WashU weekly Neuroscience publications

Regulation of neuronal connectivity in the mammalian brain by chromatin remodeling
(2019) Current Opinion in Neurobiology, 59, pp. 59-68. 

Goodman, J.V.^{a b} , Bonni, A.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Precise temporal and spatial control of gene expression is essential for brain development. Besides DNA sequence-specific transcription factors, epigenetic factors play an integral role in the control of gene expression in neurons. Among epigenetic mechanisms, chromatin remodeling enzymes have emerged as essential to the control of neural circuit assembly and function in the brain. Here, we review recent studies on the roles and mechanisms of the chromodomain-helicase-DNA-binding (Chd)family of chromatin remodeling enzymes in the regulation of neuronal morphogenesis and connectivity in the mammalian brain. We explore the field through the lens of Chd3, Chd4, and Chd5 proteins, which incorporate into the nucleosome remodeling and deacetylase (NuRD)complex, and the related proteins Chd7 and Chd8, implicated in the pathogenesis of intellectual disability and autism spectrum disorders. These studies have advanced our understanding of the mechanisms that regulate neuronal connectivity in brain development and neurodevelopmental disorders of cognition. © 2019 Elsevier Ltd

Document Type: Review
Publication Stage: Final
Source: Scopus

Aβ34 is a BACE1-derived degradation intermediate associated with amyloid clearance and Alzheimer’s disease progression
(2019) Nature Communications, 10 (1), art. no. 2240, . 

Liebsch, F.^a , Kulic, L.^b , Teunissen, C.^c , Shobo, A.^a , Ulku, I.^a , Engelschalt, V.^d , Hancock, M.A.^e , van der Flier, W.M.^f , Kunach, P.^g , Rosa-Neto, P.^g , Scheltens, P.^f , Poirier, J.^h , Saftig, P.ⁱ , Bateman, R.J.^j , Breitner, J.^h , Hock, C.^{b k} , Multhaup, G.^a

^a Department of Pharmacology and Therapeutics and Integrated Program in Neuroscience, McGill University, Montreal, QC H3G 1Y6, Canada
^b Institute for Regenerative Medicine, University of Zurich, Schlieren, CH-8952, Switzerland
^c Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081HZ, Netherlands
^d Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, 14195, Germany
^e SPR-MS Facility, McGill University, Montreal, QC H3G 1Y6, Canada
^f Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1081HZ, Netherlands
^g Translational Neuroimaging Laboratory, The McGill University Research Centre for Studies in Aging, Alzheimer’s Disease Research Unit, Douglas Research Institute, McGill University, Montreal, QC H4H 1R3, Canada
^h Department of Psychiatry, McGill University, Montreal, QC H4H 1R3, Canada
ⁱ Biochemisches Institut, Christian-Albrechts-Universität-Kiel, Kiel, 24118, Germany
^j Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^k Neurimmune, Schlieren, CH-8952, Switzerland

Abstract
The beta-site APP cleaving enzyme 1 (BACE1) is known primarily for its initial cleavage of the amyloid precursor protein (APP), which ultimately leads to the generation of Aβ peptides. Here, we provide evidence that altered BACE1 levels and activity impact the degradation of Aβ40 and Aβ42 into a common Aβ34 intermediate. Using human cerebrospinal fluid (CSF) samples from the Amsterdam Dementia Cohort, we show that Aβ34 is elevated in individuals with mild cognitive impairment who later progressed to dementia. Furthermore, Aβ34 levels correlate with the overall Aβ clearance rates in amyloid positive individuals. Using CSF samples from the PREVENT-AD cohort (cognitively normal individuals at risk for Alzheimer’s disease), we further demonstrate that the Aβ34/Aβ42 ratio, representing Aβ degradation and cortical deposition, associates with pre-clinical markers of neurodegeneration. We propose that Aβ34 represents a marker of amyloid clearance and may be helpful for the characterization of Aβ turnover in clinical samples. © 2019, The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Response to: Goldberg et al. and Severance et al. Letters to the Editor: The clinical significance of improving remission over standard of care – The reality of treatment resistant-based therapies
(2019) Journal of Psychiatric Research, 114, pp. 211-213. 

