WashU weekly Neuroscience publications

White matter microstructure associations with episodic memory in adults with Down syndrome: a tract-based spatial statistics study
(2021) Journal of Neurodevelopmental Disorders, 13 (1), art. no. 17, . 

Bazydlo, A.^a , Zammit, M.^a , Wu, M.^b , Dean, D.^a c , Johnson, S.^a c d , Tudorascu, D.^b , Cohen, A.^b , Cody, K.^a , Ances, B.^e , Laymon, C.^b , Klunk, W.^b , Zaman, S.^f , Handen, B.^b , Alexander, A.^a d , Christian, B.^a c d , Hartley, S.^d g

^a School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^b University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^c Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, United States
^d Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^e Washington University of St. Louis, St. Louis, MO, United States
^f Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom
^g School of Human Ecology, University of Wisconsin-Madison, Madison, WI, United States

Abstract
Background: Nearly all persons with Down syndrome will show pathology of Alzheimer’s disease in their 40s. There is a critical need for studies to identify early biomarkers of these various pathological changes of Alzheimer’s disease in the Down syndrome population and understand the relationship of these biomarkers to cognitive symptoms in order to inform clinical trials. Although Alzheimer’s disease is often considered a disease of gray matter, white matter degeneration has been documented during the preclinical stage of Alzheimer’s disease. The current study examined the association between diffusion tensor imaging (DTI) measures of white matter microstructure and episodic memory performance in 52 adults with Down syndrome. Methods: Seventy (N = 70) participants (M = 40.13, SD = 7.77 years) received baseline scans as part of the Neurodegeneration in Aging Down Syndrome (NiAD) study at two imaging facilities (36 at the University of Wisconsin-Madison [UW-Madison] and 34 at the University of Pittsburgh Medical Center [UPMC]). All participants had genetically confirmed trisomy 21. Fifty-two (N = 52) participants remained after QC. The DTI measures, fractional anisotropy (FA) and mean diffusivity (MD), were calculated for each participant. A combined measure of episodic memory was generated by summing the z-scores of (1) Free and Cued Recall test and (2) Rivermead Behavioural Memory Test for Children Picture Recognition. The DTI data were projected onto a population-derived FA skeleton and tract-based spatial statistics analysis was conducted using the FSL tool PALM to calculate Pearson’s r values between FA and MD with episodic memory. Results: A positive correlation of episodic memory with FA and a negative correlation of episodic memory and MD in the major association white matter tracts were observed. Results were significant (p < 0.05) after correction for chronological age, imaging site, and premorbid cognitive ability. Conclusion: These findings suggest that white matter degeneration may be implicated in early episodic memory declines prior to the onset of dementia in adults with Down syndrome. Further, our findings suggest a coupling of episodic memory and white matter microstructure independent of chronological age. © 2021, The Author(s).

Funding details
National Institutes of HealthNIHR01AG031110, T32CA009206, U01AG0514, U19 AG070043
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54 HD090256

Acetylated tau inhibits chaperone-mediated autophagy and promotes tau pathology propagation in mice
(2021) Nature Communications, 12 (1), art. no. 2238, . 

Caballero, B.^a b k , Bourdenx, M.^a b l , Luengo, E.^a b c d , Diaz, A.^a b , Sohn, P.D.^e , Chen, X.^e , Wang, C.^e , Juste, Y.R.^a b , Wegmann, S.^f g , Patel, B.^a b , Young, Z.T.^h , Kuo, S.Y.^h , Rodriguez-Navarro, J.A.^a b m , Shao, H.^h , Lopez, M.G.^c d , Karch, C.M.ⁱ , Goate, A.M.^j , Gestwicki, J.E.^h , Hyman, B.T.^f , Gan, L.^e , Cuervo, A.M.^a b

^a Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
^b Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, NY, United States
^c Institute Teofilo Hernando for Drug Discovery, Department of Pharmacology, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
^d Instituto de Investigación Biosanitaria Hospital de la Princesa, Madrid, Spain
^e Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY, United States
^f Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^g German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
^h Institute for Neurodegenerative Disease, University of California at San Francisco, San Francisco, CA, United States
ⁱ Department of Psychiatry, Washington University, St. Louis, MO, United States
^j Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^k Roche Chile Pharmaceuticals, Las Condes, Region Metropolitana, Chile
^l Institut des Maladies Neurodégénératives, CNRS, Université de Bordeaux, Bordeaux, France
^m Instituto Ramón y Cajal de Investigaciones Sanitarias Hospital Ramón y Cajal, Madrid, Spain

