orbitofrontal cortex. Thus, current results suggest that structural abnormalities, especially in structural hubs, are present in psychosis risk and are associated both with poor learning on a psychosis risk-related task and with APS severity. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
MRI; Positive schizotypy; Structural hub; Surface-based morphometry; Visual network
Funding details
National Institute of Mental HealthNIMHR21 MH100359
University of MissouriMUT32 MH014677
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Does raising the arms modify head tremor severity in cervical dystonia?” (2021) Tremor and Other Hyperkinetic Movements
Does raising the arms modify head tremor severity in cervical dystonia?
(2021) Tremor and Other Hyperkinetic Movements, 11 (1), art. no. 21, .
Cisneros, E.a , Vu, J.P.a , Lee, H.Y.a , Chen, Q.a , Benadof, C.N.a , Zhang, Z.a , Pettitt, E.A.a , Joshi, S.K.a , Barbano, R.L.b , Jankovic, J.c , Jinnah, H.A.d , Perlmutter, J.S.e f , Berman, B.D.g , Mahajan, A.h , Goetz, C.G.h , Stebbins, G.T.h , Comella, C.L.h , Peterson, D.A.a i
a Institute for Neural Computation, University of California, San Diego, La Jolla, CA, United States
b Department of Neurology, University of Rochester, Rochester, NY, United States
c Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, United States
d Departments of Neurology and Human Genetics, Emory University, Atlanta, GA, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
g Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States
h Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
i Computational Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, United States
Abstract
Background: A defining characteristic of dystonia is its position-dependence. In cervical dystonia (CD), sensory tricks ameliorate head tremor (HT). But it remains unknown whether raising the arms alone has the same impact. Methods: We analyzed data collected from patients enrolled by the Dystonia Coalition. For 120 patients with HT, we assessed how raising their arms without touching their head changed their HT severity. Results: Forty-eight out of 120 patients exhibited changes in HT severity when raising their arms. These patients were more likely to exhibit decreases in HT severity (N = 35) than increases (N = 13, χ2 (1, N = 48) = 10.1, p = 0.002). Demographic factors and sensory trick efficacy were not significant predictors of whether HT severity changed when raising their arms. Discussion: Raising the arms without touching the head is a posture that can reduce HT severity in some CD patients. Our results extend the concept of position-dependent motor symptoms in CD to include the position of the arms. Highlights Head tremor (HT) is a prevalent symptom of cervical dystonia (CD) that can often be disabling. This study demonstrates that raising the arms without touching the head is a posture that can reduce HT severity in some CD patients. Our findings also identify a novel form of position-dependence in CD. © 2021 The Author(s).
Author Keywords
Cervical dystonia; Dystonic tremor; Head tremor; Posture
Funding details
U54 TR001456
U54 NS065701, U54 NS116025
W81XWH-17-1-0393
U.S. Department of DefenseDOD
Dystonia Coalition
Rare Diseases Clinical Research NetworkRDCRN
Document Type: Article
Publication Stage: Final
Source: Scopus
“Brain volume in chronic ketamine users — relationship to sub-threshold psychotic symptoms and relevance to schizophrenia” (2021) Psychopharmacology
Brain volume in chronic ketamine users — relationship to sub-threshold psychotic symptoms and relevance to schizophrenia
(2021) Psychopharmacology, .