Greden, J.F.^a , Parikh, S.V.^a , Rothschild, A.J.^b , Thase, M.E.^c , Dunlop, B.W.^d , DeBattista, C.^e , Conway, C.R.^f , Forester, B.P.^g , Mondimore, F.M.^h , Shelton, R.C.ⁱ , Macaluso, M.^j , Li, J.^k , Brown, K.^l , Gilbert, A.^k , Burns, L.^k , Jablonski, M.R.^k , Dechairo, B.^{k l}

^a University of Michigan Comprehensive Depression Center and Department of Psychiatry, and National Network of Depression Centers, 4250 Plymouth Rd, Ann Arbor, MI 48109, United States
^b University of Massachusetts Medical School and UMass Memorial Healthcare, 55 N Lake Ave, Worcester, MA 01655, United States
^c Perelman School of Medicine of the University of Pennsylvania and the Corporal Michael Crescenz VAMC, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States
^d Emory University School of Medicine, Department of Psychiatry and Behavioral Sciences, 12 Executive Park Dr NE #200, Atlanta, GA 30329, United States
^e Stanford University School of Medicine, Department of Psychiatry and Behavioral Sciences, 401 Quarry Rd, Stanford, CA 94305, United States
^f Washington University School of Medicine, Department of Psychiatry, and the John Cochran Veteran’s Administration Hospital, 660 S Euclid Ave, St. Louis, MO 63110, United States
^g McLean Hospital, Division of Geriatric Psychiatry, Harvard Medical School, 115 Mill St, Belmont, MA 02478, United States
^h Johns Hopkins University School of Medicine, Department of Psychiatry and Behavioral Sciences, 1800 Orleans St, Baltimore, MD 21287, United States
ⁱ The University of Alabama at Birmingham, Department of Psychiatry and School of Medicine, 1720 2nd Ave S, Birmingham, AL, United States
^j University of Kansas School of Medicine-Wichita, Department of Psychiatry and Behavioral Sciences, 1010 N Kansas St, Wichita, KS 67214, United States
^k Assurex Health, Inc., 6960 Cintas Blvd, Mason, OH 45040, United States
^l Myriad Genetics, Inc., 320 Wakara Way, Salt Lake City, UT 84108, United States

Document Type: Letter
Publication Stage: Final
Source: Scopus

Parsing Pain From Anxiety Within the Locus Coeruleus Noradrenergic System
(2019) Biological Psychiatry, 85 (12), pp. 983-985. 

McCall, J.G.^{a b c}

^a Department of Anesthesiology and the Washington University Pain Center, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Pharmaceutical and Administrative Sciences, St. Louis College of Pharmacy, St. Louis, MO, United States
^c Center for Clinical Pharmacology, St. Louis College of Pharmacy and Washington University School of Medicine, St. Louis, MO, United States

Document Type: Note
Publication Stage: Final
Source: Scopus

Dynamic Cortical Connectivity during General Anesthesia in Healthy Volunteers
(2019) Anesthesiology, 130 (6), pp. 870-884. 

Li, D., Vlisides, P.E., Kelz, M.B., Avidan, M.S., Mashour, G.A., Blain-Moraes, S., Golmirzaie, G., Janke, E., Picton, P., Tarnal, V., Vanini, G., Hardie, R., Hogg, R., Maier, K., McKinstry-Wu, A., Ochroch, E.A., Schwarz, M., Maybrier, H., Muench, M., Palanca, B.J.A., ReCCognition Study Group

From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan (D.L., P.E.V., G.A.M.) the Department of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (M.B.K.) the Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (M.S.A.). From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan From the Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, Michigan From the Department of Anesthesiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania From the Department of Anesthesiology, Perelman School of Medicine

Abstract
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Anesthetic-induced loss of consciousness is accompanied by changes in functional connectivity within and between brain networks. WHAT THIS ARTICLE TELLS US THAT IS NEW: Despite a stable surgical level of anesthesia and the absence of noxious stimuli, connectivity patterns are not static but rather fluctuate dynamically and nonrandomly over time. These results suggest that single or static connectivity patterns may not be able to discriminate levels of consciousness. BACKGROUND: Recent studies of anesthetic-induced unconsciousness in healthy volunteers have focused on functional brain connectivity patterns, but the protocols rarely parallel the depth and duration of surgical anesthesia. Furthermore, it is unknown whether there is a single functional connectivity pattern that correlates with general anesthesia for the duration of prolonged anesthetic exposure. METHODS: The authors analyzed electroencephalographic data in 30 healthy participants who underwent induction of anesthesia with propofol followed by 3 h of isoflurane anesthesia at age-adjusted 1.3 minimum alveolar concentration. Functional connectivity was assessed by frequency-resolved weighted phase lag index between frontal and parietal channels and between prefrontal and frontal channels, which were classified into a discrete set of states through k-means cluster analysis. Temporal dynamics were evaluated by the occurrence rate and dwell time distribution for each state as well as the transition probabilities between states. RESULTS: Burst suppression was present, with mean suppression ratio reducing from 44.8 ± 32.3% to 14.0 ± 20.2% (mean ± SD) during isoflurane anesthesia (P < 0.001). Aside from burst suppression, eight connectivity states were classified by optimizing the reproducibility of clustering solutions, with each characterized by distinct properties. The temporal progression of dominant states revealed a successive shifting trajectory from the state associated with alpha frontal-parietal connectivity to those associated with delta and alpha prefrontal-frontal connectivity during induction, which was reversed during emergence. Cortical connectivity was dynamic during maintenance period, and it was more probable to remain in the same state (82.0 ± 8.3%) than to switch to a different state (P < 0.001). However, transitions to other states were structured, i.e., occurred more frequently than expected by chance. CONCLUSIONS: Anesthesia-induced alterations of functional connectivity are dynamic despite the stable and prolonged administration of isoflurane, in the absence of any noxious stimuli. Changes in connectivity over time will likely yield more information as a marker or mechanism of surgical anesthesia than any single pattern.