Abstract
Disrupted homeostasis of the microtubule binding protein tau is a shared feature of a set of neurodegenerative disorders known as tauopathies. Acetylation of soluble tau is an early pathological event in neurodegeneration. In this work, we find that a large fraction of neuronal tau is degraded by chaperone-mediated autophagy (CMA) whereas, upon acetylation, tau is preferentially degraded by macroautophagy and endosomal microautophagy. Rerouting of acetylated tau to these other autophagic pathways originates, in part, from the inhibitory effect that acetylated tau exerts on CMA and results in its extracellular release. In fact, experimental blockage of CMA enhances cell-to-cell propagation of pathogenic tau in a mouse model of tauopathy. Furthermore, analysis of lysosomes isolated from brains of patients with tauopathies demonstrates similar molecular mechanisms leading to CMA dysfunction. This study reveals that CMA failure in tauopathy brains alters tau homeostasis and could contribute to aggravate disease progression. © 2021, The Author(s).

Funding details
B2017/BMD-3827–NRF24ADCM
RTI2018-095793-B-I00
National Institutes of HealthNIHAG046374, T32 GM007491
National Institute on AgingNIAAG021904, AG031782, AG036884, AG038072, AG054108, AG05681, AG058674
National Institute of Neurological Disorders and StrokeNINDSNS100717
Charles H. Revson FoundationCP13-00234
JPB Foundation
Rainwater Charitable FoundationRCF
Fundación Tatiana Pérez de Guzmán el Bueno

Diffusion Magnetic Resonance Imaging of Infants
(2021) Magnetic Resonance Imaging Clinics of North America, 29 (2), pp. 185-193. 

Neil, J.J.^a b c , Smyser, C.D.^a b c

^a Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St Louis, MO 63110-1093, United States
^b Department of Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8116, St Louis, MO 63110-1093, United States
^c Department of Radiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8131, St Louis, MO 63110-1093, United States

Author Keywords
Brain development;  Diffusion imaging;  MRI;  Neonate;  Preterm

Funding details
National Institutes of HealthNIHP50 HD103525, R01 MH113570, R01 MH113883

The Dystonia Coalition: A Multicenter Network for Clinical and Translational Studies
(2021) Frontiers in Neurology, 12, art. no. 660909, . 

Kilic-Berkmen, G.^a , Wright, L.J.^b , Perlmutter, J.S.^c , Comella, C.^d , Hallett, M.^e , Teller, J.^f , Pirio Richardson, S.^g , Peterson, D.A.^h , Cruchaga, C.ⁱ , Lungu, C.^j , Jinnah, H.A.^a k

^a Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Neurology, Radiology, Neuroscience, Physical, Therapy and Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United States
^e Human Motor Control Section, National Institute of Neurological, Disorders and Stroke (NINDS), National Institute of Health (NIH), Bethesda, MD, United States
^f Dystonia Medical Research Foundation, Chicago, IL, United States
^g Department of Neurology, University of New Mexico Health Sciences Center, Albuquerque, NM, United States
^h Institute for Neural Computation, University of California, San Diego, La Jolla, CA, United States
ⁱ Department of Psychiatry, Hope Center Program on Protein Aggregation and Neurodegeneration, Washington University School of Medicine, St. Louis, MO, United States
^j Division of Clinical Research, National Institute of Neurological, Disorders and Stroke (NINDS), National Institute of Health (NIH), Bethesda, MD, United States
^k Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, United States

Abstract
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal postures, repetitive movements, or both. Research in dystonia has been challenged by several factors. First, dystonia is uncommon. Dystonia is not a single disorder but a family of heterogenous disorders with varied clinical manifestations and different causes. The different subtypes may be seen by providers in different clinical specialties including neurology, ophthalmology, otolaryngology, and others. These issues have made it difficult for any single center to recruit large numbers of subjects with specific types of dystonia for research studies in a timely manner. The Dystonia Coalition is a consortium of investigators that was established to address these challenges. Since 2009, the Dystonia Coalition has encouraged collaboration by engaging 56 sites across North America, Europe, Asia, and Australia. Its emphasis on collaboration has facilitated establishment of international consensus for the definition and classification of all dystonias, diagnostic criteria for specific subtypes of dystonia, standardized evaluation strategies, development of clinimetrically sound measurement tools, and large multicenter studies that document the phenotypic heterogeneity and evolution of specific types of dystonia. © Copyright © 2021 Kilic-Berkmen, Wright, Perlmutter, Comella, Hallett, Teller, Pirio Richardson, Peterson, Cruchaga, Lungu and Jinnah.

