WashU weekly Neuroscience publications: February 28, 2022

Are children with unilateral hearing loss more tired?
(2022) International Journal of Pediatric Otorhinolaryngology, 155, art. no. 111075, . 

Carpenter, D.^a , Dougherty, W.^b , Sindhar, S.^c , Friesen, T.-N.^c , Lieu, J.^c , Kesser, B.W.^a

^a Department of Otolaryngology-Head and Neck Surgery, University of Virginia School of Medicine, P.O. Box 800713, Charlottesville, VA 22908, United States
^b Department of Otolaryngology-Head and Neck Surgery, Eastern Virginia Medical School, 600 Gresham Dr, Norfolk, VA 23507, United States
^c Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, Campus Box 8115, St. Louis, MO 63110, United States

Abstract
Objective: To determine whether children with unilateral sensorineural hearing loss (USNHL) and unilateral conductive hearing loss (UCHL) have higher levels of fatigue than literature reported normal hearing (LRNH) children. Methods: This was a cross-sectional survey utilizing the PedsQL™ Multidimensional Fatigue Scale administered to children with unilateral hearing loss (UHL) and their parents at two tertiary care academic medical centers and a nationwide microtia/atresia conference. The PedsQL™ Multidimensional Fatigue Scale was used to compare child and parental proxy reports of fatigue among USNHL, UCHL, and LRNH children. ANOVA and post-hoc Tukey Honest Significant Difference testing were used for statistical analysis. Results: Of 69 children included in the study, 42 had UCHL (61%) and 27 (39%) had USNHL. Children with USNHL reported more total fatigue (mean 69.1, SD 19.3) than LRNH children (mean 80.5, SD 13.3; difference −11.4; 95% CI: −19.98 to −2.84) and children with UCHL (mean 78.0, SD 14.5; difference −8.95; 95% CI: −17.86 to 0.04). Children with UCHL reported similar levels of fatigue compared to LRNH children (difference −2.5; 95% CI: −9.95 to 5.03). Parents of children with USNHL reported greater levels of fatigue (mean 67.6, SD 22.6) in their children than parents of LRNH children (mean 89.6, SD 11.4; difference −22.0; 95% CI: −29.8 to −14.3) and parents of children with UCHL (mean 76.2, SD 17.3; difference −8.6; 95% CI: −17.5 to 0.21). Parents of children with UCHL also report higher levels of fatigue than parents of LRNH children (difference −13.4; 95% CI: −19.98 to −6.84). Conclusions: Children with USNHL reported greater levels of fatigue than LRNH children and children with UCHL. Results implicate cognitive load as an important consideration in children with hearing loss. The measurement of fatigue may be a useful indicator to determine the benefit of intervention (e.g., amplification) for these children. © 2022 Elsevier B.V.

Author Keywords
Cognitive load;  Conductive hearing loss;  Congenital aural atresia;  Fatigue;  Unilateral hearing loss

The Influence of Race, Sex, and Social Disadvantage on Self-reported Health in Patients Presenting With Chronic Musculoskeletal Pain
(2022) American Journal of Physical Medicine & Rehabilitation, 101 (3), pp. 211-216. 

Cheng, A.L., Bradley, E.C., Brady, B.K., Calfee, R.P., Klesges, L.M., Colditz, G.A., Prather, H.

From the Division of Physical Medicine and Rehabilitation, Department of Orthopaedic Surgery, Washington University in St Louis School of Medicine, St Louis, Missouri (ALC); The Brown School at Washington University in St Louis, St Louis, Missouri (ECB); Washington University in St Louis School of Medicine, St Louis, Missouri (BKB); Division of Hand and Microsurgery, Department of Orthopaedic Surgery, Washington University in St Louis School of Medicine, St Louis, Missouri (RPC); Division of Public Health Sciences, Department of Surgery, Washington University in St Louis School of Medicine, St Louis, Missouri (LMK, GAC); and Weill Cornell Medical College, New York City, New York (HP)

Abstract
OBJECTIVE: The aim of the study was to better address sociodemographic-related health disparities. This study examined which sociodemographic variables most strongly correlate with self-reported health in patients with chronic musculoskeletal pain. DESIGN: This single-center, cross-sectional study examined adult patients, followed by a physiatrist for chronic (≥4 yrs) musculoskeletal pain. Sociodemographic variables considered were race, sex, and disparate social disadvantage (measured as residential address in the worst vs. best Area Deprivation Index national quartile). The primary comparison was the adjusted effect size of each variable on physical and behavioral health (measured by Patient-Reported Outcomes Measurement Information System [PROMIS]). RESULTS: In 1193 patients (age = 56.3 ± 13.0 yrs), disparate social disadvantage was associated with worse health in all domains assessed (PROMIS Physical Function Β = -2.4 points [95% confidence interval = -3.8 to -1.0], Pain Interference = 3.3 [2.0 to 4.6], Anxiety = 4.0 [1.8 to 6.2], and Depression = 3.7 [1.7 to 5.6]). Black race was associated with greater anxiety than white race (3.2 [1.1 to 5.3]), and female sex was associated with worse physical function than male sex (-2.5 [-3.5 to -1.5]). CONCLUSIONS: Compared with race and sex, social disadvantage is more consistently associated with worse physical and behavioral health in patients with chronic musculoskeletal pain. Investment to ameliorate disadvantage in geographically defined communities may improve health in sociodemographically at-risk populations. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Assessing infant cognition in field settings using eye-tracking: a pilot cohort trial in Sierra Leone
(2022) BMJ Open, 12 (2), p. e049783. 

Leppänen, J.M.^a , Butcher, J.W.^b , Godbout, C.^c , Stephenson, K.^d , Hendrixson, D.T.^c , Griswold, S.^e , Rogers, B.L.^e , Webb, P.^e , Koroma, A.S.^f , Manary, M.J.^c

^a Department of Psychology and Speech-Language Pathology, University of Turku, Turku, Finland
^b Project Peanut Butter, Freetown, Sierra Leone
^c Department of Pediatrics, Washington University in St Louis School of Medicine, St Louis, MO, United States
^d Department of Internal Medicine, Washington University in St Louis School of Medicine, St Louis, MO, United States
^e Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA, United States
^f Food and Nutrition, Sierra Leone Ministry of Health and Sanitation, Freetown, Sierra Leone