Chesters, R.A.a b , Pepper, F.a b , Morgan, C.c , Cooper, J.D.a b d , Howes, O.D.a b e f , Vernon, A.C.a b f , Stone, J.M.a b e g h
a Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
b Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London, SE5 8AF, United Kingdom
c University of Exeter, Exeter, United Kingdom
d Departments of Pediatrics, Genetics and Neurology, Medical School, Washington University in St Louis, 660S Euclid Ave, St Louis, MO 63110, United States
e South London and Maudsley NHS Trust, London, SE5 8AZ, United Kingdom
f MRC Centre for Neurodevelopmental Disorders, King’s College London, London, SE1 1UL, United Kingdom
g Department of Neuroscience, Brighton and Sussex Medical School, University of Sussex, Falmer, BN1 9RY, United Kingdom
h Sussex Partnership NHS Foundation Trust, Eastbourne, BN21 2UD, United Kingdom
Abstract
Rationale: Ketamine may model aspects of schizophrenia arising through NMDA receptor activity deficits. Although acute ketamine can induce effects resembling both positive and negative psychotic symptoms, chronic use may be a closer model of idiopathic psychosis. Objectives: We tested the hypotheses that ketamine users had lower brain volumes, as measured using MRI, and greater sub-threshold psychotic symptoms relative to a poly-drug user control group. Methods: Ketamine users (n = 17) and poly-drug using controls (n = 19) were included in the study. All underwent volumetric MRI imaging and measurement of sub-threshold psychotic symptoms using the Comprehensive Assessment of At-Risk Mental State (CAARMS). Freesurfer was used to analyse differences in regional brain volume, cortical surface area and thickness between ketamine users and controls. The relationship between CAARMS ratings and brain volume was also investigated in ketamine users. Results: Ketamine users were found to have significantly lower grey matter volumes of the nucleus accumbens, caudate nucleus, cerebellum and total cortex (FDR p < 0.05; Cohen’s d = 0.36–0.75). Within the cortex, ketamine users had significantly lower grey matter volumes within the frontal, temporal and parietal cortices (Cohen’s d 0.7–1.31; FDR p < 0.05). They also had significantly higher sub-threshold psychotic symptoms (p < 0.05). Frequency of ketamine use showed an inverse correlation with cerebellar volume (p < 0.001), but there was no relationship between regional brain volumes and sub-threshold psychotic symptoms. Conclusions: Chronic ketamine use may cause lower grey matter volumes as well as inducing sub-threshold psychotic symptoms, although these likely arise through distinct mechanisms. © 2021, The Author(s).
Author Keywords
Brain volume; Ketamine; MRI; Psychosis; Schizophrenia
Funding details
Eli Lilly and Company
AstraZeneca
Roche
Medical Research CouncilMRCMC_A656_5QD30
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Long Acellular Nerve Allografts Cap Transected Nerve to Arrest Axon Regeneration and Alter Upstream Gene Expression in a Rat Neuroma Model” (2021) Plastic and Reconstructive Surgery
Long Acellular Nerve Allografts Cap Transected Nerve to Arrest Axon Regeneration and Alter Upstream Gene Expression in a Rat Neuroma Model
(2021) Plastic and Reconstructive Surgery, pp. 32E-41E.
Pan, D., Bichanich, M., Wood, I.S., Hunter, D.A., Tintle, S.M., Davis, T.A., Wood, M.D., Moore, A.M.
From the Division of Plastic and Reconstructive Surgery Washington University School of Medicine; the Department of Plastic and Reconstructive Surgery Medical College of Wisconsin Affiliated Hospitals; Orthopaedics and the Department of Surgery Uniformed Services University of the Health Sciences-Walter Reed National Military Medical Center; and the Department of Plastic and Reconstructive Surgery The Ohio State University Wexner Medical Center.
