WashU weekly Neuroscience publications

Acrylamide inhibits long-term potentiation and learning involving microglia and pro-inflammatory signaling
(2022) Scientific Reports, 12 (1), art. no. 12429, . 

Izumi, Y.^a b , Fujii, C.^a , O’Dell, K.A.^a b , Zorumski, C.F.^a b

^a Departments of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Acrylamide is a chemical used in various industries and a product following high-temperature cooking of vegetables containing asparagine. Environmental or dietary exposure to acrylamide could impair cognitive function because of its neurotoxicity. Using rat hippocampal slices, we tested whether acrylamide alters induction of long-term potentiation (LTP), a cellular model of learning and memory. We hypothesized that acrylamide impairs cognitive function via activation of pro-inflammatory cytokines because robust upregulation of NLRP3 inflammasome has been reported. Although acrylamide up to 3 mM did not alter basal synaptic transmission, incubation with 10 μM or acute administration of 100 μM acrylamide inhibited induction of LTP. Inhibitors of toll-like receptor 4 (TLR4), and minocycline, an inhibitor of microglial activation, overcame the effects of acrylamide on LTP induction. Furthermore, we observed that acrylamide failed to inhibit LTP after administration of MCC950, an inhibitor of NLRP3, or in the presence of Interleukin-1 receptor antagonist (IL-1Ra). We also found that in vivo acrylamide injection transiently impaired body weight gain and impaired one-trial inhibitory avoidance learning. This learning deficit was overcome by MCC950. These results indicate that cognitive impairment by acrylamide is mediated by mechanisms involving microglia and release of cytokines via NLRP3 activation. © 2022, The Author(s).

Funding details
Banting Research FoundationBRF
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis

Document Type: Article
Publication Stage: Final
Source: Scopus

BOLD cofluctuation ‘events’ are predicted from static functional connectivity
(2022) NeuroImage, 260, art. no. 119476, . 

Ladwig, Z.^a , Seitzman, B.A.^d , Dworetsky, A.^b , Yu, Y.^b , Adeyemo, B.^f , Smith, D.M.^j , Petersen, S.E.^{e f g h i} , Gratton, C.^a b c

^a Interdepartmental Neuroscience Program, Northwestern University
^b Department of Psychology, Northwestern University
^c Department of Neurology, Northwestern University
^d Department of Radiation Oncology, Washington University St. Louis School of Medicine
^e Department of Radiology, Washington University St. Louis School of Medicine
^f Department of Neurology, Washington University St. Louis School of Medicine
^g Department of Psychological and Brain Sciences, Washington University St. Louis School of Medicine
^h Department of Neuroscience, Washington University St. Louis School of Medicine
ⁱ Department of Biomedical Engineering, Washington University St. Louis School of Medicine
^j Division of Cognitive Neurology/Neuropsychology, The Johns Hopkins University School of Medicine

Abstract
Recent work identified single time points (“events”) of high regional cofluctuation in functional Magnetic Resonance Imaging (fMRI) which contain more large-scale brain network information than other, low cofluctuation time points. This suggested that events might be a discrete, temporally sparse signal which drives functional connectivity (FC) over the timeseries. However, a different, not yet explored possibility is that network information differences between time points are driven by sampling variability on a constant, static, noisy signal. Using a combination of real and simulated data, we examined the relationship between cofluctuation and network structure and asked if this relationship was unique, or if it could arise from sampling variability alone. First, we show that events are not discrete – there is a gradually increasing relationship between network structure and cofluctuation; ∼50% of samples show very strong network structure. Second, using simulations we show that this relationship is predicted from sampling variability on static FC. Finally, we show that randomly selected points can capture network structure about as well as events, largely because of their temporal spacing. Together, these results suggest that, while events exhibit particularly strong representations of static FC, there is little evidence that events are unique timepoints that drive FC structure. Instead, a parsimonious explanation for the data is that events arise from a single static, but noisy, FC structure. © 2022 The Author(s)

Author Keywords
Cofluctuations;  Events;  Networks;  Resting-state fMRI;  RSFC;  Simulations

Funding details
National Science FoundationNSFCAREER2048066
National Institutes of HealthNIHR01MH118370
Division of Mathematical SciencesDMST32NS047987
Northwestern UniversityNU
Office of the Provost, University of South Carolina
Biological Anthropology SectionBAS
Office of Research-Wichita, School of Medicine, University of KansasOoR

Document Type: Article
Publication Stage: Final
Source: Scopus

Peripheral nerve development in zebrafish requires muscle patterning by tcf15/paraxis
(2022) Developmental Biology, 490, pp. 37-49. 

Limbach, L.E.^a , Penick, R.L.^a , Casseday, R.S.^a , Hyland, M.A.^a , Pontillo, E.A.^b , Ayele, A.N.^a , Pitts, K.M.^b , Ackerman, S.D.^c , Harty, B.L.^c , Herbert, A.L.^c , Monk, K.R.^c , Petersen, S.C.^a b c

^a Department of Neuroscience, Kenyon College, Gambier, OH, United States
^b Department of Biology, Kenyon College, Gambier, OH, United States
^c Department of Developmental Biology, Washington University in St. LouisMO, United States

Abstract
The vertebrate peripheral nervous system (PNS) is an intricate network that conveys sensory and motor information throughout the body. During development, extracellular cues direct the migration of axons and glia through peripheral tissues. Currently, the suite of molecules that govern PNS axon-glial patterning is incompletely understood. To elucidate factors that are critical for peripheral nerve development, we characterized the novel zebrafish mutant, stl159, that exhibits abnormalities in PNS patterning. In these mutants, motor and sensory nerves that develop adjacent to axial muscle fail to extend normally, and neuromasts in the posterior lateral line system, as well as neural crest-derived melanocytes, are incorrectly positioned. The stl159 genetic lesion lies in the basic helix-loop-helix (bHLH) transcription factor tcf15, which has been previously implicated in proper development of axial muscles. We find that targeted loss of tcf15 via CRISPR-Cas9 genome editing results in the PNS patterning abnormalities observed in stl159 mutants. Because tcf15 is expressed in developing muscle prior to nerve extension, rather than in neurons or glia, we predict that tcf15 non-cell-autonomously promotes peripheral nerve patterning in zebrafish through regulation of extracellular patterning cues. Our work underscores the importance of muscle-derived factors in PNS development. © 2022 Elsevier Inc.