Author Keywords
blepharospasm;  cervical dystonia;  dystonia;  laryngeal dystonia;  rare diseases;  spasmodic dysphonia;  torticollis;  writer’s cramp

Funding details
National Institutes of HealthNIHNS065701, NS116025, TR001456
National Institute of Neurological Disorders and StrokeNINDS
National Center for Advancing Translational SciencesNCATS
Dystonia Coalition

Neuroskeletal Effects of Chronic Bioelectric Nerve Stimulation in Health and Diabetes
(2021) Frontiers in Neuroscience, 15, art. no. 632768, . 

Beeve, A.T.^a b , Shen, I.^b , Zhang, X.^a b , Magee, K.^b , Yan, Y.^c , MacEwan, M.R.^c , Scheller, E.L.^a b

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Internal Medicine, Division of Bone and Mineral Diseases, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Background/Aims: Bioelectric nerve stimulation (eStim) is an emerging clinical paradigm that can promote nerve regeneration after trauma, including within the context of diabetes. However, its ability to prevent the onset of diabetic peripheral neuropathy (DPN) has not yet been evaluated. Beyond the nerve itself, DPN has emerged as a potential contributor to sarcopenia and bone disease; thus, we hypothesized that eStim could serve as a strategy to simultaneously promote neural and musculoskeletal health in diabetes. Methods: To address this question, an eStim paradigm pre-optimized to promote nerve regeneration was applied to the sciatic nerve, which directly innervates the tibia and lower limb, for 8 weeks in control and streptozotocin-induced type 1 diabetic (T1D) rats. Metabolic, gait, nerve and bone assessments were used to evaluate the progression of diabetes and the effect of sciatic nerve eStim on neuropathy and musculoskeletal disease, while also considering the effects of cuff placement and chronic eStim in otherwise healthy animals. Results: Rats with T1D exhibited increased mechanical allodynia in the hindpaw, reduced muscle mass, decreased cortical and cancellous bone volume fraction (BVF), reduced cortical bone tissue mineral density (TMD), and decreased bone marrow adiposity. Type 1 diabetes also had an independent effect on gait. Placement of the cuff electrode alone resulted in altered gait patterns and unilateral reductions in tibia length, cortical BVF, and bone marrow adiposity. Alterations in gait patterns were restored by eStim and tibial lengthening was favored unilaterally; however, eStim did not prevent T1D-induced changes in muscle, bone, marrow adiposity or mechanical sensitivity. Beyond this, chronic eStim resulted in an independent, bilateral reduction in cortical TMD. Conclusion: Overall, these results provide new insight into the pathogenesis of diabetic neuroskeletal disease and its regulation by eStim. Though eStim did not prevent neural or musculoskeletal complications in T1D, our results demonstrate that clinical applications of peripheral neuromodulation ought to consider the impact of device placement and eStim on long-term skeletal health in both healthy individuals and those with metabolic disease. This includes monitoring for compounded bone loss to prevent unintended consequences including decreased bone mineral density and increased fracture risk. © Copyright © 2021 Beeve, Shen, Zhang, Magee, Yan, MacEwan and Scheller.

Author Keywords
bone;  bone marrow adiposity;  electrical stimulation;  gait;  muscle;  nerves;  neuropathy;  type 1 diabetes (T1D)

Funding details
National Institutes of HealthNIHP30-AR074992, S10-RR0227552, T32-AR060719, U01-DK116317

Cortical Regions Activated by Spectrally Degraded Speech in Adults With Single Sided Deafness or Bilateral Normal Hearing
(2021) Frontiers in Neuroscience, 15, art. no. 618326, . 