Abstract
Background: Treatments to manage painful neuroma are needed. An operative strategy that isolates and controls chaotic axonal growth could prevent neuroma. Using long acellular nerve allograft to “cap” damaged nerve could control axonal regeneration and, in turn, regulate upstream gene expression patterns. Methods: Rat sciatic nerve was transected, and the distal nerve end was reversed and ligated to generate a model end-neuroma. Three groups were used to assess their effects immediately following this nerve injury: no treatment (control), traction neurectomy, or 5-cm acellular nerve allograft cap attached to the proximal nerve. Regeneration of axons from the injured nerve was assessed over 5 months and paired with concurrent measurements of gene expression from upstream affected dorsal root ganglia. Results: Both control and traction neurectomy groups demonstrated uncontrolled axon regeneration revealed using Thy1-GFP rat axon imaging and histomorphometric measures of regenerated axons within the most terminal region of regenerated tissue. The acellular nerve allograft group arrested axons within the acellular nerve allograft, where no axons reached the most terminal region even after 5 months. At 5 months, gene expression associated with regeneration and pain sensitization, including Bdnf, cfos, and Gal, was decreased within dorsal root ganglia obtained from the acellular nerve allograft group compared to control or traction neurectomy group dorsal root ganglia. Conclusions: Long acellular nerve allografts to cap a severed nerve arrested axon regeneration within the acellular nerve allograft. This growth arrest corresponded with changes in regenerative and pain-related genes upstream. Acellular nerve allografts may be useful for surgical intervention of neuroma. © 2021 Lippincott Williams and Wilkins. All rights reserved.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Digital Technology Differentiates Graphomotor and Information Processing Speed Patterns of Behavior” (2021) Journal of Alzheimer’s Disease
Digital Technology Differentiates Graphomotor and Information Processing Speed Patterns of Behavior
(2021) Journal of Alzheimer’s Disease, 82 (1), pp. 17-32. Cited 1 time.
Andersen, S.L.a , Sweigart, B.b , Glynn, N.W.c , Wojczynski, M.K.d , Thyagarajan, B.e , Mengel-From, J.f , Thielke, S.g , Perls, T.T.a , Libon, D.J.h , Au, R.i j , Cosentino, S.k l , Sebastianion, P.m
a Geriatrics Section, Department of Medicine, Boston University School of Medicine, Boston, MA, United States
b Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
c Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
e Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, MN, United States
f Institute of Public Health, Epidemiology Biostatistics and Biodemography Unit, University of Southern Denmark, Odense, Denmark
g Geriatric Research, Education and Clinical Center, Puget Sound VA Medical Center, Seattle, WA, United States
h New Jersey Institute for Successful Aging, School of Osteopathic Medicine, Rowan University, Stratford, NJ, United States
i Department of Anatomy and Neurobiology and Neurology, Boston University School of Medicine, Boston, MA, United States
j Department of Epidemiology, Boston University School of Public Health, Boston, MA, United States
k Cognitive Neuroscience Division of the Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, United States
l Gertrude H. Sergievsky Center, Columbia University, New York, NY, United States
m Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, United States
Abstract
Background: Coupling digital technology with traditional neuropsychological test performance allows collection of high-precision metrics that can clarify and/or define underlying constructs related to brain and cognition. Objective: To identify graphomotor and information processing trajectories using a digitally administered version of the Digit Symbol Substitution Test (DSST). Methods: A subset of Long Life Family Study participants (n = 1,594) completed the DSST. Total time to draw each symbol was divided into ‘writing’ and non-writing or ‘thinking’ time. Bayesian clustering grouped participants by change in median time over intervals of eight consecutively drawn symbols across the 90 s test. Clusters were characterized based on sociodemographic characteristics, health and physical function data, APOE genotype, and neuropsychological test scores. Results: Clustering revealed four ‘thinking’ time trajectories, with two clusters showing significant changes within the test. Participants in these clusters obtained lower episodic memory scores but were similar in other health and functional characteristics. Clustering of ‘writing’ time also revealed four performance trajectories where one cluster of participants showed progressively slower writing time. These participants had weaker grip strength, slower gait speed, and greater perceived physical fatigability, but no differences in cognitive test scores. Conclusion: Digital data identified previously unrecognized patterns of ‘writing’ and ‘thinking’ time that cannot be detected without digital technology. These patterns of performance were differentially associated with measures of cognitive and physical function and may constitute specific neurocognitive biomarkers signaling the presence of subtle to mild dysfunction. Such information could inform the selection and timing of in-depth neuropsychological assessments and help target interventions. © 2021 – IOS Press. All rights reserved.