Document Type: Article
Publication Stage: Final
Source: Scopus

Intracochlear Electrocochleography: Influence of Scalar Position of the Cochlear Implant Electrode on Postinsertion Results
(2019) Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 40 (5), pp. e503-e510. 

Riggs, W.J.^a , Dwyer, R.T.^b , Holder, J.T.^b , Mattingly, J.K.^a , Ortmann, A.^c , Noble, J.H.^d , Dawant, B.M.^d , Valenzuela, C.V.^c , O’Connell, B.P.^e , Harris, M.S.^f , Litvak, L.M.^g , Koka, K.^g , Buchman, C.A.^c , Labadie, R.F.^d , Adunka, O.F.^a

^a Department of Otolaryngology – Head and Neck Surgery, Ohio State University, Columbus, OH, United States
^b Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
^c Department of Otolaryngology – Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Otolaryngology – Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
^e Department of Otolaryngology – Head and Neck Surgery, University of North Carolina, Chapel Hill, NC, United States
^f Department of Otolaryngology and Communication Sciences, United States
^g Research and Technology, Advanced Bionics Corp., Valencia, CA, United States

Abstract
HYPOTHESIS: Electrocochleography (ECochG) recorded during cochlear implant (CI) insertion from the apical electrode in conjunction with postinsertion ECochG can identify electrophysiologic differences that exist between groups with and without a translocation of the array from the scala tympani (ST) into the scala vestibuli (SV). BACKGROUND: Translocation of the CI electrode from ST into SV can limit performance postoperatively. ECochG markers of trauma may be able to aid in the ability to detect electrode array-induced trauma/scalar translocation intraoperatively. METHODS: Twenty-one adult CI patients were included. Subjects were postoperatively parsed into two groups based on analysis of postoperative imaging: 1) ST (n = 14) insertion; 2) SV (n = 7) insertion, indicating translocation of the electrode. The ECochG response elicited from a 500 Hz acoustic stimulus was recorded from the lead electrode during insertion when the distal electrode marker was at the round window, and was compared to the response recorded from a basal electrode (e13) after complete insertion. RESULTS: No statistically significant change in mean ECochG magnitude was found in either group between recording intervals. There was a mean loss of preoperative pure-tone average of 52% for the nontranslocation group and 94% for the translocation group. CONCLUSIONS: Intraoperative intracochlear ECochG through the CI array provides a unique opportunity to explore the impact of the CI electrode on the inner ear. Specifically, a translocation of the array from ST to SV does not seem to change the biomechanics of the cochlear region that lies basal to the area of translocation in the acute period.

Document Type: Article
Publication Stage: Final
Source: Scopus

Image processing to improve detection of mesial temporal sclerosis in adults
(2019) American Journal of Neuroradiology, 40 (5), pp. 798-801. 

Dahi, F.^a , Parsons, M.S.^b , Orlowski, H.L.P.^b , Salter, A.^c , Dahiya, S.^{d e} , Sharma, A.^b

^a Progressive Physicians Association, Bethlehem, PA, United States
^b Mallinckrodt Institute of Radiology, Washington, United States
^c Department of Biostatistics, Washington, United States
^d Department of Pathology and Immunology, Washington, United States
^e University School of Medicine, Washington University in St Louis, St Louis, MO, United States

Abstract
SUMMARY: In this retrospective case-control study, we investigated whether an image-processing algorithm designed to exaggerate the intensity of diseased hippocampi on FLAIR images can improve the diagnostic accuracy and interobserver reliability of radiologists in detecting mesial temporal sclerosis-related hippocampal signal alteration. Herein, we share the results of this study that showed that the image processing improved the confidence of radiologists in detecting mesial temporal sclerosis-related signal alteration, allowing an improved sensitivity, specificity, and interobserver reliability. © 2019 American Society of Neuroradiology. All rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

High-density diffuse optical tomography for imaging human brain function
(2019) Review of Scientific Instruments, 90 (5), art. no. 051101, . 