Burton, H.^a , Reeder, R.M.^b , Holden, T.^b , Agato, A.^a , Firszt, J.B.^b

^a Department of Neuroscience, Washington University School of Medicine, Saint LouisMO, United States
^b Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Those with profound sensorineural hearing loss from single sided deafness (SSD) generally experience greater cognitive effort and fatigue in adverse sound environments. We studied cases with right ear, SSD compared to normal hearing (NH) individuals. SSD cases were significantly less correct in naming last words in spectrally degraded 8- and 16-band vocoded sentences, despite high semantic predictability. Group differences were not significant for less intelligible 4-band sentences, irrespective of predictability. SSD also had diminished BOLD percent signal changes to these same sentences in left hemisphere (LH) cortical regions of early auditory, association auditory, inferior frontal, premotor, inferior parietal, dorsolateral prefrontal, posterior cingulate, temporal-parietal-occipital junction, and posterior opercular. Cortical regions with lower amplitude responses in SSD than NH were mostly components of a LH language network, previously noted as concerned with speech recognition. Recorded BOLD signal magnitudes were averages from all vertices within predefined parcels from these cortex regions. Parcels from different regions in SSD showed significantly larger signal magnitudes to sentences of greater intelligibility (e.g., 8- or 16- vs. 4-band) in all except early auditory and posterior cingulate cortex. Significantly lower response magnitudes occurred in SSD than NH in regions prior studies found responsible for phonetics and phonology of speech, cognitive extraction of meaning, controlled retrieval of word meaning, and semantics. The findings suggested reduced activation of a LH fronto-temporo-parietal network in SSD contributed to difficulty processing speech for word meaning and sentence semantics. Effortful listening experienced by SSD might reflect diminished activation to degraded speech in the affected LH language network parcels. SSD showed no compensatory activity in matched right hemisphere parcels. © Copyright © 2021 Burton, Reeder, Holden, Agato and Firszt.

Author Keywords
functional magnetic resonance imaging;  normal hearing;  semantic processing;  single sided deafness;  spectrally degraded speech

Funding details
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCD

Role of sirt1 in isoflurane conditioning‐induced neurovascular protection against delayed cerebral ischemia secondary to subarachnoid hemorrhage
(2021) International Journal of Molecular Sciences, 22 (8), art. no. 4291, . 

Liu, M.^a , Jayaraman, K.^a , Giri, T.^a , Zipfel, G.J.^b , Athiraman, U.^a

^a Department of Anesthesiology, Washington University in Saint Louis, Saint Louis, MO 63110, United States
^b Department of Neurological Surgery, Washington University in Saint Louis, Saint Louis, MO 63110, United States

Abstract
We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)‐induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD‐dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning‐induced neurovascular protection against SAH‐induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX‐527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX‐527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX‐527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX‐527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Aneurysmal subarachnoid hemorrhage;  Delayed cerebral ischemia;  Isoflurane conditioning;  SIRT1

Funding details
National Institutes of HealthNIHR01 NS091603
Brain Aneurysm FoundationBAF

Resting-State Functional Connectivity Disruption as a Pathological Biomarker in Autosomal Dominant Alzheimer Disease
(2021) Brain Connectivity, 11 (3), pp. 239-249. 

Smith, R.X.^a , Strain, J.F.^a , Tanenbaum, A.^a , Fagan, A.M.^a d , Hassenstab, J.^a , McDade, E.^a , Schindler, S.E.^a , Gordon, B.A.^b d , Xiong, C.^c , Chhatwal, J.^e , Jack, C.^f , Karch, C.^d g , Berman, S.^h , Brosch, J.R.ⁱ , Lah, J.J.^j , Brickman, A.M.^k , Cash, D.M.^l , Fox, N.C.^l , Graff-Radford, N.R.^m , Levin, J.ⁿ , Noble, J.^k , Holtzman, D.M.^a d , Masters, C.L.^o , Farlow, M.R.ⁱ , Laske, C.^p , Schofield, P.R.^q , Marcus, D.S.^b , Morris, J.C.^a d , Benzinger, T.L.S.^b d , Bateman, R.J.^a d , Ances, B.M.^a d