Author Keywords
Aging; bayesian approach; boston process approach; digit symbol substitution test; executive function; graphomotor performance; neuropsychological tests
Funding details
National Institutes of HealthNIHP30 AG024827
National Institute on AgingNIAK01AG057798, U01AG023712, U01AG023744, U01AG023746, U01AG023749, U01AG023755, U19AG063893
National Institute of General Medical SciencesNIGMST32 GM74905
Document Type: Article
Publication Stage: Final
Source: Scopus
“Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer’s Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study” (2021) Journal of Alzheimer’s Disease
Cerebral Blood Flow Predicts Conversion of Mild Cognitive Impairment into Alzheimer’s Disease and Cognitive Decline: An Arterial Spin Labeling Follow-up Study
(2021) Journal of Alzheimer’s Disease, 82 (1), pp. 293-305.
Duan, W.a , Zhou, G.D.a , Balachandrasekaran, A.b , Bhumkar, A.B.a , Boraste, P.B.a , Becker, J.T.c , Kuller, L.H.d , Lopez, O.L.e , Gach, H.M.f , Dai, W.a
a Computer Science, State University of New York at Binghamton, Binghamton, NY, United States
b Harvard Medical School/Boston Children’s Hospital, Boston, MA, United States
c Psychiatry, Psychology and Neurology, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, United States
e Neurology and Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
f Radiation Oncology, Radiology and Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
Abstract
Background: This is the first longitudinal study to assess regional cerebral blood flow (rCBF) changes during the progression from normal control (NC) through mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: We aim to determine if perfusion MRI biomarkers, derived from our prior cross-sectional study, can predict the onset and cognitive decline of AD. Methods: Perfusion MRIs using arterial spin labeling (ASL) were acquired in 15 stable-NC, 14 NC-to-MCI, 16 stable-MCI, and 18 MCI/AD-to-AD participants from the Cardiovascular Health Study (CHS) cognition study. Group comparisons, predictions of AD conversion and time to conversion, and Modified Mini-Mental State Examination (3MSE) from rCBF were performed. Results: Compared to the stable-NC group: 1) the stable-MCI group exhibited rCBF decreases in the right temporoparietal (p = 0.00010) and right inferior frontal and insula (p = 0.0094) regions; and 2) the MCI/AD-to-AD group exhibited rCBF decreases in the bilateral temporoparietal regions (p = 0.00062 and 0.0035). Compared to the NC-to-MCI group, the stable-MCI group exhibited a rCBF decrease in the right hippocampus region (p = 0.0053). The baseline rCBF values in the posterior cingulate cortex (PCC) (p = 0.0043), bilateral superior medial frontal regions (BSMF) (p = 0.012), and left inferior frontal (p = 0.010) regions predicted the 3MSE scores for all the participants at follow-up. The baseline rCBF in the PCC and BSMF regions predicted the conversion and time to conversion from MCI to AD (p < 0.05; not significant after multiple corrections). Conclusion: We demonstrated the feasibility of ASL in detecting rCBF changes in the typical AD-affected regions and the predictive value of baseline rCBF on AD conversion and cognitive decline. © 2021 – IOS Press. All rights reserved.
Author Keywords
Alzheimer’s disease; arterial spin labeling; cerebral blood flow; longitudinal study; mild cognitive impairment; prediction
Funding details
National Institute on AgingNIAHL080295, N01 HC-15103, N01 HC-55222, N01-HC-35129, N01-HC-45133, N01-HC-75150, N01-HC-85079, N01-HC-85086, N01-HC-85239
National Heart, Lung, and Blood InstituteNHLBI
National Institute of Neurological Disorders and StrokeNINDS
State University of New YorkSUNY
Washington University in St. LouisWUSTLR01AG066430
University of Pittsburgh
Document Type: Article
Publication Stage: Final
Source: Scopus