Abstract
OBJECTIVES: To investigate the feasibility of eye-tracking-based testing of the speed of visual orienting in malnourished young children at rural clinics in Sierra Leone. DESIGN: Prospective dual cohort study nested in a cluster-randomised trial. SETTING: 8 sites participating in a cluster-randomised trial of supplementary feeding for moderate acute malnutrition (MAM). PARTICIPANTS: For the MAM cohort, all infants aged 7-11 months at the eight sites were enrolled, 138 altogether. For controls, a convenience sample of all non-malnourished infants aged 7-11 months at the same sites were eligible, 60 altogether. A sample of 30 adults at the sites also underwent eye-tracking tests as a further control. INTERVENTIONS: Infants with MAM were provided with supplementary feeding. OUTCOME MEASURES: The primary outcomes were feasibility and reliability of eye-tracking-based testing of saccadic reaction time (SRT). Feasibility was assessed by the percent of successful tests in the infants. Reliability was measured with intraclass correlation coefficients (ICCs). Secondary outcomes were mean SRT based on nutritional state as well as and changes in mean SRT after supplementary feeding of MAM children. RESULTS: Infants exhibited consistent orienting to targets on a computer screen (>95% of valid trials). Mean SRTs had moderate stability within visits (ICCs 0.60-0.69) and across the 4-week test-retest interval (0.53) in infants; the adult control group had greater SRT stability (within visit ICC=0.92). MAM infants had a trend toward higher adjusted SRT at baseline (difference=12.4 ms, 95% CI -2 to 26.9, p=0.09) and improvement in SRT 4 weeks thereafter (difference=-14 ms, 95% CI -26.2 to -1.7, p=0.025) compared with age-matched controls. CONCLUSIONS: The results demonstrate the feasibility of eye-tracking-based testing in a resource-poor field setting and suggest eye-tracking measures have utility in the detection of group level effects of supplementary feeding. © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
developmental neurology & neurodisability;  nutrition;  paediatric neurology

Astrocytic α2-Na+/K+ ATPase inhibition suppresses astrocyte reactivity and reduces neurodegeneration in a tauopathy mouse model
(2022) Science Translational Medicine, 14 (632), p. eabm4107. 

Mann, C.N.^a b , Devi, S.S.^a b , Kersting, C.T.^a b , Bleem, A.V.^a b , Karch, C.M.^b c d , Holtzman, D.M.^a b d , Gallardo, G.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
^b Hope Center for Neurological Disorders, Washington University, St. Louis, MO 63110, USA
^c Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
^d Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University, St. Louis, MO 63110, USA

Abstract
Alzheimer’s disease (AD) is the most dominant form of dementia characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tau tangles (NFTs). In addition to these pathologies, an emerging pathophysiological mechanism that influences AD is neuroinflammation. Astrocytes are a vital type of glial cell that contribute to neuroinflammation, and reactive astrocytes, or astrogliosis, are a well-known pathological feature of AD. However, the mechanisms by which astrocytes contribute to the neurodegenerative process in AD have not been fully elucidated. Here, we showed that astrocytic α2-Na+/K+ adenosine triphosphatase (α2-NKA) is elevated in postmortem human brain tissue from AD and progressive nuclear palsy, a primary tauopathy. The increased astrocytic α2-NKA was also recapitulated in a mouse model of tauopathy. Pharmacological inhibition of α2-NKA robustly suppressed neuroinflammation and reduced brain atrophy. In addition, α2-NKA knockdown in tauopathy mice halted the accumulation of tau pathology. We also demonstrated that α2-NKA promoted tauopathy, in part, by regulating the proinflammatory protein lipocalin-2 (Lcn2). Overexpression of Lcn2 in tauopathy mice increased tau pathology, and prolonged Lcn2 exposure to primary neurons promoted tau uptake in vitro. These studies collectively highlight the contribution of reactive astrocytes to tau pathogenesis in mice and define α2-NKA as a major regulator of astrocytic-dependent neuroinflammation.

The prevalance of binge eating disorder and associated psychiatric and substance use disorders in a student population in Kenya – towards a public health approach
(2022) BMC Psychiatry, 22 (1), p. 122. 

Mutiso, V.N.^a , Ndetei, D.M.^a b , N Muia, E.^c , K Alietsi, R.^a , Onsinyo, L.^a , Kameti, F.^a , Masake, M.^c , Musyimi, C.^a , Mamah, D.^d

^a Africa Mental Health Research and Training Foundation, Nairobi, Mawensi Road ,Off Elgon road ,Mawensi Garden ,P.O. Box 48423-00100, Kenya
^b Department of Psychiatry, University of Nairobi, Nairobi, Mawensi Road ,Off Elgon road ,Mawensi Garden ,P.O. Box 48423-00100, Kenya
^c Department of Public and Community Health, Machakos UniversityMachakos, Kenya
^d Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States

Abstract
INTRODUCTION: Kenya in particular and Africa in general lack data on Binge Eating Disorder (BED). The overarching objective of this study is to fill that gap. Kenyans may not be aware that BED exists when a “very good” appetite is considered a sign of good health, especially if food is available either at home, in fast food shops or when communally eating together, a very common cultural practice. On the other hand where there is relatively insufficient food, it is not expected that one could be having a problem of eating too much. METHOD: We administered the following tools and measurements to 9742 participants (high school, college and university students): 1) Researcher designed socio-demographic and economic indicator questionnaire; 2) An instrument documenting DSM-IV diagnostic criteria for BED and its various symptoms; 3) An instrument to determine DSM-IV psychiatric disorders and substance abuse;4) An instrument measuring high risk for psychosis ,affectivity and stress; 5) A WHO designed instrument measuring the severity of substance abuse for specific substances. We used descriptive and inferential analysis to determine the prevalence and association of the different variables. Independent predictors of BED were generated from a generalized linear model (p<0.05). RESULTS: We found a prevalence of 3.2% of BED and a wide range of prevalence for BED and BED related symptoms (8.1% to 19%). The least prevalent was “To prevent weight gain from eating binge did you force yourself to vomit, or used laxatives?”. The most common was “Did you often go on eating binges (eating a very large amount of food very quickly over a short period of time).” Major depression, obsessive compulsive disorder, panic disorder, agoraphobia, generalized anxiety disorder ,a positive stress screen and drug abuse were independent predictors of BED (p<0.05). CONCLUSION: Our findings on the prevalence of BED and significant associations with various psychiatric disorders and substance use disorders are similar to those obtained in High Income Countries (HIC) using similar large-scale samples in non-clinical populations. Our findings suggest the need fora public health approach to enhance awareness of BED and to promote health-seeking behaviour towards management of BED. © 2022. The Author(s).

Author Keywords
Binge Eating;  Co-morbidity;  Eating Disorders;  Kenya

Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors
(2022) Science Translational Medicine, 14 (632), p. eabj8186. 

Tavares-Ferreira, D.^a , Shiers, S.^a , Ray, P.R.^a , Wangzhou, A.^a , Jeevakumar, V.^a , Sankaranarayanan, I.^a , Cervantes, A.M.^b , Reese, J.C.^b , Chamessian, A.^c , Copits, B.A.^c , Dougherty, P.M.^d , Gereau, R.W., 4th^c , Burton, M.D.^a , Dussor, G.^a , Price, T.J.^a

^a Department of Neuroscience and Center for Advanced Pain Studies, University of Texas at Dallas, United States
^b Southwest Transplant Alliance, Dallas, United States
^c Department of Anesthesiology , Washington University Pain Center, St. Louis, MO 63110, USA
^d Department of Pain Medicine, Division of Anesthesiology and Critical Care, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States

Abstract
Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha (CALCA) expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.

Validation of Plasma Amyloid-β 42/40 for Detecting Alzheimer Disease Amyloid Plaques
(2022) Neurology, 98 (7), pp. e688-e699. 