Wheelock, M.D.^a , Culver, J.P.^{a b c d} , Eggebrecht, A.T.^a

^a Mallinckrodt Institute of Radiology, Washington University, School of Medicine, St. Louisa, MO 63110, United States
^b Department of Physics, Washington University in St. Louis, St. Louis, MO 63130, United States
^c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, United States
^d Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
This review describes the unique opportunities and challenges for noninvasive optical mapping of human brain function. Diffuse optical methods offer safe, portable, and radiation free alternatives to traditional technologies like positron emission tomography or functional magnetic resonance imaging (fMRI). Recent developments in high-density diffuse optical tomography (HD-DOT) have demonstrated capabilities for mapping human cortical brain function over an extended field of view with image quality approaching that of fMRI. In this review, we cover fundamental principles of the diffusion of near infrared light in biological tissue. We discuss the challenges involved in the HD-DOT system design and implementation that must be overcome to acquire the signal-to-noise necessary to measure and locate brain function at the depth of the cortex. We discuss strategies for validation of the sensitivity, specificity, and reliability of HD-DOT acquired maps of cortical brain function. We then provide a brief overview of some clinical applications of HD-DOT. Though diffuse optical measurements of neurophysiology have existed for several decades, tremendous opportunity remains to advance optical imaging of brain function to address a crucial niche in basic and clinical neuroscience: that of bedside and minimally constrained high fidelity imaging of brain function. © 2019 Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus
Access Type: Open Access

Novel Nerve Transfers for Motor and Sensory Restoration in High Cervical Spinal Cord Injury
(2019) World Neurosurgery, . 

Dibble, C.F.^a , Khalifeh, J.M.^a , VanVoorhis, A.^a , Rich, J.T.^b , Ray, W.Z.^a

^a Department of Neurological Surgery, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Otolaryngology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Background: Tetraplegia caused by cervical spinal cord injury is devastating for patients and represents a significant public health problem in both developed and developing countries. Improved functional outcomes after nerve transfers are increasingly reported in the literature, but thus far, no options exist for injuries above the C5 level. Case Description: We report the cases of 2 patients with C4 spinal cord injury, American Spinal Injury Association A, who underwent successful bilateral spinal accessory nerve transfers, on 1 side to the triceps nerve with long intervening sural graft and on the other side direct transfer to the motor fascicles of the middle trunk. Patients improved from Medical Research Council 0 to 4 on the side of the nerve graft and 0 to 2 or 3 on the side of the direct transfer. Both patients also underwent transfer of the greater auricular nerve to sensory fascicles of the middle trunk, and they experienced sensory recovery in the C6 distribution. Notably, both patients were far removed from the traditional window of nerve transfer surgery at 4 years and almost 11 years out from injury. Conclusions: We describe 2 successful cases of the first and to date only option for motor and sensory reinnervation in high cervical spinal cord injuries. These procedures provide a robust nerve transfer option capable of improving quality of life in tetraplegic patients. There may be a significant undertreated population of patients with cervical spinal cord injury patients in the United States who were previously considered outside the window for benefiting from nerve transfers but who would benefit from these techniques. © 2019 Elsevier Inc.

Author Keywords
Cervical spinal cord;  Nerve transfer;  Neurotization;  Spinal cord injury;  Tetraplegia

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

Elecsys® Total-Tau and Phospho-Tau (181P) CSF assays: Analytical performance of the novel, fully automated immunoassays for quantification of tau proteins in human cerebrospinal fluid
(2019) Clinical Biochemistry, . 

Lifke, V.^a , Kollmorgen, G.^a , Manuilova, E.^a , Oelschlaegel, T.^a , Hillringhaus, L.^a , Widmann, M.^b , von Arnim, C.A.F.^c , Otto, M.^c , Christenson, R.H.^d , Powers, J.L.^e , Shaw, L.M.^f , Hansson, O.^{g h} , Doecke, J.D.ⁱ , Li, Q.-X.^j , Teunissen, C.^k , Tumani, H.^c , Blennow, K.^{l m}

^a Roche Diagnostics GmbH, Nonnenwald 2, Penzberg, 82377, Germany
^b Amsterdam University Medical Center, Vrije Universiteit, De Boelelaan 1117Amsterdam 1081 HV, Germany
^c Clinic for Neurology, University Clinic Ulm, Oberer Eselsberg 45, Ulm, 89081, Germany
^d Department of Pathology, University of Maryland School of Medicine, 655 W Baltimore S, Baltimore, MD 21201, United States
^e Division of Endocrinology, Metabolism and Lipid Research, School of Medicine, Washington University in St Louis, 660 S Euclid Ave, St. Louis, MO 63110, United States
^f Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States
^g Clinical Memory Research Unit, Lund University, VO Minnessjukdomar, Simrisbanv 14/4, Malmö, 212 24, Sweden
^h Memory Clinic, Skåne University Hospital, Inga Marie Nilssons gata 47, Malmö, 214 21, Sweden
ⁱ The Commonwealth Scientific and Industrial Research Organisation/Australian E-Health Research Centre, Butterfield St & Bowen Bridge Rd, Herston, QLD 4029, Australia
^j The Florey Institute of Neuroscience and Mental Health, University of Melbourne, 30 Royal Parade, Parkville, VIC 3052, Australia
^k Neurochemistry Laboratory and Biobank, Department of Clinical Chemistry, Amsterdam University Medical Center, Vrije Universiteit, De Boelelaan 1117, Amsterdam, HV 1081, Netherlands
^l Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Göteborgsvägen 31, Mölndal, 431 80, Sweden
^m Institute of Neuroscience and Physiology, Dept. of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Wallinsgatan 6, Mölndal, 431 41, Sweden