Author Keywords
Lateral line nerve;  Myelin;  Paraxial mesoderm;  Schwann cells;  Zebrafish

Funding details
National Science FoundationNSF1941664, R01 HD080601
National Institutes of HealthNIHF32 NS087786
Washington University in St. LouisWUSTL

Document Type: Article
Publication Stage: Final
Source: Scopus

Psychedelic drugs for psychiatric disorders
(2022) Journal of the Neurological Sciences, 440, art. no. 120332, . 

da Costa, S.C.^a , Oesterle, T.^b , Rummans, T.A.^b , Richelson, E.^c , Gold, M.^d

^a Department of Psychiatry and Psychology, Mayo Clinic Health System, La Crosse, WI, United States
^b Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
^c Department of Psychiatry and Psychology, Mayo Clinic Florida, Jacksonville, FL, United States
^d University of Florida & McKnight Brain Institute, Department of Psychiatry and National Council, Institute for Public Health, Washington University in St Louis School of Medicine, United States

Abstract
Existing pharmacological treatments for psychiatric disorders have demonstrated limited efficacy, delayed onset of action, and significant burden of side effects. Recent findings from human studies with psychedelics have shown promise, demonstrating rapid and sustained clinical benefits of these compounds for a variety of psychiatric disorders. Classical psychedelics have a rich history and some of these compounds have been used in shamanic and spiritual ceremonies for millennia. The psychoactive effects of these drugs, particularly on human consciousness, have generated great scientific curiosity, and early research on psychedelics suggested their clinical benefits for psychiatric conditions, including alcohol use disorders and anxiety and depressive symptoms in terminal illness and life-threatening conditions. Since the 1990s, after a period of dormancy that followed the criminalization of psychedelic drugs since the Controlled Substance Act of 1970, the continued interest in their unique psychoactive effects along with the pursuit for novel and more effective treatments in psychiatry have led to a renewed interest in research on these compounds. While preliminary findings on psychedelics are encouraging, current evidence is still insufficient to support extensive use of these drugs routinely. Long-term safety and efficacy of these compounds remain unclear, and several clinical trials are underway and may add clarity to these questions. Therefore, this article intends to provide an overview of the evidence to date on psychedelic drugs – particularly psilocybin, MDMA, and LSD – for the treatment of psychiatric disorders. © 2022

Author Keywords
Hallucinogens;  LSD;  MDMA (ecstasy);  Psilocybin;  Psychedelic-assisted psychotherapy;  Psychedelics;  Psychiatric disorders

Document Type: Article
Publication Stage: Final
Source: Scopus

Minimal change prion retinopathy: Morphometric comparison of retinal and brain prion deposits in Creutzfeldt-Jakob disease
(2022) Experimental Eye Research, 222, art. no. 109172, . 

Goodwill, V.S.^a , Dryden, I.^b c , Choi, J.^b c , De Lillo, C.^b , Soldau, K.^a , Llibre-Guerra, J.^e f , Sanchez, H.^d , Sigurdson, C.J.^a , Lin, J.H.^b c

^a Department of Pathology, University of California, San Diego, CA 92093, United States
^b Departments of Pathology and Ophthalmology, Stanford UniversityCA 94305, United States
^c VA Palo Alto Healthcare System, Palo AltoCA 94304, United States
^d Department of Neurology, University of California, San Francisco, CA 94143, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO 63108, United States
^f Global Brain Health Institute, University of California, San Francisco, CA 94143, United States

Abstract
Sporadic Creutzfeldt-Jakob disease (sCJD) is the most commonly diagnosed human prion disease caused by the abnormal misfolding of the ‘cellular’ prion protein (PrPC) into the transmissible ‘scrapie-type’ prion form (PrPSc). Neuropathologic evaluation of brains with sCJD reveals abnormal PrPSc deposits primarily in grey matter structures, often associated with micro-vacuolar spongiform changes in neuropil, neuronal loss, and gliosis. Abnormal PrPSc deposits have also been reported in the retina of patients with sCJD, but few studies have characterized the morphology of these retinal PrPSc deposits or evaluated for any retinal neurodegenerative changes. We performed histopathologic and morphometric analyses of retinal and brain prion deposits in 14 patients with sCJD. Interestingly, we discovered that the morphology of retinal PrPSc deposits generally differs from that of brain PrPSc deposits in terms of size and shape. We found that retinal PrPSc deposits consistently localize to the outer plexiform layer of the retina. Additionally, we observed that the retinal PrPSc deposits are not associated with the spongiform change, neuronal loss, and gliosis often seen in the brain. The stereotypic morphology and location of PrPSc deposits in sCJD retinas may help guide the use of ocular imaging devices in the detection of these deposits for a clinical diagnosis. © 2022

Author Keywords
Brain;  Eye;  Immunohistochemistry;  Prion;  Retina;  Spongiform encephalopathy;  sporadic Creutzfeldt-Jakob disease

Funding details
National Institutes of HealthNIHNS069566, NS076896, R01NS088485
U.S. Department of Veterans AffairsVAI01BX002284, I01RX002340

Document Type: Article
Publication Stage: Final
Source: Scopus

Long-term prescription opioid users’ risk for new-onset depression increases with frequency of use
(2022) Pain, 163 (8), pp. 1581-1589. 

Scherrer, J.F.^a , Salas, J.^a b , Miller-Matero, L.R.^c , Sullivan, M.D.^d , Ballantyne, J.C.^e , Debar, L.^f , Grucza, R.A.^a , Lustman, P.J.^g , Ahmedani, B.^c

^a Department of Family and Community Medicine, Saint Louis University School of Medicine, 1402 N. Grand Blvd, St. Louis, MO 63104, United States
^b Advanced HEAlth Data (AHEAD) Research Institute, Saint Louis University School of Medicine, St. Louis, MO, United States
^c Center for Health Policy and Health Services Research and Behavioral Health Services, Henry Ford Health System, One Ford Place, Detroit, MI, United States
^d Department of Psychiatry and Behavioral Science, University of Washington School of Medicine, Seattle, WA, United States
^e Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, United States
^f Kaiser Permanente Washington Health Research Institute, Seattle, WA, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Long-term opioid therapy (LTOT) is associated with increased risk for depression. It is not known if the frequency of opioid use during LTOT is associated with new-onset depression. We used Optum’s de-identified Integrated Claims-Clinical dataset (2010-2018) to create a cohort of 5146 patients, 18 to 80 years of age, with an encounter or claims in the year before new LTOT. New LTOT was defined by >90-day opioid use after remaining opioid free for 6 months. Opioid use frequency during the first 90 days of LTOT was categorized into occasional use (<50% days covered), intermittent use (50% to <80% days covered), frequent use (80% to <90% days covered), and daily use (≥90% days covered). Propensity scores and inverse probability of exposure weighting controlled for confounding in models estimating risk for new-onset depression. Patients were on average 54.5 (SD ± 13.6) years of age, 55.7% were female, 72.5% were White, and 9.5% were African American. After controlling for confounding, daily users (hazard ratio = 1.40; 95% confidence interval: 1.14-1.73) and frequent users (hazard ratio = 1.34; 95% confidence interval: 1.05-1.71) were significantly more likely to develop new-onset depression compared with occasional users. This association remained after accounting for the contribution of post-index pain diagnoses and opioid use disorder. In LTOT, risk for new depression episodes is up to 40% greater in near-daily users compared with occasional users. Patients could reduce depression risk by avoiding opioid use on as many low pain days as possible. Repeated screening for depression during LTOT is warranted. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
Cohort;  Depression;  Epidemiology;  Opioid;  Pain

Document Type: Article
Publication Stage: Final
Source: Scopus

The cannabinoid agonist CB-13 produces peripherally mediated analgesia in mice but elicits tolerance and signs of central nervous system activity with repeated dosing
(2022) Pain, 163 (8), pp. 1603-1621. 