Li, Y., Schindler, S.E., Bollinger, J.G., Ovod, V., Mawuenyega, K.G., Weiner, M.W., Shaw, L.M., Masters, C.L., Fowler, C.J., Trojanowski, J.Q., Korecka, M., Martins, R.N., Janelidze, S., Hansson, O., Bateman, R.J.

From the Department of Neurology (Y.L., S.E.S., J.G.B., V.O., K.G.M., R.J.B.), Division of Biostatistics (Y.L.), Knight Alzheimer’s Disease Research Center (S.E.S., R.J.B.), and Hope Center for Neurological Disorders (R.J.B.), Washington University School of Medicine, St. Louis, MO; Departments of Psychiatry, Radiology and Biomedical Imaging, Medicine, and Neurology (M.W.W.), Center for Imaging and Neurodegenerative Diseases, Northern California Institute for Research and Education, Department of Veterans Affairs Medical Center, University of California San Francisco; Department of Pathology and Laboratory Medicine (S.M.L., J.Q.T., M.K.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; The Florey Institute of Neuroscience and Mental Health (C.L.M., C.J.F.), University of Melbourne, Victoria; Edith Cowan University (R.N.M.), Joondalup, Australia; Department of Clinical Sciences, Clinical Memory Research Unit (S.J., O.H.), Lund University; and Memory Clinic (O.H.), Skåne University Hospital, Malmö, Sweden

Abstract
BACKGROUND AND OBJECTIVES: To determine the diagnostic accuracy of a plasma Aβ42/Aβ40 assay in classifying amyloid PET status across global research studies using samples collected by multiple centers that utilize different blood collection and processing protocols. METHODS: Plasma samples (n = 465) were obtained from 3 large Alzheimer disease (AD) research cohorts in the United States (n = 182), Australia (n = 183), and Sweden (n = 100). Plasma Aβ42/Aβ40 was measured by a high precision immunoprecipitation mass spectrometry (IPMS) assay and compared to the reference standards of amyloid PET and CSF Aβ42/Aβ40. RESULTS: In the combined cohort of 465 participants, plasma Aβ42/Aβ40 had good concordance with amyloid PET status (receiver operating characteristic area under the curve [AUC] 0.84, 95% confidence interval [CI] 0.80-0.87); concordance improved with the inclusion of APOE ε4 carrier status (AUC 0.88, 95% CI 0.85-0.91). The AUC of plasma Aβ42/Aβ40 with CSF amyloid status was 0.85 (95% CI 0.78-0.91) and improved to 0.93 (95% CI 0.89-0.97) with APOE ε4 status. These findings were consistent across the 3 cohorts, despite differences in protocols. The assay performed similarly in both cognitively unimpaired and impaired individuals. DISCUSSION: Plasma Aβ42/Aβ40 is a robust measure for detecting amyloid plaques and can be utilized to aid in the diagnosis of AD, identify those at risk for future dementia due to AD, and improve the diversity of populations enrolled in AD research and clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that plasma Aβ42/Aβ40, as measured by a high precision IPMS assay, accurately diagnoses brain amyloidosis in both cognitively unimpaired and impaired research participants. © 2021 American Academy of Neurology.

Creating Ion Channel Kinetic Models Using Cloud Computing
(2022) Current Protocols, 2 (2), p. e374. 

Mangold, K.E.^a , Zhou, Z.^a , Schoening, M.^a , Moreno, J.D.^a b , Silva, J.R.^a

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Computational modeling of ion channels provides key insight into experimental electrophysiology results and can be used to connect channel dynamics to emergent phenomena observed at the tissue and organ levels. However, creation of these models requires substantial mathematical and computational background. This tutorial seeks to lower the barrier to creating these models by providing an automated pipeline for creating Markov models of an ion channel kinetics dataset. We start by detailing how to encode sample voltage-clamp protocols and experimental data into the program and its implementation in a cloud computing environment. We guide the reader on how to build a containerized instance, push the machine image, and finally run the routine on cluster nodes. While providing open-source code has become more standard in computational studies, this tutorial provides unprecedented detail on the use of the program and the creation of channel models, starting from inputting the raw experimental data. © 2022 Wiley Periodicals LLC. Basic Protocol: Creation of ion channel kinetic models with a cloud computing environment Alternate Protocol: Instructions for use in a standard high-performance compute cluster. © 2022 Wiley Periodicals LLC.

Author Keywords
ion channels;  kinetic models;  optimization

Connectivity and dynamics in the olfactory bulb
(2022) PLoS Computational Biology, 18 (2), art. no. e1009856, . 

Chen Kersen, D.E.^a b c , Tavoni, G.^a d e , Balasubramanian, V.^a b d f

^a Computational Neuroscience Initiative, University of Pennsylvania, Philadelphia, PA, United States
^b Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, United States
^c Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA, United States
^e Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neuroscience, University of Pennsylvania, Philadelphia, PA, United States

Abstract
Dendrodendritic interactions between excitatory mitral cells and inhibitory granule cells in the olfactory bulb create a dense interaction network, reorganizing sensory representations of odors and, consequently, perception. Large-scale computational models are needed for revealing how the collective behavior of this network emerges from its global architecture. We propose an approach where we summarize anatomical information through dendritic geometry and density distributions which we use to calculate the connection probability between mitral and granule cells, while capturing activity patterns of each cell type in the neural dynamical systems theory of Izhikevich. In this way, we generate an efficient, anatomically and physiologically realistic large-scale model of the olfactory bulb network. Our model reproduces known connectivity between sister vs. non-sister mitral cells; measured patterns of lateral inhibition; and theta, beta, and gamma oscillations. The model in turn predicts testable relationships between network structure and several functional properties, including lateral inhibition, odor pattern decorrelation, and LFP oscillation frequency. We use the model to explore the influence of cortex on the olfactory bulb, demonstrating possible mechanisms by which cortical feedback to mitral cells or granule cells can influence bulbar activity, as well as how neurogenesis can improve bulbar decorrelation without requiring cell death. Our methodology provides a tractable tool for other researchers. Copyright: © 2022 Kersen 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
400425
575556
Simons Foundation

Depressive Symptomatology and Functional Status Among Stroke Survivors: A Network Analysis
(2022) Archives of Physical Medicine and Rehabilitation, . 