Abstract
Background: Total tau (tTau) and phosphorylated 181P tau (pTau) are supportive diagnostic cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. Manual CSF tau assays are limited by lot-to-lot and between-laboratory variability and long incubation/turnaround times. Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF immunoassays were developed for fully automated cobas e analyzers, allowing broader access in clinical practice and trials. Methods: Analytical performance, reproducibility, method comparisons with commercially available assays, and lot-to-lot and platform comparability (cobas e 601/411) of the Elecsys® CSF assays were assessed. Tau distributions and concentration ranges were evaluated in CSF samples from two clinical cohorts. Results: Both assays showed high sensitivity (limit of quantitation [LoQ]: 63 pg/mL [tTau]; 4 pg/mL [pTau]) and linearity over the measuring range (80–1300 pg/mL; 8–120 pg/mL), which covered the entire concentration range measured in clinical samples. Lot-to-lot and platform comparability demonstrated good consistency (Pearson’s r: 0.998; 1.000). Multicenter evaluation coefficients of variation (CVs): repeatability, &lt; 1.8%; intermediate precision, &lt; 2.8%; between-laboratory variability, &lt; 2.7% (both assays); and total reproducibility, &lt; 6.7% (tTau) and &lt; 4.7% (pTau). Elecsys® CSF assays demonstrated good correlation with commercially available tau assays. Conclusions: Elecsys® Total-Tau CSF and Phospho-Tau (181P) CSF assays demonstrate good analytical performance with clinically relevant measuring ranges; data support their use in clinical trials and practice. © 2019

Author Keywords
Alzheimer’s disease;  Biomarkers;  CSF;  Fully automated immunoassay;  Phosphorylated tau;  Total tau

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

The Genetic Relationship Between Alcohol Consumption and Aspects of Problem Drinking in an Ascertained Sample
(2019) Alcoholism: Clinical and Experimental Research, . 

Johnson, E.C.^a , St. Pierre, C.L.^b , Meyers, J.L.^c , Aliev, F.^{d e} , McCutcheon, V.V.^a , Lai, D.^f , Dick, D.M.^g , Goate, A.M.^h , Kramer, J.ⁱ , Kuperman, S.ⁱ , Nurnberger, J.I., Jr.^j , Schuckit, M.A.^k , Porjesz, B.^c , Edenberg, H.J.^{f l} , Bucholz, K.K.^a , Agrawal, A.^a

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Division of Biological and Biomedical Sciences, Washington University School of Medicine, Saint Louis, MO, United States
^c Henri Begleiter Neurodynamics Laboratory, Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, United States
^d Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, United States
^e Department of Actuarial and Risk Management, Faculty of Business, Karabuk University, Karabük, Turkey
^f Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^g Department of Psychology and Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, United States
^h Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
ⁱ Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, University of Iowa, Iowa City, IA, United States
^j Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^k Department of Psychiatry, University of California San Diego, San Diego, CA, United States
^l Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States

Abstract
Background: Genomewide association studies (GWAS) have begun to identify loci related to alcohol consumption, but little is known about whether this genetic propensity overlaps with specific indices of problem drinking in ascertained samples. Methods: In 6,731 European Americans who had been exposed to alcohol, we examined whether polygenic risk scores (PRS) from a GWAS of weekly alcohol consumption in the UK Biobank predicted variance in 6 alcohol-related phenotypes: alcohol use, maximum drinks within 24 hours (MAXD), total score on the Self-Rating of the Effects of Ethanol Questionnaire (SRE-T), DSM-IV alcohol dependence (DSM4AD), DSM-5 alcohol use disorder symptom counts (DSM5AUDSX), and reduction/cessation of problematic drinking. We also examined the extent to which an single nucleotide polymorphism (rs1229984) in ADH1B, which is strongly associated with both alcohol consumption and dependence, contributed to the polygenic association with these phenotypes and whether PRS interacted with sex, age, or family history of alcoholism to predict alcohol-related outcomes. We performed mixed-effect regression analyses, with family membership and recruitment site included as random effects, as well as survival modeling of age of onset of DSM4AD. Results: PRS for alcohol consumption significantly predicted variance in 5 of the 6 outcomes: alcohol use (Δmarginal R2 = 1.39%, Δ area under the curve [AUC] = 0.011), DSM4AD (Δmarginal R2 = 0.56%; ΔAUC = 0.003), DSM5AUDSX (Δmarginal R2 = 0.49%), MAXD (Δmarginal R2 = 0.31%), and SRE-T (Δmarginal R2 = 0.22%). PRS were also associated with onset of DSM4AD (hazard ratio = 1.11, p = 2.08e−5). The inclusion of rs1229984 attenuated the effects of the alcohol consumption PRS, particularly for DSM4AD and DSM5AUDSX, but the PRS continued to exert an independent effect for all 5 alcohol measures (Δmarginal R2 after controlling for ADH1B = 0.14 to 1.22%). Interactions between PRS and sex, age, or family history were nonsignificant. Conclusions: Genetic propensity for typical alcohol consumption was associated with alcohol use and was also associated with 4 of the additional 5 outcomes, though the variance explained in this sample was modest. Future GWAS that focus on the multifaceted nature of AUD, which goes beyond consumption, might reveal additional information regarding the polygenic underpinnings of problem drinking. © 2019 by the Research Society on Alcoholism