Slivicki, R.A.^a , Yi, J.^a b , Brings, V.E.^a , Huynh, P.N.^a , Gereau, R.W.^a c d

^a Department of Anesthesiology, Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Neuroscience Graduate Program, Division of Biology & Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neuroscience, Washington University, St. Louis, MO, United States
^d Department of Biomedical Engineering, Washington University, St. Louis, MO, United States

Abstract
Activation of cannabinoid receptor type 1 (CB1) produces analgesia in a variety of preclinical models of pain; however, engagement of central CB1receptors is accompanied by unwanted side effects, such as psychoactivity, tolerance, and dependence. Therefore, some efforts to develop novel analgesics have focused on targeting peripheral CB1receptors to circumvent central CB1-related side effects. In the present study, we evaluated the effects of acute and repeated dosing with the peripherally selective CB1-preferring agonist CB-13 on nociception and central CB1-related phenotypes in a model of inflammatory pain in mice. We also evaluated cellular mechanisms underlying CB-13-induced antinociception in vitro using cultured mouse dorsal root ganglion neurons. CB-13 reduced inflammation-induced mechanical allodynia in male and female mice in a peripheral CB1-receptor-dependent manner and relieved inflammatory thermal hyperalgesia. In cultured mouse dorsal root ganglion neurons, CB-13 reduced TRPV1 sensitization and neuronal hyperexcitability induced by the inflammatory mediator prostaglandin E2, providing potential mechanistic explanations for the analgesic actions of peripheral CB1receptor activation. With acute dosing, phenotypes associated with central CB1receptor activation occurred only at a dose of CB-13 approximately 10-fold the ED50for reducing allodynia. Strikingly, repeated dosing resulted in both analgesic tolerance and CB1receptor dependence, even at a dose that did not produce central CB1-receptor-mediated phenotypes on acute dosing. This suggests that repeated CB-13 dosing leads to increased CNS exposure and unwanted engagement of central CB1receptors. Thus, caution is warranted regarding therapeutic use of CB-13 with the goal of avoiding CNS side effects. Nonetheless, the clear analgesic effect of acute peripheral CB1receptor activation suggests that peripherally restricted cannabinoids are a viable target for novel analgesic development. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
Cannabinoid;  CB-13;  CB1;  Hyperexcitability;  Pain;  Peripherally restricted;  PGE2;  TRPV1

Funding details
National Institute on Drug AbuseNIDAF32 DA051160
National Institute of General Medical SciencesNIGMST32 GM108539
National Institute of Neurological Disorders and StrokeNINDSR01 NS042595, R34 NS126036
American Heart AssociationAHA
Washington University in St. LouisWUSTL

Document Type: Article
Publication Stage: Final
Source: Scopus

Detecting slow narrowband modulation in EEG signals
(2022) Journal of Neuroscience Methods, 378, p. 109660. 

Loe, M.E.^a , Morrissey, M.J.^b , Tomko, S.R.^c , Guerriero, R.M.^c , Ching, S.^a

^a Department of Electrical and Systems Engineering, Washington University in St. Louis, 1 Brookings Drive, St. Louis 63130, MO, USA
^b St. Louis Children’s Hospital, One Children’s Place, St. Louis 63110, MO, USA
^c Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis 63110, MO, USA

Abstract
BACKGROUND: We observed an unusual modulatory phenomenon in the electroencephalogram (EEG) of pediatric patients with acquired brain injury. The modulation is orders of magnitude slower than the fast EEG background activity, necessitating new analysis procedures to systematically detect and quantify the phenomenon. NEW METHOD: We propose a method for analyzing spatial and temporal relationships associated with slow, narrowband modulation of EEG. We extract envelope signals from physiological frequency bands of EEG. Then, we construct a sparse representation of the spectral content of the envelope signal across sliding windows. For the latter, we use an augmented LASSO regression to incorporate spatial and temporal filtering into the solution. The method can be applied to windows of variable length, depending on the desired frequency resolution. RESULTS: The sparse estimates of the envelope power spectra enable the detection of narrowband modulation in the millihertz frequency range. Subsequently, we are able to assess non-stationarity in the frequency and spatial relationships across channels. The method can be paired with unsupervised anomaly detection to identify windows with significant modulation. We validated such findings by applying our method to a control set of EEGs. COMPARISON WITH EXISTING METHODS: To our knowledge, no methods have been previously proposed to quantify second order modulation at such disparate time-scales. CONCLUSIONS: We provide a general EEG analysis framework capable of detecting signal content below 0.1 Hz, which is especially germane to clinical recordings that may contain multiple hours worth of continuous data. Copyright © 2022 Elsevier B.V. All rights reserved.

Author Keywords
EEG modulation;  Slow oscillations

Document Type: Article
Publication Stage: Final
Source: Scopus

Electro-mechanical coupling of KCNQ channels is a target of epilepsy-associated mutations and retigabine
(2022) Science Advances, 8 (29), p. eabo3625. 

Yang, N.-D.^a , Kanyo, R.^b , Zhao, L.^a , Li, J.^b , Kang, P.W.^a , Dou, A.K.^a , White, K.M.^a , Shi, J.^a , Nerbonne, J.M.^c , Kurata, H.T.^b , Cui, J.^a

^a Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, and Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO 63130, USA
^b Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada
^c Departments of Developmental Biology and Internal Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110, USA

Abstract
KCNQ2 and KCNQ3 form the M-channels that are important in regulating neuronal excitability. Inherited mutations that alter voltage-dependent gating of M-channels are associated with neonatal epilepsy. In the homolog KCNQ1 channel, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, physiological, and pharmacological properties of KCNQ1. However, whether the M-channel shares the same mechanism is unclear. Here, we show that KCNQ2 and KCNQ3 feature only a single conductive AO state but with a conserved mechanism for the electro-mechanical (E-M) coupling between voltage sensor activation and pore opening. We identified some epilepsy-linked mutations in KCNQ2 and KCNQ3 that disrupt E-M coupling. The antiepileptic drug retigabine rescued KCNQ3 currents that were abolished by a mutation disrupting E-M coupling, suggesting that modulating the E-M coupling in KCNQ channels presents a potential strategy for antiepileptic therapy.

Document Type: Article
Publication Stage: Final
Source: Scopus

Graded Variation in T1w/T2w Ratio during Adolescence: Measurement, Caveats, and Implications for Development of Cortical Myelin
(2022) Journal of Neuroscience, 42 (29), pp. 5681-5694. 