Lau, S.C.L.^a , Connor, L.T.^a b , Lee, J.-M.^b , Baum, C.M.^a b c

^a Program in Occupational Therapy, Washington University School of Medicine, MO, St. Louis
^b Department of Neurology, Washington University School of Medicine, MO, St. Louis
^c Brown School of Social Work, Washington University in St Louis, St Louis, MO, United States

Abstract
Objective: To (1) characterize poststroke depressive symptom network and identify the symptoms most central to depression and (2) examine the symptoms that bridge depression and functional status. Design: Secondary data analysis of the Stroke Recovery in Underserved Population database. Networks were estimated using regularized partial correlation models. Topology, network stability and accuracy, node centrality and predictability, and bridge statistics were investigated. Setting: Eleven inpatient rehabilitation facilities across 9 states of the United States. Participants: Patients with stroke (N=1215) who received inpatient rehabilitation. Interventions: Not applicable. Main Outcome Measures: The Center for Epidemiologic Studies Depression Scale and FIM were administered at discharge from inpatient rehabilitation. Results: Depressive symptoms were positively intercorrelated within the network, with stronger connections between symptoms within the same domain. “Sadness” (expected influence=1.94), “blues” (expected influence=1.14), and “depressed” (expected influence=0.97) were the most central depressive symptoms, whereas “talked less than normal” (bridge expected influence=−1.66) emerged as the bridge symptom between depression and functional status. Appetite (R2=0.23) and sleep disturbance (R2=0.28) were among the least predictable symptoms, whose variance was less likely explained by other symptoms in the network. Conclusions: Findings illustrate the potential of network analysis for discerning the complexity of poststroke depressive symptomology and its interplay with functional status, uncovering priority treatment targets and promoting more precise clinical practice. This study contributes to the need for expansion in the understanding of poststroke psychopathology and challenges clinicians to use targeted intervention strategies to address depression in stroke rehabilitation. © 2022 The American Congress of Rehabilitation Medicine

Author Keywords
Depression;  Functional Status;  Rehabilitation;  Stroke

Funding details
Washington University in St. LouisWUSTL

Molecular ontology of the parabrachial nucleus
(2022) Journal of Comparative Neurology, .

^a Department of Neurology, University of Iowa, Iowa City, IA, United States
^b Department of Anatomy and Neurobiology, Washington University School of Medicine, Saint Louis, MO, United States
^c Iowa Neuroscience Institute, Iowa City, IA, United States
^d Department of Biology, University of Iowa, Iowa City, IA, United States
^e Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN, United States

Abstract
Diverse neurons in the parabrachial nucleus (PB) communicate with widespread brain regions. Despite evidence linking them to a variety of homeostatic functions, it remains difficult to determine which PB neurons influence which functions because their subpopulations intermingle extensively. An improved framework for identifying these intermingled subpopulations would help advance our understanding of neural circuit functions linked to this region. Here, we present the foundation of a developmental-genetic ontology that classifies PB neurons based on their intrinsic, molecular features. By combining transcription factor labeling with Cre fate-mapping, we find that the PB is a blend of two, developmentally distinct macropopulations of glutamatergic neurons. Neurons in the first macropopulation express Lmx1b (and, to a lesser extent, Lmx1a) and are mutually exclusive with those in a second macropopulation, which derive from precursors expressing Atoh1. This second, Atoh1-derived macropopulation includes many Foxp2-expressing neurons, but Foxp2 also identifies a subset of Lmx1b-expressing neurons in the Kölliker–Fuse nucleus (KF) and a population of GABAergic neurons ventrolateral to the PB (“caudal KF”). Immediately ventral to the PB, Phox2b-expressing glutamatergic neurons (some coexpressing Lmx1b) occupy the KF, supratrigeminal nucleus, and reticular formation. We show that this molecular framework organizes subsidiary patterns of adult gene expression (including Satb2, Calca, Grp, and Pdyn) and predicts output projections to the amygdala (Lmx1b), hypothalamus (Atoh1), and hindbrain (Phox2b/Lmx1b). Using this molecular ontology to organize, interpret, and communicate PB-related information could accelerate the translation of experimental findings from animal models to human patients. © 2022 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals LLC

Author Keywords
breathing;  development;  interoception;  interoceptive;  Kölliker–Fuse;  pain;  parabrachial complex;  parabrachialis;  pontine pneumotaxic center;  pontine taste area

The Challenges in Designing a Prevention Chatbot for Eating Disorders: Observational Study
(2022) JMIR Formative Research, 6 (1), art. no. e28003, . 

Chan, W.W.^a b , Fitzsimmons-Craft, E.E.^f , Smith, A.C.^c , Firebaugh, M.-L.^c , Fowler, L.A.^c , DePietro, B.^c , Topooco, N.^b d , Wilfley, D.E.^c , Taylor, C.B.^a b , Jacobson, N.C.^e

^a Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, United States
^b Center for m2Health, Palo Alto University, Los Altos, CA, United States
^c Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^d Department of Behavioural Sciences and Learning, Linköping University, Linköping, Sweden
^e Center for Technology and Behavioral Health, Geisel School of Medicine, Dartmouth College, Lebanon, NH, United States

Abstract
Background: Chatbots have the potential to provide cost-effective mental health prevention programs at scale and increase interactivity, ease of use, and accessibility of intervention programs. Objective: The development of chatbot prevention for eating disorders (EDs) is still in its infancy. Our aim is to present examples of and solutions to challenges in designing and refining a rule-based prevention chatbot program for EDs, targeted at adult women at risk for developing an ED. Methods: Participants were 2409 individuals who at least began to use an EDs prevention chatbot in response to social media advertising. Over 6 months, the research team reviewed up to 52,129 comments from these users to identify inappropriate responses that negatively impacted users’ experience and technical glitches. Problems identified by reviewers were then presented to the entire research team, who then generated possible solutions and implemented new responses. Results: The most common problem with the chatbot was a general limitation in understanding and responding appropriately to unanticipated user responses. We developed several workarounds to limit these problems while retaining some interactivity. Conclusions: Rule-based chatbots have the potential to reach large populations at low cost but are limited in understanding and responding appropriately to unanticipated user responses. They can be most effective in providing information and simple conversations. Workarounds can reduce conversation errors. © 2022. JMIR Publications Inc.. All rights reserved.

Author Keywords
Chatbot;  Digital mental health;  Eating disorders;  Intervention development;  Prevention

Funding details
National Institute of Mental HealthNIMHK08 MH120341, R01 MH115128
National Heart, Lung, and Blood InstituteNHLBIR01 MH123482, T32 HL130357
National Eating Disorders AssociationNEDA
National Health and Medical Research CouncilNHMRCAPP1170937
VetenskapsrådetVR2018-06585

Anthropometric Measures Correspond with Functional Motor Outcomes in Females with Rett Syndrome
(2022) Journal of Pediatrics, . 