Author Keywords
ADH1B;  Alcohol Consumption;  Alcohol Dependence;  Polygenic Risk

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

Publisher Correction: Sensory experience remodels genome architecture in neural circuit to drive motor learning (Nature, (2019), 10.1038/s41586-019-1190-7)
(2019) Nature, . 

Yamada, T.^{a b} , Yang, Y.^{a e} , Valnegri, P.^a , Juric, I.^c , Abnousi, A.^c , Markwalter, K.H.^{a d} , Guthrie, A.N.^a , Godec, A.^a , Oldenborg, A.^a , Hu, M.^c , Holy, T.E.^a , Bonni, A.^a

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^b Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
^c Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
^d MD-PhD Program, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurobiology, Northwestern University, Evanston, IL, United States

Abstract
In this Letter, ‘≥’ should be ‘≤’ in the sentence: “Intra-chromosomal reads were further split into short-range reads (≥1 kb) and long-range reads (>1 kb)”. This error has been corrected online. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.

Document Type: Erratum
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

Severity Assessment in CDKL5 Deficiency Disorder
(2019) Pediatric Neurology, . 

Demarest, S.^{a b} , Pestana-Knight, E.M.^{c d} , Olson, H.E.^e , Downs, J.^{f g} , Marsh, E.D.^{h i j} , Kaufmann, W.E.^{k l} , Partridge, C.-A.^m , Leonard, H.^g , Gwadry-Sridhar, F.ⁿ , Frame, K.E.^o , Cross, J.H.^p , Chin, R.F.M.^q , Parikh, S.^d , Panzer, A.^r , Weisenberg, J.^s , Utley, K.^t , Jaksha, A.^t , Amin, S.^u , Khwaja, O.^v , Devinsky, O.^w , Neul, J.L.^x , Percy, A.K.^y , Benke, T.A.^{a b z aa ab}

^a Children’s Hospital Colorado and University of Colorado School of Medicine AuroraCO, United States
^b Department of Pediatrics, Aurora, CO, United States
^c Cleveland Clinic, Neurological Institute ClevelandOH, United States
^d Epilepsy Center, Cleveland, OH, United States
^e Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, MA, United States
^f Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
^g School of Physiotherapy and Exercise Science, Curtin University, Perth, Western Australia, Australia
^h Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
ⁱ Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^j Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^k M.I.N.D. Institute, Department of Neurology, University of California Davis Health System, Sacramento, CA, United States
^l Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, Georgia
^m CDKL5 UKSomerset, United Kingdom
ⁿ Department of Computer Science, University of Western Ontario and Pulse Infoframe, London, Ontario, Canada
^o CDKL5 Research Collaborative, Dexter, MI, United States
^p UCL Great Ormond Street Institute of Child Health & NIHR GOSH BRC, London, United Kingdom
^q University of Edinburgh and Royal Hospital for Sick Children, Edinburgh, United Kingdom
^r DRK Westend Clinic Berlin, Berlin, Germany
^s Neurology, Division of Pediatric Neurology, Epilepsy Section, Washington University School of Medicine, St. Louis Children’s Hospital, St Louis, MO, United States
^t International Foundation for CDKL5 Research, Wadwsorth, OH, United States
^u University of Bristol, United Kingdom
^v Roche Innovation Center Basel, Roche Pharmaceutical Research and Early Development NORD, Basel, Switzerland
^w Department of Neurology, New York University, New York, NY, United States
^x Vanderbilt Kennedy Center, Vanderbilt University Medical CenterTN, United States
^y University of Alabama at Birmingham, Pediatrics, Neurology, Neurobiology, Genetics, and Psychology, Birmingham, AL, United States
^z Department of Pharmacology, Aurora, CO, United States
^aa Department of Neurology, Aurora, CO, United States
^ab Department of Otolaryngology, Aurora, CO, United States