^a Department of Neurology, Washington University in Saint Louis, St. Louis, MO, United States
^b Department of Radiology, Washington University in Saint Louis, St. Louis, MO, United States
^c Department of Biostatistics, Washington University in Saint Louis, St. Louis, MO, United States
^d Hope Center for Neurological Disorders, Knight Adrc, Washington University, St. Louis, MO, United States
^e Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^f Department of Radiology, Mayo Clinic, Rochester, MN, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
ⁱ Department of Neurology, Indiana University, Indianapolis, IN, United States
^j Department of Neurology, Emory University, Atlanta, GA, United States
^k Department of Neurology, Columbia University, New York, NY, United States
^l Department of Neurodegenerative Disease, Dementia Research Centre, Institute of Neurology, University College London, London, United Kingdom
^m Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
ⁿ German Center for Neurodegenerative Disease (DZNE) Munich, Munich, Germany
^o The Florey Institute, University of Melbourne, Parkvile, Australia
^p Eberhard Karls University of Tubingen, Tubingen, Germany
^q Neuroscience Research Australia and School of Medical Sciences, The University of New South Wales (UNSW) Sydney, Sydney, Australia

Abstract
Aim: Identify a global resting-state functional connectivity (gFC) signature in mutation carriers (MC) from the Dominantly Inherited Alzheimer Network (DIAN). Assess the gFC with regard to amyloid (A), tau (T), and neurodegeneration (N) biomarkers, and estimated years to symptom onset (EYO). Introduction: Cross-sectional measures were assessed in MC (n = 171) and mutation noncarrier (NC) (n = 70) participants. A functional connectivity (FC) matrix that encompassed multiple resting-state networks was computed for each participant. Methods: A global FC was compiled as a single index indicating FC strength. The gFC signature was modeled as a nonlinear function of EYO. The gFC was linearly associated with other biomarkers used for assessing the AT(N) framework, including cerebrospinal fluid (CSF), positron emission tomography (PET) molecular biomarkers, and structural magnetic resonance imaging. Results: The gFC was reduced in MC compared with NC participants. When MC participants were differentiated by clinical dementia rating (CDR), the gFC was significantly decreased in MC CDR >0 (demented) compared with either MC CDR 0 (cognitively normal) or NC participants. The gFC varied nonlinearly with EYO and initially decreased at EYO =-24 years, followed by a stable period followed by a further decline near EYO = 0 years. Irrespective of EYO, a lower gFC associated with values of amyloid PET, CSF Aβ1-42, CSF p-tau, CSF t-tau, 18F-fluorodeoxyglucose, and hippocampal volume. Conclusions: The gFC correlated with biomarkers used for defining the AT(N) framework. A biphasic change in the gFC suggested early changes associated with CSF amyloid and later changes associated with hippocampal volume. © Copyright 2021, Mary Ann Liebert, Inc.

Author Keywords
18F-fluorodeoxyglucose (FDG);  amyloid;  autosomal dominant Alzheimer disease;  cerebrospinal fluid (CSF);  estimated years to onset (EYO);  hippocampus;  positron emission tomography (PET);  resting-state functional connectivity;  tau

Is presymptomatic ALS perivascular?
(2021) Nature Medicine, 27 (4), pp. 585-586. 

Kreple, C.J., Schoch, K.M., Miller, T.M.

Department of Neurology, Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States

Genetics of substance use disorders: A review
(2021) Psychological Medicine, . 

Deak, J.D.^a b , Johnson, E.C.^c

^a Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^b Department of Psychiatry, Veterans Affairs Connecticut Healthcare Center, West Haven, CT, United States
^c Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ∼50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine. Copyright © The Author(s), 2021. Published by Cambridge University Press.

Author Keywords
genetic epidemiology;  genetics;  genome wide association study;  heritability;  substance use disorders;  twin and family studies

Using idiographic models to distinguish personality and psychopathology
(2021) Journal of Personality, . 

Jackson, J.J., Beck, E.D.

Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Objective: While the overlap between personality and psychopathology is well documented, few studies examine how the two overlap at a lower, moment-to-moment level. We took an idiographic approach to examine personality and psychopathology processes at the individual level. Doing so offers a unique perspective by incorporating both dynamic time and structural analysis, two components that are traditionally examined separately when investigating the overlap between personality and psychopathology. Method: Two experience sample studies measured personality states and personality problems up to four-times a day over a two-week period (Study 1 N = 349, observations = 11,124; Study 2 N = 161, observations = 8,261). Results: For some, personality states and personality problems are deeply intertwined, mirroring existing between-person findings. But for others the two are separate, indicating it is possible to separate personality (states) from a person’s problems. Between-person differences in levels of depression had no association with the idiographic structure, indicating that between-person constructs operate separately from within-person processes. Finally, situations that are more likely to bring out personality problems did not alter the association between personality states and personality problems. Conclusions: This method provides a novel conceptualization of personality–psychopathology overlap, bringing the focus beyond mostly static, between-person models to more dynamic, individual-level models. © 2021 Wiley Periodicals LLC.