Motil, K.J.^a , Geerts, S.^b , Annese, F.^c , Neul, J.L.^d , Benke, T.^e , Marsh, E.^f , Lieberman, D.^g , Skinner, S.A.^c , Glaze, D.G.^h , Heydemann, P.ⁱ , Beisang, A.^j , Standridge, S.^k , Ryther, R.^l , Lane, J.B.^m , Edwards, L.ⁿ , Percy, A.K.^m

^a Children’s Nutrition Research Center, Baylor College of Medicine, Houston, TX, United States
^b Sparks Clinics/Nutrition, University of Alabama at Birmingham, Birmingham, AL, United States
^c Genetics Center, Greenwood Genetic Center, Greenwood, SC, United States
^d Department of Pediatrics/Child Neurology, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States
^e Department of Pediatrics/Child Neurology, University of Colorado-Denver, Denver, CO, United States
^f Department of Pediatrics/Child Neurology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA, United States
^g Department of Child Neurology, Children’s Hospital Boston, Harvard University, Boston, MA, United States
^h Department of Pediatrics/Child Neurology, Baylor College of Medicine, Houston, TX, United States
ⁱ Department of Pediatrics/Child Neurology, Rush Medical Center, Chicago, IL, United States
^j Department of Pediatrics, Gillette Children’s Hospital, St. Paul, MN, United States
^k Department of Pediatrics/Child Neurology, Cincinnati Children’s Hospital, Cincinnati, OH, United States
^l Department of Pediatrics/Child Neurology, Washington University, St. Louis, MO, United States
^m Department of Pediatrics/Child Neurology, University of Alabama at Birmingham, Birmingham, AL, United States
ⁿ School of Public Health/Biostatistics, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract
Objective: To characterize growth and anthropometric measurements in females with Rett syndrome and compare these measurements with functional outcomes. Study design: We obtained longitudinal growth and anthropometric measurements from 1154 females with classic and atypical Rett syndrome seen between 2006 and 2019 in the US Natural History Study. We calculated the Clinical Severity Score, Motor Behavior Assessment score, and arm and leg muscle areas and recorded the functional assessments of arm and hand use and ambulation. We compared growth and anthropometric variables from females with Rett syndrome in regard to normative data. We analyzed Clinical Severity Score, Motor Behavior Assessment, and anthropometric measurements in regard to functional assessments. Results: Growth and anthropometric measurements were significantly lower in females with classic and severe atypical Rett syndrome compared with those classified as mild atypical Rett syndrome and deviated from normative patterns among all 3 groups. Suprailiac skinfold measurements correlated with body mass index measurements in each group. Lower leg muscle area measurements were significantly greater among females in all 3 Rett syndrome groups who ambulated independently compared with those who did not. In females with classic Rett syndrome, arm, thigh, and lower leg muscle area measurements increased significantly over time and were significantly greater among those who had purposeful arm and hand use and independent ambulation compared with those who did not. Conclusions: The pattern of growth and anthropometric measures in females with Rett syndrome differs from normative data and demonstrates clear differences between classic and mild or severe atypical Rett syndrome. Anthropometric measures correspond with functional outcomes and could provide markers supporting efficacy outcomes in clinical trials. © 2022 Elsevier Inc.

Funding details
National Institutes of HealthNIH
U.S. Department of AgricultureUSDA
Baylor College of Medicine
Agricultural Research ServiceUSDA ARS58-3092-5-001
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDHD-061222

An affordable and easy-to-use focused ultrasound device for noninvasive and high precision drug delivery to the mouse brain
(2022) IEEE Transactions on Biomedical Engineering, . 

Hu, Z., Chen, S., Yang, Y., Gong, Y., Chen, H.

Department of Biomedical Engineering, Washington University in St Louis, 7548 St Louis, Missouri, United States

Abstract
Objective: Focused ultrasound (FUS) combined with microbubble-mediated blood-brain barrier (BBB) opening (FUS-BBBO) is not only a promising technique for clinical applications but also a powerful tool for preclinical research. However, existing FUS devices for preclinical research are expensive, bulky, and lack the precision needed for small animal research, which limits the broad adoption of this promising technique by the research community. Our objective was to design and fabricate an affordable, easy-to-use, high-precision FUS device for small animal research. Methods: We designed and fabricated in-house mini-FUS transducers (~$80 each in material cost) with three frequencies (1.5, 3.0, and 6.0 MHz) and integrated them with a stereotactic frame for precise mouse brain targeting using established stereotactic procedures. The BBB opening volume by FUS-BBBO at different acoustic pressures (0.20-0.57 MPa) was quantified using T1-weighted contrast-enhanced magnetic resonance imaging of gadolinium leakage and fluorescence imaging of Evans blue extravasation. Results: The targeting accuracy of the device as measured by the offset between the desired target location and the centroid of BBBO was 0.63 ± 0.19 mm. The spatial precision of the device in targeting individual brain structures was improved by the use of higher frequency FUS transducers. The BBB opening volume had high linear correlations with the cavitation index (defined by the ratio between acoustic pressure and frequency) and mechanical index (defined by the ratio between acoustic pressure and the square root of frequency). The correlation coefficient of cavitation index was higher than that of the mechanical index. Conclusion: This study demonstrated that spatially accurate and precise BBB opening was achievable using an affordable and easy-to-use FUS device. The BBB opening volume was tunable by modulating the cavitation index. This device is expected to decrease the barriers for the adoption of FUS-BBBO technique by the broad research community. IEEE

Author Keywords
Acoustics;  Blood-brain barrier;  Brain drug delivery;  Cavitation index;  Drug delivery;  Focused ultrasound;  Indexes;  Mechanical inde;  Mice;  Three-dimensional displays;  Transducers;  Ultrasonic imaging

Differential Placebo Responses for Pharmacotherapy and Neurostimulation in Late-Life Depression
(2022) Neuromodulation, . 

Wathra, R.A.^a b , Mulsant, B.H.^a b , Reynolds, C.F., III^c , Lenze, E.J.^d , Karp, J.F.^e , Daskalakis, Z.J.^f , Blumberger, D.M.^a b

^a Temerty Centre for Therapeutic Brain Intervention, Centre for Addiction and Mental Health, Toronto, ON, Canada
^b Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
^c Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^d Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, University of Arizona College of Medicine – Tucson, Tucson, AZ, United States
^f Department of Psychiatry, University of California San Diego, San Diego, CA, United States

Abstract
Background: The magnitude of the placebo response depends on both the modality used as the “placebo” and the intervention with which it is compared, both of which can complicate the interpretation of randomized controlled trials (RCTs) for depression in late life. Given that neurostimulation and pharmacotherapy are among the most common interventions studied for late-life depression, comparing the relative placebo responses in studies of these interventions can aid interpretation of relative effect sizes. Materials and Methods: We analyzed data from two RCTs of adults aged ≥60 years in an episode of treatment-resistant major depression, one comparing aripiprazole and matching placebo pills and the other comparing deep repetitive transcranial magnetic stimulation (rTMS) and sham rTMS. In both RCTs, depression was assessed using the 17-item Hamilton Depression Rating Scale (HDRS-17). The primary comparison occurred after four weeks using analysis of covariance (ANCOVA) of HDRS-17 scores in participants who received placebo pills or sham rTMS. Relevant covariates included years of education, duration of depressive episode, and baseline HDRS-17 score. Results: Accounting for covariates, there was a larger reduction of HDRS-17 after four weeks in the sham rTMS group (estimated marginal mean ± SE: −5.90 ± 1.45; 95% CI: [−8.82, 2.98]) than in the placebo pills group (−1.07 ± 1.45; [−3.98, 1.85]). There were no significant differences between these groups in the binary outcome analysis of response and remission rates at four weeks or any outcome at trial end point comparison. Conclusions: Sham rTMS may have a larger placebo response than placebo pills early in the treatment of older adults with treatment-resistant depression. Differential placebo responses should be considered in both the interpretation and design of RCTs. © 2021 International Neuromodulation Society

Author Keywords
Aripiprazole;  depression;  geriatric;  placebo;  rTMS

Salience network anatomical and molecular markers are linked with cognitive dysfunction in mild cognitive impairment
(2022) Journal of Neuroimaging, . 