Abstract
Background: Pathologic mutations in cyclin-dependent kinase-like 5 cause CDKL5 deficiency disorder, a genetic syndrome associated with severe epilepsy and cognitive, motor, visual, and autonomic disturbances. This disorder is a relatively common genetic cause of early-life epilepsy. A specific severity assessment is lacking, required to monitor the clinical course and needed to define the natural history and for clinical trial readiness. Methods: A severity assessment was developed based on clinical and research experience from the International Foundation for CDKL5 Research Centers of Excellence consortium and the National Institutes of Health Rett and Rett-Related Disorders Natural History Study consortium. An initial draft severity assessment was presented and reviewed at the annual CDKL5 Forum meeting (Boston, 2017). Subsequently it was iterated through four cycles of a modified Delphi process by a group of clinicians, researchers, industry, patient advisory groups, and parents familiar with this disorder until consensus was achieved. The revised version of the severity assessment was presented for review, comment, and piloting to families at the International Foundation for CDKL5 Research-sponsored family meeting (Colorado, 2018). Final revisions were based on this additional input. Results: The final severity assessment comprised 51 items that comprehensively describe domains of epilepsy; motor; cognition, behavior, vision, and speech; and autonomic functions. Parental ratings of therapy effectiveness and child and family functioning are also included. Conclusions: A severity assessment was rapidly developed with input from multiple stakeholders. Refinement through ongoing validation is required for future clinical trials. The consensus methods employed for the development of severity assessment may be applicable to similar rare disorders. © 2019 Elsevier Inc.

Author Keywords
CDKL5;  Cortical visual impairment;  Epilepsy;  Intellectual disability;  Rare disorder;  Severity assessment

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

Longer-term follow-up of college students screening positive for anorexia nervosa: psychopathology, help seeking, and barriers to treatment
(2019) Eating Disorders, . 

Fitzsimmons-Craft, E.E.^a , Eichen, D.M.^b , Monterubio, G.E.^a , Firebaugh, M.-L.^a , Goel, N.J.^{c d} , Taylor, C.B.^{e f} , Wilfley, D.E.^a

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pediatrics, University of California, San Diego, CA, United States
^c Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^d Institute for Inclusion, Inquiry and Innovation (iCubed), Virginia Commonwealth University, Richmond, VA, United States
^e Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^f Center for m²Health, Palo Alto University, Palo Alto, CA, United States

Abstract
The purpose of this study was to conduct a longer-term (i.e., 9-month) follow-up of students identified with possible anorexia nervosa (AN) as part of the Healthy Body Image Program, an online platform for screening and delivering tailored feedback and interventions, offered at 36 US universities. Participants were 61 individuals who screened positive for AN and who completed the follow-up. Regarding results, some indices of ED pathology and psychiatric comorbidity decreased over time, while others did not. Participants most commonly endorsed feeling ashamed, nervous, validated, and sad in response to receiving the referral. One-third (33%) reported already being in treatment at the time they received the referral, 26% initiated treatment since that time, and 41% did not initiate treatment. The most common reasons for seeking treatment were emotional distress, concern with eating, and health concerns. The strongest treatment barriers were believing one should be able to help themselves, believing the problem was not serious enough to warrant treatment, and not having time. Findings highlight the high level of pathology in students identified with possible AN, even nine months after they were first identified and provided resources, and the relatively low rates of treatment utilization given the seriousness of these illnesses. © 2019, © 2019 Taylor & Francis.

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

A novel player in the field: Merkel disc in touch, itch and pain
(2019) Experimental Dermatology, . 

Feng, J., Hu, H.

Department of Anesthesiology, The Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The mechanosensitive Merkel cell-neurite complex comprising two distinct cell types in both hairy and glabrous skin has been widely recognized as touch receptor for more than 100 years. In 2014, three elegant studies further demonstrated that the Merkel cell-neurite complex mediates touch transduction via the mechanosensitive Piezo2 channel. However, whether it is involved in genesis of itch and pain sensations, has been unclear. Recently, we reported that Merkel cells modulate the development of mechanical itch under the conditions of dry skin and aging, whereas two other studies demonstrated that Piezo2 channel mediates mechanical pain. In this assay, we summarized the current knowledge of Merkel disk under both normal and pathological conditions, with a focus on its role in touch, itch, and pain. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Author Keywords
itch;  Merkel disc;  pain;  Piezo2;  touch

Document Type: Note
Publication Stage: Article in Press
Source: Scopus
Access Type: Open Access

Challenges to Routine Genetic Testing for Inherited Rod Dystrophies
(2019) Ophthalmology, . 

Li, A.S., MacKay, D., Chen, H., Rajagopal, R., Apte, R.S.

John F. Hardesty Department of Ophthalmology and Visual Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

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

Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM): Study Design and Treatment Characteristics of the First 396 Participants Randomized
(2019) American Journal of Geriatric Psychiatry, . 