Author Keywords
GIMME;  idiographic;  personality pathology;  personality problems;  personality structure

Funding details
National Science FoundationNSFBCS‐1125553
National Institute on AgingNIAR01‐AG018436, R01‐AG067622, T32 AG00030‐3

Low-dose interleukin-2 and regulatory T cell treatments attenuate punctate and dynamic mechanical allodynia in a mouse model of sciatic nerve injury
(2021) Journal of Pain Research, 14, pp. 893-906. 

Hu, R.^a b c , Zhang, J.^a b d , Liu, X.^a b , Huang, D.^c , Cao, Y.-Q.^a b

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Washington University Pain Center, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pain Management, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
^d Department of Anesthesiology, Nanfang Hospital, Southern Medical University, Guangzhou, China

Abstract
Purpose: Nerve injury-induced mechanical hyper-sensitivity, in particular stroking-induced dynamic allodynia, is highly debilitating and difficult to treat. Previous studies indicate that the immunosuppressive regulatory T (Treg) cells modulate the magnitude of punctate mechanical allodynia resulting from sciatic nerve injury. However, whether enhancing Treg-mediated suppression attenuates dynamic allodynia is not known. In the present study, we addressed this knowledge gap by treating mice with low-dose interleukin-2 (ld-IL2) injections or adoptive transfer of Treg cells. Methods: Female Swiss Webster mice received daily injections of ld-IL2 (1 μg/mouse, intraper-itoneally) either before or after unilateral spared nerve injury (SNI). Male C57BL/6J mice received adoptive transfer of 1 x 106 Treg cells 3 weeks post-SNI. The responses to punctate and dynamic mechanical stimuli on the hindpaw were monitored before and up to 4–6 weeks post-SNI. We also compared the distribution of Treg cells and CD3+ total T cells after SNI and/or ld-IL2 treatment. Results: Ld-IL2 pretreatment in female Swiss Webster mice completely blocked the development of SNI-induced dynamic mechanical allodynia and reduced the magnitude of punc-tate allodynia. Delayed ld-IL2 treatment in female mice significantly attenuated the morphine-resistant punctate and dynamic allodynia at 3–5 weeks post-SNI. Adoptive transfer of Treg cells to male C57BL/6J mice 3 weeks post-SNI effectively reversed the persistent punctate and dynamic allodynia, supporting that the effect of ld-IL2 is mediated through endogenous Treg cells, and is likely independent of mouse strain and sex. Neither ld-IL2 treatment nor Treg transfer affected the basal responses to punctate or brush stimuli. Ld-IL2 significantly increased the frequency of Treg cells among total CD3+ T cells in the injured sciatic nerves but not in the uninjured nerves or the dorsal root ganglia, suggesting the injured nerve as ld-IL2’s site of action. Conclusion: Collectively, results from the present study supports Treg as a cellular target and ld-IL2 as a potential therapeutic option for nerve injury-induced persistent punctate and dynamic mechanical allodynia. © 2021 Hu et al.

Author Keywords
Chronic pain;  Dynamic allodynia;  Low-dose interleukin-2;  Punctate allodynia;  Regulatory T cell;  Spared nerve injury

Funding details
National Institutes of HealthNIHNS103350-02S1

Emotion’s role in the unity of consciousness
(2021) Philosophical Psychology, . 

Doulatova, M.

Department of Philosophy, Washington University in St. Louis, United States

Abstract
In subjects with the split-brain syndrome, some conscious states appear to be disunified (e.g., visual states), while others remain unified (e.g., affective states). While placing emphasis on the disunities, disunity accounts conclude that split-brain subjects have two subjective perspectives and not one. I argue that affective unity is more important than perceptual disunity in delineating our subjective perspective. Unlike enjoying an objective perspective, enjoying a subjective perspective entails experiencing aspects of your phenomenal field in terms of their overall relation to you. What it’s like to be you at any given time entails experiencing certain aspects of the phenomenal field as peripheral to others. Emotion creates and sustains a center/periphery structure in our phenomenal field by signaling orders of perceived importance as well as orders of perceived changeability (e.g., to someone feeling grief, the experience of getting a ticket is felt as peripheral/unimportant to the experience of grief; to someone feeling depressed, the experience of reaching a hilltop is felt as peripheral/unattainable to the experience of laying down to rest). Since emotion plays a greater role than perception in creating and sustaining this periphery/center structure, and split-brain patients remain affectively unified, split-brain patients retain a unified subjective perspective on the world. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
access consciousness;  agency;  emotion;  perception;  phenomenal consciousness;  split-brain syndrome;  Unity of consciousness