Chand, G.B., Thakuri, D.S., Soni, B.

Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background and Purpose: Recent studies indicate disrupted functional mechanisms of salience network (SN) regions—right anterior insula, left anterior insula, and anterior cingulate cortex—in mild cognitive impairment (MCI). However, the underlying anatomical and molecular mechanisms in these regions are not clearly understood yet. It is also unknown whether integration of multimodal—anatomical and molecular—markers could predict cognitive impairment better in MCI. Methods: Herein we quantified anatomical volumetric markers via structural MRI and molecular amyloid markers via PET with Pittsburgh compound B in SN regions of MCI (n = 33) and healthy controls (n = 27). From these markers, we built support vector machine learning models aiming to estimate cognitive dysfunction in MCI. Results: We found that anatomical markers are significantly reduced and molecular markers are significantly elevated in SN nodes of MCI compared to healthy controls (p <.05). These altered markers in MCI patients were associated with their worse cognitive performance (p <.05). Our machine learning-based modeling further suggested that the integration of multimodal markers predicts cognitive impairment in MCI superiorly compared to using single modality-specific markers. Conclusions: These findings shed light on the underlying anatomical volumetric and molecular amyloid alterations in SN regions and show the significance of multimodal markers integration approach in better predicting cognitive impairment in MCI. © 2022 American Society of Neuroimaging

Author Keywords
machine learning;  neuroimaging;  PET;  structural MRI

The posterior dominant rhythm: an electroencephalographic biomarker for cognitive recovery after general anaesthesia
(2022) British Journal of Anaesthesia, . 

Labonte, A.K.^a b , Kafashan, M.^a c , Huels, E.R.^a d , Blain-Moraes, S.^e , Basner, M.^f , Kelz, M.B.^g , Mashour, G.A.^d , Avidan, M.S.^a c h i , Palanca, B.J.A.^{a b c i j} , Muench, M.^k , Tarnal, V.^k , Vanini, G.^k , Ochroch, E.A.^k , Hogg, R.^k , Schwarz, M.^k , Janke, E.^k , Golmirzaie, G.^k , Picton, P.^k , McKinstry-Wu, A.R.^k , the ReCCognition Study Group^l

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. LouisMissouri, United States
^d Department of Anesthesiology, Center for Consciousness Science and Neuroscience Graduate Program, University of Michigan Medical School, Ann Arbor, MI, United States
^e School of Physical and Occupational Therapy, McGill University, Montreal, QC, Canada
^f Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^g Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
^h Department of Surgery, Division of Cardiothoracic Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
ⁱ Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^j Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: The posterior dominant rhythm (PDR) was the first oscillatory pattern noted in the EEG. Evoked by wakeful eyelid closure, these oscillations dissipate over seconds during loss of arousal. The peak frequency of the PDR maintains stability over years, suggesting utility as a state biomarker in the surveillance of acute cognitive impairments. This EEG signature has not been systematically investigated for tracking cognitive dysfunction after anaesthetic-induced loss of consciousness. Methods: This substudy of Reconstructing Consciousness and Cognition (NCT01911195) investigated the PDR and cognitive function in 60 adult volunteers randomised to either 3 h of isoflurane general anaesthesia or resting wakefulness. Serial measurements of EEG power and cognitive task performance were assessed relative to pre-intervention baseline. Mixed-effects models allowed quantification of PDR and neurocognitive trajectories after return of responsiveness (ROR). Results: Individuals in the control group showed stability in the PDR peak frequency over several hours (median difference/inter-quartile range [IQR] of 0.02/0.20 Hz, P=0.39). After isoflurane general anaesthesia, the PDR peak frequency was initially reduced at ROR (median difference/IQR of 0.88/0.65 Hz, P&lt;0.001). PDR peak frequency recovered at a rate of 0.20 Hz h−1. After ROR, the PDR peak frequency correlated with reaction time and accuracy on multiple cognitive tasks (P&lt;0.001). Conclusion: The temporal trajectory of the PDR peak frequency may be a useful perioperative marker for tracking cognitive dysfunction on the order of hours after surgery, particularly for cognitive domains of working memory, visuomotor speed, and executive function. Clinical trial registration: NCT01911195. © 2022 British Journal of Anaesthesia

Author Keywords
alpha oscillations;  anaesthesia;  biomarker;  cognitive function;  electroencephalography;  posterior dominant rhythm

Funding details
National Institute on AgingNIAR01 AG057901
James S. McDonnell FoundationJSMF
Washington University in St. LouisWUSTL
McDonnell Center for Systems Neuroscience

Reduced Pupil Oscillation During Facial Emotion Judgment in People with Autism Spectrum Disorder
(2022) Journal of Autism and Developmental Disorders, . 

Sun, S.^a b , Webster, P.J.^c , Wang, Y.^d , Yu, H.^e , Yu, R.^f , Wang, S.^c g

^a Frontier Research Institute for Interdisciplinary Sciences, Tohoku University, Aoba-6-3 Aramaki, Aoba Ward, Sendai, 980-8578, Japan
^b Research Institute of Electrical Communication, Tohoku University, 2-1-1 Katahira, Aoba Ward, Sendai, 980-8577, Japan
^c Department of Chemical and Biomedical Engineering and Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV 26506, United States
^d Department of Neurology, University of Michigan, Ann Arbor, MI 48109, United States
^e Department of Psychological & Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, United States
^f Department of Management, School of Business, Hong Kong Baptist University, HKSAR, Kowloon Tong, Hong Kong
^g Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
People with autism spectrum disorder (ASD) show abnormal face perception and emotion recognition. However, it remains largely unknown whether these differences are associated with abnormal physiological responses when viewing faces. In this study, we employed a sensitive emotion judgment task and conducted a detailed investigation of pupil dilation/constriction and oscillation in high-functioning adult participants with ASD and matched controls. We found that participants with ASD showed normal pupil constriction to faces; however, they demonstrated reduced pupil oscillation, which was independent of stimulus properties and participants’ perception of the emotion. Together, our results have revealed an abnormal physiological response to faces in people with ASD, which may in turn be associated with impaired face perception previously found in many studies. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Ambiguity;  Autism spectrum disorder;  Emotion;  Eye Tracking;  Face Perception;  Pupil

Funding details
National Science FoundationNSFBCS-1945230, IIS-2114644
Air Force Office of Scientific ResearchAFOSRFA9550-21-1-0088

The relationship between temperament, polygenic score for intelligence and cognition: A population-based study of middle-aged adults
(2022) Genes, Brain and Behavior, . 