Baum, G.L.^a , Flournoy, J.C.^a , Glasser, M.F.^b c , Harms, M.P.^d , Mair, P.^a , Sanders, A.F.P.^d , Barch, D.M.^d e , Buckner, R.L.^a , Bookheimer, S.^f , Dapretto, M.^f , Smith, S.^g , Thomas, K.M.^h , Yacoub, E.^h , Van Essen, D.C.^c , Somerville, L.H.^a

^a Department of Psychology and Center for Brain Science, Harvard University, Cambridge, MA 02138, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Psychological and Brain Sciences, Washington University, St. Louis, MO 63130, United States
^f Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095, United States
^g Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, OX3 9DU, United Kingdom
^h Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN 55455, United States

Abstract
Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/ T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D; N = 628, ages 8-21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organization reported by others. In sensorimotor areas, T1w/T2w ratio measures start at high levels at early ages, increase at a fast pace, and decelerate at later ages (18-21). In intermediate multimodal areas along the S-A axis, T1w/T2w starts at intermediate levels and increases linearly at an intermediate pace. In transmodal/paralimbic association areas, T1w/T2w starts at low levels and increases linearly at the slowest pace. These data provide evidence for graded variation of the T1w/T2w ratio along the S-A axis that may reflect cortical myelination changes during adolescence underlying the development of complex information processing and psychological functioning. We discuss the implications of these results as well as caveats in interpreting magnetic resonance imaging (MRI)-based estimates of myelination. Copyright © 2022 the authors.

Author Keywords
adolescence;  development;  MRI;  myelin;  T1w/T2w

Funding details
R01 MH60974, S10OD020039
National Institutes of HealthNIH
National Institute of Mental HealthNIMHR01MH129493, R24MH108315, R24MH122820, U01MH109589-S1
National Institute of Biomedical Imaging and BioengineeringNIBIBT32 EB021955
NIH Blueprint for Neuroscience Research
University of WashingtonUW
McDonnell Center for Systems Neuroscience

Document Type: Article
Publication Stage: Final
Source: Scopus

Picky Eating in Childhood: Associations With Obsessive-Compulsive Symptoms
(2022) Journal of Pediatric Psychology, 47 (7), pp. 816-826. 

Schwarzlose, R.F., Hennefield, L., Hoyniak, C.P., Luby, J.L., Gilbert, K.E.

Department of Psychiatry, Washington University School of Medicine in St Louis, United States

Abstract
OBJECTIVE: To test whether childhood picky eating (PE)-a behavior previously linked to many forms of psychopathology-is specifically associated with symptoms of obsessive-compulsive disorder (OCD). METHODS: We investigated the relationship between PE and symptoms of several forms of psychopathology in two separate observational samples: a sample of 110 children (5 and 6 years old) and a sample of 210 children (8 and 9 years old) drawn from a longitudinal study. In each sample, regression models based on psychiatric symptoms or diagnoses were used to assess the specificity of PE associations while accounting for cooccurring symptoms or comorbidities. RESULTS: Although bivariate associations emerged between PE and multiple forms of psychopathology, multivariate analyses revealed these associations were driven by a strong and specific association between PE and symptoms of OCD in both samples. Moreover, PE among 8- and 9-year-olds in the longitudinal study predicted emergence of additional later psychopathology, specifically attention-deficit/hyperactivity disorder (ADHD). CONCLUSIONS: Findings suggest that PE, an easily identifiable clinical presentation, is also a specific marker for obsessive-compulsive symptomatology in school-age children and may impart risk for ADHD later in childhood. © The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
ADHD;  contamination;  obsessive-compulsive disorder;  picky eating;  selective eating

Document Type: Article
Publication Stage: Final
Source: Scopus

Simultaneous differential network analysis and classification for matrix-variate data with application to brain connectivity
(2022) Biostatistics (Oxford, England), 23 (3), pp. 967-989. 

Chen, H.^a , Guo, Y.^b , He, Y.^c , Ji, J.^c , Liu, L.^d , Shi, Y.^c , Wang, Y.^b , Yu, L.^e , Zhang, X.^e , Alzheimers Disease Neuroimaging Initiative^f

^a School of Statistics, Shandong University of Finance and Economics, Jinan, 250014, China
^b Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, United States
^c Institute for Financial Studies, Shandong University, Jinan, 250100, China
^d Division of Biostatistics, Washington University in St.Louis, St. Louis, MO 63110, USA
^e Department of Statistics, School of Management, Fudan UniversityShanghai 200433, China

Abstract
Growing evidence has shown that the brain connectivity network experiences alterations for complex diseases such as Alzheimer’s disease (AD). Network comparison, also known as differential network analysis, is thus particularly powerful to reveal the disease pathologies and identify clinical biomarkers for medical diagnoses (classification). Data from neurophysiological measurements are multidimensional and in matrix-form. Naive vectorization method is not sufficient as it ignores the structural information within the matrix. In the article, we adopt the Kronecker product covariance matrices framework to capture both spatial and temporal correlations of the matrix-variate data while the temporal covariance matrix is treated as a nuisance parameter. By recognizing that the strengths of network connections may vary across subjects, we develop an ensemble-learning procedure, which identifies the differential interaction patterns of brain regions between the case group and the control group and conducts medical diagnosis (classification) of the disease simultaneously. Simulation studies are conducted to assess the performance of the proposed method. We apply the proposed procedure to the functional connectivity analysis of an functional magnetic resonance imaging study on AD. The hub nodes and differential interaction patterns identified are consistent with existing experimental studies, and satisfactory out-of-sample classification performance is achieved for medical diagnosis of AD. © The Author 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Classification and prediction;  Ensemble learning;  Heterogeneity analysis;  Logistic regression;  Matrix data;  Network comparison

Document Type: Article
Publication Stage: Final
Source: Scopus

Frequency of Screening-Detected Intracranial Aneurysms in Patients with Loeys-Dietz Syndrome
(2022) Circulation, 146 (2), pp. 142-143. 

Huguenard, A.L.^a , Johnson, G.W.^a , Osbun, J.W.^a , Dacey, R.G.^a , Braverman, A.C.^b

^a Department of Neurosurgery, Washington University School of Medicine, 660 S Euclid Ave, CB 8057, St. Louis, MO 63110, United States
^b Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States

Author Keywords
connective tissue diseases;  intracranial aneurysm;  Loeys-Dietz Syndrome;  subarachnoid hemorrhage

Document Type: Article
Publication Stage: Final
Source: Scopus

An IL1RL1 genetic variant lowers soluble ST2 levels and the risk effects of APOE-ε4 in female patients with Alzheimer’s disease
(2022) Nature Aging, 2 (7), pp. 616-634. Cited 1 time.