Apathy, cognitive impairment, and social support contribute to participation in cognitively demanding activities poststroke
(2021) Behavioural Neurology, 2021, art. no. 8810632, . 

Ho, A.^a , Nicholas, M.L.^b , Dagli, C.^c , Connor, L.T.^c d

^a Department of Occupational Therapy, Mgh Institute of Health Professions, Boston, MA, United States
^b Department of Communication Sciences and Disorders, Mgh Institute of Health Professions, Boston, MA, United States
^c Program in Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Importance. Individuals with chronic stroke experience decreased participation in activities with cognitive demands across all areas of occupation. Objective. To understand the extent to which apathy, cognition, and social support predict participation in activities with cognitive demands. Design. Prospective, quantitative correlational, cross-sectional study. Setting. Outpatient treatment centers and community stroke support groups located in St. Louis, MO, and Boston, MA. Participants. 81 community-dwelling individuals ≥ 6-month poststroke with and without aphasia. Measures. Participants completed the Activity Card Sort (ACS), Apathy Evaluation Scale (AES), Medical Outcomes Study Social Support Survey (MOS-SSS), and Delis-Kaplan Executive Function System (DKEFS) Design Fluency and Trail-Making subtests. Results. Cognitive deficits limit participation in activities with high cognitive demands. Apathy and positive social interaction influence participation, regardless of high or low cognitive demands. Poststroke aphasia did not impact return to participation in activities with high and low cognitive demands. Conclusions and Relevance. Cognitive deficits seen poststroke contribute to participation only for activities with high cognitive demands. Apathy has a significant and negative influence on participation overall. Social support is a modifiable contextual factor that can facilitate participation. Poststroke apathy can be detrimental to participation but is not well recognized. The availability of companionship from others to enjoy time with can facilitate participation. © 2021 Amy Ho et al.

Does Digital Nerve Injury Affect Range of Motion Recovery After Zone 2 Flexor Tendon Repair?
(2021) Hand, . 

Keane, G., Stonner, M., Pet, M.A.

Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Evidence surrounding the impact of concomitant digital nerve injury on the outcome of zone 2 flexor tendon repair is sparse and conflicting. The purpose of this study is to assess the impact of digital nerve injury on the range of motion recovery after zone 2 flexor tendon repair. We hypothesized that digital nerve injury is independently associated with decreased motion after zone 2 flexor digitorum profundus (FDP) repair. Methods: This is a single-institution, multisurgeon retrospective analysis of patients treated with primary zone 2 FDP repair. Patients with or without digital nerve injuries were included. Patients with fracture, extensor tendon injury, dysvascularity, follow-up duration of less than 10 weeks, and younger than 15 years were excluded. The primary outcome measure was Strickland percentage at the last therapy visit. Bivariate analysis was performed using simple linear regression. These results were used to guide backward stepwise multivariable analysis of qualifying exploratory variables. Results: Forty-one patients with a total of 54 zone 2 FDP injuries qualified. Mean follow-up duration was 24 ± 10 weeks, and mean age was 38 ± 18 years. Thirty-three digits had a concomitant digital nerve injury, 26 digits had multidigit involvement, and 42 digits had combined FDP and flexor digitorum superficialis (FDS) injuries. Both older age and concomitant FDS injury exhibited independent relationships with poorer range of motion outcomes (P <.05). Digital nerve injury, follow-up duration, gender, and multidigit involvement did not influence final digital motion. Conclusions: In patients undergoing zone 2 FDP repair, concomitant digital nerve injury is not independently associated with poorer postoperative active range of motion. © The Author(s) 2021.

Author Keywords
anatomy;  diagnosis;  digits;  epidemiology;  nerve;  nerve injury;  outcomes;  research and health outcomes;  tendon