Tölli, P.^a , Keltikangas-Järvinen, L.^a , Lehtimäki, T.^b c , Ravaja, N.^a , Hintsanen, M.^d , Ahola-Olli, A.^e f g , Pahkala, K.^h i , Kähönen, M.^c j , Hutri-Kähönen, N.^k , Laitinen, T.T.^h i , Tossavainen, P.^l m , Taittonen, L.^n o , Dobewall, H.^d , Jokinen, E.^p q , Raitakari, O.^e r s , Cloninger, C.R.^t , Rovio, S.^h , Saarinen, A.^a

^a Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland
^b Department of Clinical Chemistry, Fimlab Laboratories, and Finnish Cardiovascular Research Center, Tampere, Finland
^c Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
^d Research Unit of Psychology, Faculty of Education, University of Oulu, Oulu, Finland
^e Department of Internal Medicine, Satasairaala Central Hospital, Pori, Finland
^f Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, United States
^g Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
^h Research Centre for Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland
ⁱ Sports Exercise Medicine Unit, Department of Physical Activity and Health, Paavo Nurmi Centre, Turku, Finland
^j Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland
^k Tampere Centre for Skills Training and Simulation, Tampere University, Tampere, Finland
^l Department of Pediatrics and Adolescents, Oulu University Hospital, Oulu, Finland
^m PEDEGO Research Unit and Medical Research Center Oulu, University of Oulu, Oulu, Finland
ⁿ Vaasa Central Hospital, Vaasa, Finland
^o Department of Pediatrics, University of Oulu, Oulu, Finland
^p Department of Pediatrics, University of Helsinki, Helsinki, Finland
^q Hospital for Children and Adolescents, Helsinki University Hospital, Helsinki, Finland
^r Centre for Population Health Research, University of Turku and Turku University Hospital, Turku, Finland
^s Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
^t Department of Psychiatry, Washington University, St. Louis, WA, United States

Abstract
We investigated whether temperament modifies an association between polygenic intelligence potential and cognitive test performance in midlife. The participants (n = 1647, born between 1962 and 1977) were derived from the Young Finns Study. Temperament was assessed with Temperament and Character Inventory over a 15-year follow-up (1997, 2001, 2007, 2012). Polygenic intelligence potential was assessed with a polygenic score for intelligence. Cognitive performance (visual memory, reaction time, sustained attention, spatial working memory) was assessed with CANTAB in midlife. The PGSI was significantly associated with the overall cognitive performance and performance in visual memory, sustained attention and working memory tests but not reaction time test. Temperament did not correlate with polygenic score for intelligence and did not modify an association between the polygenic score and cognitive performance, either. High persistence was associated with higher visual memory (B = 0.092; FDR-adj. p = 0.007) and low harm avoidance with higher overall cognitive performance, specifically better reaction time (B = −0.102; FDR-adj; p = 0.007). The subscales of harm avoidance had different associations with cognitive performance: higher “anticipatory worry,” higher “fatigability,” and lower “shyness with strangers” were associated with lower cognitive performance, while the role of “fear of uncertainty” was subtest-related. In conclusion, temperament does not help or hinder one from realizing their genetic potential for intelligence. The overall modest relationships between temperament and cognitive performance advise caution if utilizing temperament-related information e.g. in working-life recruitments. Cognitive abilities may be influenced by temperament variables, such as the drive for achievement and anxiety about test performance, but they involve distinct systems of learning and memory. © 2022 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Author Keywords
CANTAB;  cognitive abilities;  cognitive performance;  cognitive test;  genetic;  GWAS;  intelligence;  polygenic score;  prospective;  TCI;  temperament

Funding details
Yrjö Jahnssonin Säätiö
Horizon 2020 Framework ProgrammeH2020755320, 848146
ADEA Diabetes Research FoundationADRF
European CommissionEC
European Research CouncilERC742927
Academy of Finland117787, 121584, 124282, 126925, 129378, 134309, 286284, 322098, 41071
Suomen KulttuurirahastoSKR
Juho Vainion Säätiö
Signe ja Ane Gyllenbergin Säätiö
Emil Aaltosen Säätiö
Sydäntutkimussäätiö
Sigrid Juséliuksen Säätiö
Tampereen Tuberkuloosisäätiö
Horizon 2020
Diabetesliitto
Paavo Nurmen Säätiö
Tays
Turun Yliopistollinen KeskussairaalaTYKSX51001

Phenotypic responses to climate change are significantly dampened in big-brained birds
(2022) Ecology Letters, . 

Baldwin, J.W., Garcia-Porta, J., Botero, C.A.

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

Abstract
Anthropogenic climate change is rapidly altering local environments and threatening biodiversity throughout the world. Although many wildlife responses to this phenomenon appear largely idiosyncratic, a wealth of basic research on this topic is enabling the identification of general patterns across taxa. Here, we expand those efforts by investigating how avian responses to climate change are affected by the ability to cope with ecological variation through behavioural flexibility (as measured by relative brain size). After accounting for the effects of phylogenetic uncertainty and interspecific variation in adaptive potential, we confirm that although climate warming is generally correlated with major body size reductions in North American migrants, these responses are significantly weaker in species with larger relative brain sizes. Our findings suggest that cognition can play an important role in organismal responses to global change by actively buffering individuals from the environmental effects of warming temperatures. © 2022 John Wiley & Sons Ltd.

Author Keywords
birds;  body size;  brain size;  climate change;  cognitive buffer

Funding details
National Science FoundationNSFDEB 1841470

Integrase Inhibitors are Associated with Neuropsychiatric Symptoms in Women with HIV
(2022) Journal of Neuroimmune Pharmacology, . 

Rubin, L.H.^a b c , O’Halloran, J.A.^d , Williams, D.W.^e f , Li, Y.^g , Fitzgerald, K.C.^a , Dastgheyb, R.^a , Damron, A.L.^a , Maki, P.M.^h , Spence, A.B.ⁱ , Sharma, A.^j , Gustafson, D.R.^k , Milam, J.^l , Weber, K.M.^m , Adimora, A.A.ⁿ , Ofotokun, I.^o , Fischl, M.A.^p , Konkle-Parker, D.^q , Xu, Y.^g r

^a Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^b Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^c Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
^d Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^f Division of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^g Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, United States
^h Departments of Psychiatry and Psychology, University of Illinois at Chicago, Chicago, IL, United States
ⁱ Department of Medicine, Division of Infectious Disease and Travel Medicine, Georgetown University, Washington, DC, United States
^j Albert Einstein College of Medicine, Bronx, NY, United States
^k Department of Neurology, State University of New York Downstate Health Sciences University, New York City, United States
^l Institute for Health Promotion & Disease Prevention Research, University of Southern California, Los Angeles, CA, United States
^m CORE Center, Cook County Health and Hektoen Institute of Medicine, Chicago, IL, United States
ⁿ Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^o Department of Medicine, Division of Infectious Diseases, Emory University, Atlanta, GA, United States
^p University of Miami Miller School of Medicine, Miami, FL, United States
^q Division of Infectious Diseases, University of Mississippi Medical Center, Jackson, MS, United States
^r Division of Biostatistics and Bioinformatics at The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Abstract
Objective: Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women’s Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects(CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35–55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms(P’s < 0.01); dolutegravir was also associated with greater re-experiencing symptoms(P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities(P’s < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years(P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk–benefit ratio of dolutegravir and elvitegravir in WWH. Graphical abstract: [Figure not available: see fulltext.] © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Antiretroviral;  Heterogeneity;  HIV;  PTSD;  Stress;  Women

SIRT1 mediates hypoxic postconditioning- and resveratrol-induced protection against functional connectivity deficits after subarachnoid hemorrhage
(2022) Journal of Cerebral Blood Flow and Metabolism, . 