Jiang, Y.^a b , Zhou, X.^a b c , Wong, H.Y.^a b , Ouyang, L.^a b , Ip, F.C.F.^a b c , Chau, V.M.N.^a b , Lau, S.-F.^a b , Wu, W.^a b , Wong, D.Y.K.^a b , Seo, H.^a , Fu, W.-Y.^a b , Lai, N.C.H.^a b , Chen, Y.^a c d , Chen, Y.^a c d , Tong, E.P.S.^a b , Weiner, M.W.^q , Aisen, P.^r , Petersen, R.^s , Jack, C.R.^s , Jagust, W.^t , Trojanowski, J.Q.^u , Toga, A.W.^v , Beckett, L.^w , Green, R.C.^x , Saykin, A.J.^y , Morris, J.^z , Shaw, L.M.^u , Khachaturian, Z.^w aa , Sorensen, G.^ab , Kuller, L.^ac , Raichle, M.^z , Paul, S.^ad , Davies, P.^ae , Fillit, H.^af , Hefti, F.^ag , Holtzman, D.^z , Mesulam, M.M.^ah , Potter, W.^ai , Snyder, P.^aj , Schwartz, A.^ak , Montine, T.^al , Thomas, R.G.^al , Donohue, M.^al , Walter, S.^al , Gessert, D.^al , Sather, T.^al , Jiminez, G.^al , Harvey, D.^w , Bernstein, M.^s , Thompson, P.^am , Schuff, N.^q w , Borowski, B.^s , Gunter, J.^s , Senjem, M.^s , Vemuri, P.^s , Jones, D.^s , Kantarci, K.^s , Ward, C.^s , Koeppe, R.A.^an , Foster, N.^ao , Reiman, E.M.^ap , Chen, K.^ap , Mathis, C.^af , Landau, S.^t , Cairns, N.J.^z , Householder, E.^z , Taylor-Reinwald, L.^z , Lee, V.^u , Korecka, M.^u , Figurski, M.^u , Crawford, K.^v , Neu, S.^v , Foroud, T.M.^y , Potkin, S.G.^aq , Shen, L.^y , Faber, K.^y , Kim, S.^y , Nho, K.^y , Thal, L.^r , Buckholtz, N.^ar , Albert, M.^as , Frank, R.^at , Hsiao, J.^ar , Kaye, J.^au , Quinn, J.^au , Lind, B.^au , Carter, R.^au , Dolen, S.^au , Schneider, L.S.^v , Pawluczyk, S.^v , Beccera, M.^v , Teodoro, L.^v , Spann, B.M.^v , Brewer, J.^r , Vanderswag, H.^r , Fleisher, A.^r ap , Heidebrink, J.L.^an , Lord, J.L.^an , Mason, S.S.^s , Albers, C.S.^s , Knopman, D.^s , Johnson, K.^s , Doody, R.S.^av , Villanueva-Meyer, J.^av , Chowdhury, M.^av , Rountree, S.^av , Dang, M.^av , Stern, Y.^av , Honig, L.S.^av , Bell, K.L.^av , Ances, B.^z , Carroll, M.^z , Leon, S.^z , Mintun, M.A.^z , Schneider, S.^z , Oliver, A.^z , Marson, D.^aw , Griffith, R.^aw , Clark, D.^aw , Geldmacher, D.^aw , Brockington, J.^aw , Roberson, E.^aw , Grossman, H.^ax , Mitsis, E.^ax , de Toledo-Morrell, L.^ay , Shah, R.C.^ay , Duara, R.^az , Varon, D.^az , Greig, M.T.^az , Roberts, P.^az , Onyike, C.^as , D’Agostino, D.^as , Kielb, S.^as , Galvin, J.E.^ba , Cerbone, B.^ba , Michel, C.A.^ba , Rusinek, H.^ba , de Leon, M.J.^ba , Glodzik, L.^ba , De Santi, S.^ba , Doraiswamy, P.M.^bb , Petrella, J.R.^bb , Wong, T.Z.^bb , Arnold, S.E.^u , Karlawish, J.H.^u , Wolk, D.^u , Smith, C.D.^bc , Jicha, G.^bc , Hardy, P.^bc , Sinha, P.^bc , Oates, E.^bc , Conrad, G.^bc , Lopez, O.L.^ac , Oakley, M.A.^ac , Simpson, D.M.^as , Porsteinsson, A.P.^bd , Goldstein, B.S.^be , Martin, K.^be , Makino, K.M.^be , Ismail, M.S.^be , Brand, C.^be , Mulnard, R.A.^aq , Thai, G.^aq , McAdams-Ortiz, C.^aq , Womack, K.^be , Mathews, D.^be , Quiceno, M.^be , Diaz-Arrastia, R.^be , King, R.^be , Weiner, M.^be , Martin-Cook, K.^be , DeVous, M.^be , Levey, A.I.^bf , Lah, J.J.^bf , Cellar, J.S.^bf , Burns, J.M.^bg , Anderson, H.S.^bg , Swerdlow, R.H.^bg , Apostolova, L.^am , Tingus, K.^am , Woo, E.^am , Silverman, D.H.S.^am , Lu, P.H.^am , Bartzokis, G.^am , Graff-Radford, N.R.^bh , Parfitt, F.^bh , Kendall, T.^bh , Johnson, H.^bh , Farlow, M.R.^y , Hake, A.M.^y , Matthews, B.R.^y , Herring, S.^y , Hunt, C.^y , van Dyck, C.H.^bi , Carson, R.E.^bi , MacAvoy, M.G.^bi , Chertkow, H.^bj , Bergman, H.^bj , Hosein, C.^bj , Hsiung, G.-Y.R.^bk , Feldman, H.^bk , Mudge, B.^bk , Assaly, M.^bk , Bernick, C.^bl , Munic, D.^bl , Kertesz, A.^bm , Rogers, J.^bm , Trost, D.^bm , Kerwin, D.^ah , Lipowski, K.^ah , Wu, C.-K.^ah , Johnson, N.^ah , Sadowsky, C.^bn , Martinez, W.^bn , Villena, T.^bn , Turner, R.S.^bo , Johnson, K.^bo , Reynolds, B.^bo , Sperling, R.A.^x , Johnson, K.A.^x , Marshall, G.^x , Frey, M.^x , Lane, B.^x , Rosen, A.^x , Tinklenberg, J.^x , Sabbagh, M.N.^bp , Belden, C.M.^bp , Jacobson, S.A.^bp , Sirrel, S.A.^bp , Kowall, N.^bp , Killiany, R.^bq , Budson, A.E.^bq , Norbash, A.^bq , Johnson, P.L.^bq , Allard, J.^br , Lerner, A.^bs , Ogrocki, P.^bs , Hudson, L.^bs , Fletcher, E.^w , Carmichael, O.^w , Olichney, J.^w , DeCarli, C.^w , Kittur, S.^bt , Borrie, M.^bu , Lee, T.-Y.^bu , Bartha, R.^bu , Johnson, S.^bv , Asthana, S.^bv , Carlsson, C.M.^bv , Preda, A.^am , Nguyen, D.^am , Tariot, P.^ao , Reeder, S.^ao , Bates, V.^bw , Capote, H.^bw , Rainka, M.^bw , Scharre, D.W.^bx , Kataki, M.^bx , Adeli, A.^bx , Zimmerman, E.A.^by , Celmins, D.^by , Brown, A.D.^by , Pearlson, G.D.^bz , Blank, K.^bz , Anderson, K.^bz , Santulli, R.B.^ca , Kitzmiller, T.J.^ca , Schwartz, E.S.^ca , Sink, K.M.^cb , Williamson, J.D.^cb , Garg, P.^cb , Watkins, F.^cb , Ott, B.R.^cc , Querfurth, H.^cc , Tremont, G.^cc , Salloway, S.^cd , Malloy, P.^cd , Correia, S.^cd , Rosen, H.J.^q , Miller, B.L.^q , Mintzer, J.^ce , Spicer, K.^ce , Bachman, D.^ce , Pasternak, S.^bm , Rachinsky, I.^bm , Drost, D.^bm , Pomara, N.^cf , Hernando, R.^cf , Sarrael, A.^cf , Schultz, S.K.^cg , Ponto, L.L.B.^cg , Shim, H.^cg , Smith, K.E.^cg , Relkin, N.^ad , Chaing, G.^ad , Raudin, L.^aa ad , Smith, A.^ch , Fargher, K.^ch , Raj, B.A.^ch , Neylan, T.^q , Grafman, J.^ah , Davis, M.^r , Morrison, R.^r , Hayes, J.^q , Finley, S.^q , Friedl, K.^ci , Fleischman, D.^ay , Arfanakis, K.^ay , James, O.^bb , Massoglia, D.^ce , Fruehling, J.J.^bv , Harding, S.^bv , Peskind, E.R.^al , Petrie, E.C.^bx , Li, G.^bx , Yesavage, J.A.^cj , Taylor, J.L.^cj , Furst, A.J.^cj , Mok, V.C.T.^e , Kwok, T.C.Y.^f , Mok, K.Y.^a b g h , Shoai, M.^g h , Lehallier, B.^i ck , Losada, P.M.^i j , O’Brien, E.^k l , Porter, T.^k l m , Laws, S.M.^k l m , Hardy, J.^b g h n , Wyss-Coray, T.^b i j o , Masters, C.L.^p , Fu, A.K.Y.^a b c , Ip, N.Y.^a b c , Alzheimer’s Disease Neuroimaging Initiative^cl