Cristancho, P.^a , Lenard, E.^a , Lenze, E.J.^a , Miller, J.P.^b , Brown, P.J.^c , Roose, S.P.^c , Montes-Garcia, C.^c , Blumberger, D.M.^d , Mulsant, B.H.^d , Lavretsky, H.^e , Rollman, B.L.^f , Reynolds, C.F., III^g , Karp, J.F.^g

^a Department of Psychiatry, Healthy Mind Lab, School of Medicine, Washington University in St. Louis, St. Louis, United States
^b the Division of Biostatistics, School of Medicine, Washington University in St. Louis, St. Louis, United States
^c the Department of Geriatric Psychiatry, Program on Healthy Aging and Late Life Brain Disorders, New York State Psychiatric Institute, Columbia University Medical Center, New York, United States
^d the Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Canada
^e the Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, United States
^f the Department of Medicine and Center for Behavioral Health and Smart Technology, University of Pittsburgh School of Medicine, Pittsburgh, United States
^g the Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, United States

Abstract
Objective: Evidence from clinical trials comparing effectiveness and safety of pharmacological strategies in older adults unresponsive to first-line antidepressants is limited. The study, Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM), tests three hypotheses concerning pharmacotherapy strategies for treatment-resistant late-life depression: 1) augmentation strategies will provide greater improvement than switching monotherapies; 2) augmentation strategies will have lower tolerability and more safety concerns than switching monotherapies; and 3) age will moderate the effectiveness and safety differences between treatment strategies. The authors describe the methodology, processes for stakeholder engagement, challenges, and lessons learned in the early phases of OPTIMUM. Methods: This pragmatic randomized clinical trial located in five North American regions will enroll 1,500 participants aged 60 years and older unresponsive to two or more antidepressant trials. The authors evaluate two strategies (medication augmentation versus switch) using four medications (aripiprazole, bupropion, lithium, and nortriptyline) via a stepwise, prespecified protocol. Primary outcomes include: 1) symptom remission (Montgomery Asberg Depression scale ≤10); 2) psychological well-being, comprising positive affect, general life satisfaction, and purpose; and 3) safety (rates of serious adverse events and prevalence of falls and fall-related injuries). Results: To date, 396 participants have been randomized. The authors report on four challenges: 1) engagement and recruitment; 2) increasing polypharmacy in older adults, resulting in potentially hazardous scenarios; 3) reporting adverse events and procedure standardization across sites; and 4) dissemination of results. Conclusion: Solutions to these challenges, including early inclusion of stake holders, will inform future pragmatic studies in older adults with depression. © 2019

Author Keywords
antidepressants;  augmentation;  Depression;  older adults;  pragmatic trial;  treatment-resistant depression

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

Strain-specific altered nicotine metabolism in 3,3′-diindolylmethane (DIM) exposed mice
(2019) Biopharmaceutics and Drug Disposition, . 

Bloom, A.J.^a , Upadhyaya, P.^b , Kharasch, E.D.^c

^a Department of Genetics, Washington University, St Louis, MO, United States
^b Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
^c Department of Anesthesiology, Duke University School of Medicine, Durham, NC, United States

Abstract
Two indole compounds, indole-3-carbinol (I3C) and its acid condensation product, 3,3′-diindolymethane (DIM), have been shown to suppress the expression of flavin-containing monooxygenases (FMO) and to induce some hepatic cytochrome P450s (CYPs) in rats. In liver microsomes prepared from rats fed I3C or DIM, FMO-mediated nicotine N-oxygenation was decreased, whereas CYP-mediated nicotine metabolism to nicotine iminium and subsequently to cotinine was unchanged. Therefore, it was hypothesized that in mice DIM would also suppress nicotine N-oxygenation without affecting CYP-mediated nicotine metabolism. Liver microsomes were produced from male and female C57BL/6 J and CD1 mice fed 2500 parts per million (ppm) DIM for 14 days. In liver microsomes from DIM-fed mice, FMO-mediated nicotine N-oxygenation did not differ from the controls, but CYP-mediated nicotine metabolism was significantly increased, with results varying by sex and strain. To confirm the effects of DIM in vivo, control and DIM-fed CD1 male mice were injected subcutaneously with nicotine, and the plasma concentrations of nicotine, cotinine and nicotine-N-oxide were measured over 30 minutes. The DIM-fed mice showed greater cotinine concentrations compared with the controls 10 minutes following injection. It is concluded that the effects of DIM on nicotine metabolism in vitro and in vivo differ between mice and rats and between mouse strains, and that DIM is an effective inducer of CYP-mediated nicotine metabolism in commonly studied mouse strains. © 2019 John Wiley & Sons, Ltd.

Author Keywords
DIM;  IC3;  metabolism;  mouse;  nicotine

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