Clarke, J.V.^a , Brier, L.M.^b , Rahn, R.M.^b , Diwan, D.^a , Yuan, J.Y.^a , Bice, A.R.^b , Imai, S.-I.^c , Vellimana, A.K.^a , Culver, J.P.^b , Zipfel, G.J.^a

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, United States
^c Department of Developmental Biology, Washington University School of Medicine, St. Louis, United States

Abstract
Functional connectivity (FC) is a sensitive metric that provides a readout of whole cortex coordinate neural activity in a mouse model. We examine the impact of experimental SAH modeled through endovascular perforation, and the effectiveness of subsequent treatment on FC, through three key questions: 1) Does the endovascular perforation model of SAH induce deficits in FC; 2) Does exposure to hypoxic conditioning provide protection against these FC deficits and, if so, is this neurovascular protection SIRT1-mediated; and 3) does treatment with the SIRT1 activator resveratrol alone provide protection against these FC deficits? Cranial windows were adhered on skull-intact mice that were then subjected to either sham or SAH surgery and either left untreated or treated with hypoxic post-conditioning (with or without EX527) or resveratrol for 3 days. Mice were imaged 3 days post-SAH/sham surgery, temporally aligned with the onset of major SAH sequela in mice. Here we show that the endovascular perforation model of SAH induces global and network-specific deficits in FC by day 3, corresponding with the time frame of DCI in mice. Hypoxic conditioning provides SIRT1-mediated protection against these network-specific FC deficits post-SAH, as does treatment with resveratrol. Conditioning-based strategies provide multifaceted neurovascular protection in experimental SAH. © The Author(s) 2022.

Author Keywords
delayed cerebral ischemia;  experimental subarachnoid hemorrhage;  Functional connectivity;  optical intrinsic signal;  sirtuins

Funding details
National Institute on AgingNIAF30AG061932
National Institute of Neurological Disorders and StrokeNINDSP01NS080675, R01NS091603, R01NS099429
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54HD087011

Acylated and alkylated benzo(crown-ethers) form ion-dependent ion channels in biological membranes
(2022) Biophysical Journal, . 

Carrasquel-Ursulaez, W.^a , Dehghany, M.^b , Jones, C.L.^b , Idikuda, V.^a , Lu, B.^a , Schomaker, J.M.^b , Chanda, B.^a

^a Department of Anesthesiology, Washington University in St. Louis, St. Louis, Missouri, United States
^b Department of Chemistry, University of Wisconsin, Madison, WI, United States

Abstract
Synthetic ion channels based on benzo(crown-ether) compounds have been previously reported to function as ion-selective channels in planar lipid bilayers, with hydrogen bonding networks implicated in the formation of self-aggregated complexes. Herein, we report the synthesis and characterization of two new families of benzo(crown-ether) compounds, termed monoacylated and monoalkylated benzo(crown-ethers) (MABCE), both of which lack hydrogen bond donors. Depending on the length of alkyl chain substituent and the size of macrocycle, MABCE compounds inhibit bacterial growth and transport ions across biological membranes. Single-channel recordings show that the activity is higher in the presence of K+ as compared with Na+; however, under bionic conditions, open channels do not exhibit any preference between the two ions. These findings reveal that the ionic preference of benzo(crown-ether) compounds is either due to the regulation of assembly of ion-conducting supramolecular complexes or its membrane insertion by cations, as opposed to ion-selective transport through these scaffolds. Furthermore, our data show that the H-bonding network is not needed to form these assemblies in the membrane. © 2022 Biophysical Society

Funding details
National Science FoundationNSFCHE-0342998, CHE-1048642, CHE-9208463, CHE-9304546
National Institute of General Medical SciencesNIGMS5R21GM131662
National Institute of Neurological Disorders and StrokeNINDSR35NS116850
College of Engineering, University of Wisconsin-Madison63/229265, 63/275987

Cerebral Perfusion and Sensory Testing Results Differ in Interstitial Cystitis/Bladder Pain Syndrome Patients with and without Fibromyalgia: A Site-Specific MAPP Network Study
(2021) Journal of Pain Research, 14, pp. 3887-3895. 

Deutsch, G.^a , Deshpande, H.^a , Lai, H.H.^b , Kutch, J.J.^c , Ness, T.J.^d e

^a Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, United States
^b Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA, United States
^d Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
^e Department of Anesthesiology, University of Alabama at Birmingham, BMR2-208; 901 19th St. S, Birmingham, AL 35205, United States

Abstract
Purpose: Fibromyalgia is a common co-morbidity in patients with interstitial cystitis/bladder pain syndrome. Quantitative sensory testing measures and regional cerebral blood flow measures have been noted to differ from healthy controls in both subjects with fibromyalgia and those with interstitial cystitis when studied independently. The present study examined such measures in subjects with the diagnosis of interstitial cystitis both with and without the co-diagnosis of fibromyalgia to determine whether differences in these measures may be associated with comorbidity. Patients and Methods: Female subjects with the diagnosis of interstitial cystitis with (n = 15) and without (n = 19) the co-diagnosis of fibromyalgia as well as healthy control subjects (n = 41) underwent quantitative sensory testing. A subset of these patients (9 with and 9 without fibromyalgia) underwent brain perfusion studies using arterial spin labeled functional magnetic resonance imaging. An analysis was performed of absolute regional cerebral blood flow of regions-of-interest when experiencing a full bladder compared with an empty bladder. Results: Subjects with both interstitial cystitis and fibromyalgia were more hypersensitive than those without fibromyalgia as well as healthy controls in most sensory measures except heat. Subjects with interstitial cystitis, but no fibromyalgia, differed from healthy controls only in toleration of the ischemic forearm task. Other co-morbidities were more common in those subjects with both interstitial cystitis and fibromyalgia. Bladder fullness was associated with significantly greater whole brain gray matter blood flow in subjects with interstitial cystitis and fibromyalgia when compared with that of subjects with interstitial cystitis without fibromyalgia. Examination of regional cerebral blood flow in individual regions-of-interest demonstrated statistically significant differences between the subjects with interstitial cystitis with and those without fibromyalgia bilaterally in the thalamus, amygdala and hippocampus, as well as the right prefrontal cortex and greater responsiveness to changes in bladder fullness in the insula. Conclusion: Quantitative sensory testing and brain perfusion data support that there are two phenotypes of interstitial cystitis patients, which can be differentiated by a co-diagnosis of fibromyalgia. This may affect responsiveness to treatment and suggest the utility of stratifying interstitial cystitis patients according to their co-morbidities. © 2021 Deutsch et al.

Author Keywords
Arterial spin labelling;  fMRI;  Interstitial cystitis;  QST

Funding details
National Institutes of HealthNIHDK051413, U01 DK082315
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
National Institute for Health ResearchNIHR