^a Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
^b Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong
^c Guangdong Provincial Key Laboratory of Brain Science, Disease and Drug Development; Shenzhen–Hong Kong Institute of Brain Science, HKUST Shenzhen Research Institute, Shenzhen, China
^d The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences; Shenzhen–Hong Kong Institute of Brain Science–Shenzhen Fundamental Research Institutions, Shenzhen, China
^e Gerald Choa Neuroscience Centre, Lui Che Woo Institute of Innovative Medicine, Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Neurology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
^f Therese Pei Fong Chow Research Centre for Prevention of Dementia, Division of Geriatrics, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
^g Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
^h UK Dementia Research Institute, University College London, London, United Kingdom
ⁱ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, United States
^j Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, United States
^k Centre for Precision Health, Edith Cowan University, Joondalup, Australia
^l Collaborative Genomics and Translation Group, School of Medical and Health Sciences, Edith Cowan University, Joondalup, Australia
^m School of Pharmacy and Biomedical Sciences, Faculty of Health Sciences, Curtin Health Innovation Research Institute, Curtin University, Bentley, Australia
ⁿ Institute for Advanced Study, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong
^o The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, United States
^p The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Australia
^q UC San Francisco, San Francisco, CA, United States
^r UC San Diego, San Diego, CA, United States
^s Mayo Clinic, Rochester, NY, United States
^t UC Berkeley, Berkeley, CA, United States
^u University of Pennsylvania, Philadelphia, PA, United States
^v University of Southern California, Los Angeles, CA, United States
^w UC Davis, Davis, CA, United States
^x Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, United States
^y Indiana University, Bloomington, IN, United States
^z Washington University in St. Louis, St. Louis, MO, United States
^aa Prevent Alzheimer’s Disease 2020, Rockville, MD, United States
^ab Siemens, Munich, Germany
^ac University of Pittsburgh, Pittsburgh, PA, United States
^ad Weill Cornell Medical College, Cornell University, New York City, NY, United States
^ae Albert Einstein College of Medicine, Yeshiva University, Bronx, NY, United States
^af Alzheimer’s Drug Discovery Foundation, New York City, NY, United States
^ag Acumen Pharmaceuticals, Livermore, CA, United States
^ah Northwestern University, Evanston and Chicago, Evanston, IL, United States
^ai National Institute of Mental Health, Rockville, MD, United States
^aj Brown University, Providence, RI, United States
^ak Eli Lilly, IndianapolisIN, United States
^al University of Washington, Seattle, WA, United States
^am UCLA, Los Angeles, CA, United States
^an University of Michigan, Ann Arbor, MI, United States
^ao University of Utah, Salt Lake City, UT, United States
^ap Banner Alzheimer’s Institute, Phoenix, AZ, United States
^aq UC Irvine, Irvine, CA, United States
^ar National Institute on Aging, Bethesda, MD, United States
^as Johns Hopkins University, Baltimore, MD, United States
^at Richard Frank ConsultingWA, United States
^au Oregon Health and Science University, Portland, OR, United States
^av Baylor College of Medicine, Houston, TX, United States
^aw University of Alabama, Birmingham, AL, United States
^ax Mount Sinai School of Medicine, New York City, NY, United States
^ay Rush University Medical Center, Chicago, IL, United States
^az Wien Center, Miami, FL, United States
^ba New York University, New York City, NY, United States
^bb Duke University Medical Center, Durham, NC, United States
^bc University of Kentucky, Lexington, KY, United States
^bd University of Rochester Medical Center, Rochester, NY, United States
^be University of Texas Southwestern Medical School, Dallas, TX, United States
^bf Emory University, Atlanta, GA, United States
^bg Medical Center, University of Kansas, Kansas City, KS, United States
^bh Mayo Clinic, Jacksonville, FL, United States
^bi Yale University School of Medicine, New Haven, CT, United States
^bj McGill University/Montreal-Jewish General Hospital, Montreal, QC, Canada
^bk University of British Columbia Clinic for Alzheimer’s Disease and Related Disorders, Vancouver, BC, Canada
^bl Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, United States
^bm St Joseph’s Health Care, London, ON, Canada
^bn Premiere Research Institute, Palm Beach Neurology, Miami, FL, United States
^bo Georgetown University Medical Center, Washington, DC, United States
^bp Banner Sun Health Research Institute, Sun City, AZ, United States
^bq Boston University, Boston, MA, United States
^br Howard University, Washington, DC, United States
^bs Case Western Reserve University, Cleveland, OH, United States
^bt Neurological Care of CNY, Liverpool, NY, United States
^bu Parkwood Hospital, London, ON, Canada
^bv University of Wisconsin, Madison, WI, United States
^bw Dent Neurologic Institute, Amherst, NY, United States
^bx Ohio State University, Columbus, OH, United States
^by Albany Medical College, Albany, NY, United States
^bz Olin Neuropsychiatry Research Center, Hartford Hospital, Hartford, CT, United States
^ca Dartmouth-Hitchcock Medical Center, Lebanon, NH, United States
^cb Wake Forest University Health Sciences, Winston-Salem, NC, United States
^cc Rhode Island Hospital, Providence, RI, United States
^cd Butler Hospital, Providence, RI, United States
^ce Medical University South Carolina, Charleston, SC, United States
^cf Nathan Kline Institute, Orangeburg, NY, United States
^cg University of Iowa College of Medicine, Iowa City, IA, United States
^ch USF Health Byrd Alzheimer’s Institute, University of South Florida, Tampa, FL, United States
^ci Department of Defense, Arlington, VA, United States
^cj Stanford University, Stanford, CA, United States
^ck Alkahest Inc, San Carlos, CA, United States

Abstract
Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD. © 2022, The Author(s).

Funding details
CTFCF18SC01
2019B1515130004
2018B030336001
National Institute on AgingNIA
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Alzheimer’s Disease Neuroimaging InitiativeADNI
Science and Industry Endowment FundSIEF
Medical Research CouncilMRC
Alzheimer’s Society
National Health and Medical Research CouncilNHMRCAPP1161706
Commonwealth Scientific and Industrial Research OrganisationCSIRO
Institut National de la Santé et de la Recherche MédicaleInserm
Edith Cowan UniversityECU
National Natural Science Foundation of ChinaNSFC31671047
University Grants CommitteeUGCAoE/M-604/16
Alzheimer’s Research UKARUK
Research Grants Council, University Grants Committee研究資助局T13-605/18-W
Dementia Collaborative Research Centres, AustraliaDCRC
Innovation and Technology CommissionITCINNOHK18SC01, ITCPD/17-9, MRP/042/18X
State Government of Victoria
National Key Research and Development Program of ChinaNKRDPC2017YFE0190000, 2018YFE0203600
Australian Alzheimer’s Research Foundation
Yulgilbar Foundation
Shenzhen Knowledge Innovation ProgramJCYJ20170413173717055, JCYJ20180507183642005

Document Type: Article
Publication Stage: Final
Source: Scopus

Partial repetition costs index a mixture of binding and signaling
(2022) Attention, Perception, and Psychophysics, . 

Weissman, D.H.^a , Grant, L.D.^b , Koch, I.^c , Hazeltine, E.^d e

^a Department of Psychology, University of Michigan, 530 Church Street, Ann Arbor, MI 48109, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Psychology, RWTH Aachen University, Aachen, Germany
^d Department of Psychological and Brain Sciences, University of Iowa, Iowa City, IA, United States
^e Cognitive Control Collaborative, University of Iowa, Iowa City, IA, United States

Abstract
People respond more slowly in two-choice tasks when either a previous stimulus feature or the previous response repeats in partial repetition trials than when (a) both repeat in complete repetition trials or (b) both alternate in complete alternation trials. The binding account posits that such partial repetition costs index a memory-retrieval conflict, which occurs because partial repetition trials trigger the retrieval of a previous stimulus feature or response that conflicts with a current stimulus feature or response. However, such costs may additionally reflect a simple decision-making heuristic that uses the repetition or alternation of a previous stimulus feature as a “signal” to bias response selection toward a repetition or an alternation of the previous response. To determine whether signaling contributes to partial repetition costs, we employed a four-choice task. Here, a stimulus feature repetition still signals a response repetition, but a stimulus feature alternation does not signal which of the three remaining responses to make. Consistent with an influence of signaling, we sometimes observed complete repetition advantages without complete alternation advantages. Exploratory analyses further revealed that partial repetition costs measured more broadly were smaller in the four-choice task than in a matched two-choice task. These findings suggest that partial repetition costs index a mixture of binding and signaling. © 2022, The Psychonomic Society, Inc.

Author Keywords
Adaptation and Aftereffects;  Attention and memory;  Attention: Interactions with Memory

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

Childhood behavioral inhibition and overcontrol: Relationships with cognitive functioning, error monitoring, anxiety and obsessive-compulsive symptoms
(2022) Research on Child and Adolescent Psychopathology, . 

Gilbert, K.^a , Gilbert, K.^a , Sudit, E.^a , Fox, N.^d , Barch, D.M.^a b c , Luby, J.L.^a

^a Department of Psychiatry, 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 Radiology, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Human Development and Quantitative Methodology, University of Maryland, College Park, MD, United States

Abstract
Anxiety and obsessive-compulsive disorders are common childhood psychiatric disorders. Behavioral inhibition (BI) is a widely studied risk factor for anxiety. Less is known about overcontrol, a related behavioral phenotype characterized by concern for errors, perfectionism, and inflexibility and also associated with anxiety and obsessive-compulsive disorder. Both BI and overcontrol show associations with aberrant cognitive control and neural error responding (via the error-related negativity; ERN) yet it is unknown whether each imparts differential risk. Understanding whether overcontrol demonstrates independent associations from BI with cognitive functioning, neural error monitoring, and childhood anxiety and obsessive-compulsive presentations could aid in identifying a novel mechanistic treatment target. We assessed BI, overcontrol, cognitive functioning and psychopathology in a cross-sectional sample of 5–6 year old children (N = 126). Children completed an electroencephalogram (EEG) to assess the ERN. Overcontrol was associated with worse cognitive shifting, worse inhibitory control and higher anxiety and obsessive-compulsive symptoms, beyond BI. BI was associated with worse cognitive shifting, better inhibitory control and higher anxiety symptoms, beyond overcontrol. When assessed simultaneously, only overcontrol demonstrated a significant relationship with a blunted ERN. Moreover, overcontrol mediated (cross-sectionally) the well-established relationship between ERN and anxiety and obsessive-compulsive symptoms. BI and overcontrol impart differential risk for child cognitive functioning and anxiety while overcontrol demonstrates additional risk for aberrant neural error monitoring, anxiety and obsessive-compulsive presentations. Overcontrol may also be a mechanistic pathway between the ERN and transdiagnostic anxiety and obsessive-compulsive symptoms. Overcontrol may be a target warranted for early-childhood intervention in anxiety and OCD. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Behavioral inhibition;  Error-related negativity;  OCD;  Overcontrol;  Pediatric anxiety;  Performance monitoring

Funding details
National Institute of Mental HealthNIMHK23MH115074

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

ALSUntangled #62: vitamin C
(2022) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 23 (5-6), pp. 476-479. 

Bedlack, R.^a , Barkhaus, P.^b , Carter, G.^c , Crayle, J.^d , Mcdermott, C.^e , Pattee, G.^f , Polak, M.^g , Salmon, K.^h , Wicks, P.ⁱ

^a Department of Neurology, Duke University, Durham, NC, United States
^b Department of Neurology, Medical College of Wisconsin, Milwaukee, WI, United States
^c Department of Rehabilitation Medicine, University of Washington, Seattle, WA, United States
^d Department of Neurology, Washington University in St Louis School of Medicine, St Louis, MO, United States
^e Department of Neuroscience, The University of Sheffield Institute for Translational Neuroscience, Sheffield, United Kingdom
^f Department of Neurology, Neurology Associates, Lincoln, NE, United States
^g Department of Neurology, Emory Healthcare, Atlanta, GA, United States
^h Department of Neurology, McGill Centre for Research in Neuroscience, Montreal, Canada
ⁱ United Kingdom

Abstract
Vitamin C is one of the most common supplements taken by people with ALS. As an antioxidant, it has a plausible mechanism for slowing disease progression and there are some flawed pre-clinical studies and case reports suggesting benefit. However, a small human trial showed no benefit. Given this negative trial, we do not currently advise vitamin C as an ALS treatment. © 2021 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.

Author Keywords
acorbic acid;  ascorbate;  clinical trials;  models;  therapy;  Vitamin C

Funding details
ALS AssociationALSA

Document Type: Article
Publication Stage: Final
Source: Scopus

Joint Consideration of Inhibitory Control and Irritability in Young Children: Contributions to Emergent Psychopathology
(2022) Research on Child and Adolescent Psychopathology, . 

Nili, A.N.^a b , Krogh-Jespersen, S.^b , Perlman, S.B.^c , Estabrook, R.^d , Petitclerc, A.^e , Briggs-Gowan, M.J.^f , Sherlock, P.R.^a , Norton, E.S.^b g , Wakschlag, L.S.^a b

^a Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, 633 N. St. Clair, Suite 1900, Chicago, IL 60611, United States
^b Institute for Innovations in Developmental Sciences, Northwestern University, Evanston, IL, United States
^c Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Psychology, University of Illinois at Chicago, Chicago, IL, United States
^e Ecole de Psychologie, Universite Laval, Quebec City, QC, Canada
^f Department of Psychiatry, University of Connecticut, Storrs, CT, United States
^g School of Communications, Northwestern University, Evanston, IL, United States

Abstract
Deficits in self-regulation capacity have been linked to subsequent impairment and clinical symptomology across the lifespan. Prior work has identified difficulty regulating angry emotions (i.e., irritability) as a powerful transdiagnostic indicator of current and future clinical concerns. Less is known regarding how irritability intersects with cognitive features of self-regulation, in particular inhibitory control, despite its mental health relevance. A promising avenue for improving specificity of clinical predictions in early childhood is multi-method, joint consideration of irritability and inhibitory control capacities. To advance early identification of impairment and psychopathology risk, we contrast group- and variable-based models of neurodevelopmental vulnerability at the interface of irritability and inhibitory control in contexts of varied motivational and emotional salience. This work was conducted in a longitudinal study of children recruited at well-child visits in Midwestern pediatric clinics at preschool age (N = 223, age range = 3–7 years). Group-based models (clustering and regression of clusters on clinical outcomes) indicated significant heterogeneity of self-regulation capacity in this sample. Meanwhile, variable-based models (continuous multiple regression) evidenced associations with concurrent clinical presentation, future symptoms, and impairment across the broad spectrum of psychopathology. Irritability transdiagnostically indicated internalizing and externalizing problems, concurrently and longitudinally. In contrast, inhibitory control was uniquely associated with attention-deficit/hyperactivity symptoms. We present these findings to advance a joint consideration approach to two promising indicators of neurodevelopmental vulnerability and mental health risk. Models suggest that both emotional and cognitive self-regulation capacities can address challenges in characterizing the developmental unfolding of psychopathology from preschool to early childhood age. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Early childhood;  Inhibitory control;  Irritability;  Self-regulation

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

Parental ADHD and ASD symptoms and contributions of psychosocial risk to childhood ADHD and ASD symptoms in children born very preterm
(2022) Journal of Perinatology, . 

Liljenwall, H.^a , Lean, R.E.^b , Smyser, T.A.^b , Smyser, C.D.^c d e , Rogers, C.E.^b e

^a Medical Education, Washington University School of Medicine, St Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^c 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
^e Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Objectives: Examine maternal and paternal ADHD and ASD symptoms in relation to very preterm (VPT) and full-term (FT) children’s ADHD and ASD symptoms. Study design: In this longitudinal study, maternal- and teacher-report of child ADHD and ASD symptoms were obtained for 119 children (VPT = 79, FT = 40) at age 5-years using the Conner’s Rating Scale-Revised (CRS-R) and Social Responsiveness Scale-2 (SRS-2). A biological parent completed self- and observer-report CRS-R and SRS-2, and measures of mood/affect, stress, and social support to assess psychosocial distress. Data were analyzed using mixed-effect models adjusted for covariates. Results: Child ADHD symptoms were associated with VPT birth, maternal distress, and maternal ADHD symptoms (p ≤ 0.02), and paternal ADHD symptoms (p < 0.001). Regarding ASD, VPT birth and parental ASD symptoms were associated with child ASD symptoms (p ≤ 0.009). Parental symptoms and birth group had no interaction. Conclusions: VPT birth and parental psychopathology represent independent risks for ADHD and ASD. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
U54-HD087011
National Institutes of HealthNIHK01-MH122735, K02-NS089852, K23-MH105179, R01-DA046224, R01-HD057098, R01-MH113570, R01-MH113883, R34-DA050272, UL1-TR000448
National Heart, Lung, and Blood InstituteNHLBI
Doris Duke Charitable FoundationDDCF
Brain and Behavior Research FoundationBBRF
March of Dimes FoundationMDF
Dana FoundationDF
Cerebral Palsy International Research FoundationCPIRF
Child Neurology FoundationCNF
National Alliance for Research on Schizophrenia and DepressionNARSAD

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

Cognition and Daily Life Activities in Stroke: A Network Analysis
(2022) OTJR Occupation, Participation and Health, . 

Lau, S.C.L.^a , Connor, L.T.^a , Heinemann, A.W.^b c , Baum, C.M.^a d

^a Washington University School of Medicine, St. Louis, MO, United States
^b Shirley Ryan AbilityLab, Chicago, IL, United States
^c Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^d Washington University in St. LouisMO, United States

Abstract
Understanding complex dynamics of cognitive constructs and the interplay between cognition and daily life activities is possible through network analysis. The objectives of this study are to characterize the cognition network and identify central cognitive constructs, and identify the cognitive constructs bridging cognition and daily life activities. In 210 community-dwelling stroke survivors, we employed network analysis to characterize the cognition network, identify the central cognitive constructs, and examine the bridge pathway connecting cognition and daily life activities. Cognitive constructs were positively correlated within the network, forming clusters of fluid (e.g., components of active problem-solving), crystallized (e.g., world knowledge), and functional cognition. Central constructs included inhibition, organization, and cognitive flexibility, whereas bridge constructs included organization, sequencing, and inhibition. Central and bridge constructs identified by this study are potential targets for future research and intervention. The emergence of functional cognition as central and bridge constructs may support its inclusion in occupational therapy practice. © The Author(s) 2022.

Author Keywords
cognition;  daily living;  stroke

Funding details
Washington University in St. LouisWUSTL
National Institute on Disability, Independent Living, and Rehabilitation ResearchNIDILRRH133B090024

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