WashU weekly Neuroscience publications

Basal ganglia shape features differentiate schizoaffective disorder from schizophrenia
(2021) Psychiatry Research – Neuroimaging, 317, art. no. 111352, . 

Cobia, D.^a e , Rich, C.^b , Smith, M.J.^c , Mamah, D.^d , Csernansky, J.G.^e , Wang, L.^e f g

^a Department of Psychology and Neuroscience Center, Brigham Young University, 1036 KMBL, Provo, UT 84602, United States
^b Department of Psychology, University of Notre Dame, Notre Dame, Indiana, United States
^c School of Social Work, University of Michigan, Ann Arbor, Michigan, United States
^d Department of Psychiatry, Washington University, St. Louis, Missouri, United States
^e Departments of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
^f Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
^g Department of Psychiatry and Behavioral Health, Ohio State University Wexner Medical Center, Columbus, OH, United States

Abstract
There is growing evidence that schizophrenia and schizoaffective disorder represent closely related syndromes that vary in severity along a neurobiological continuum. In the present study, volume and shape of the basal ganglia was examined in people with schizophrenia and schizoaffective disorder relative to healthy controls and hypothesized that unique neuroanatomical differences would be observed in each patient group. Magnetic resonance 1.5T images were obtained from schizophrenia (n = 47), schizoaffective disorder (n = 15), and from healthy control (n = 42) participants, matched for age, gender, parental socioeconomic status, and race. The caudate, putamen, and globus pallidus were characterized using high-dimensional brain mapping procedures (Csernansky et al., 2004b). Results revealed significant shape deformations between schizophrenia and schizoaffective disorder that also differed from control subjects. Relative to schizophrenia, schizoaffective subjects showed exaggerated inward deformations indicative of localized volume loss in subregions of the caudate, putamen, and globus pallidus (all p < 0.001). These shape features correlated with mental flexibility and negative symptoms in schizophrenia (all p < 0.05), but not schizoaffective disorder. To the extent that differences in important basal ganglia substructures reflect biological heterogeneity among these two psychotic illnesses, this data could prove useful in improving diagnostic precision, as well as informing the affective component of mental illness. © 2021

Author Keywords
Cognition;  Neuroimaging;  Psychosis;  Subcortical

Funding details
National Science FoundationNSFBCS 1734853, SP0037646
National Institutes of HealthNIHP50 MH071616, R01 EB020062, R01 MH056584, R01 MH084803, U01 MH097435
National Institute of Neurological Disorders and StrokeNINDST32 NS047987

What have we really learned from functional connectivity in clinical populations?
(2021) NeuroImage, 242, art. no. 118466, . 

Zhang, J.^a , Kucyi, A.^a , Raya, J.^a , Nielsen, A.N.^b , Nomi, J.S.^c , Damoiseaux, J.S.^d , Greene, D.J.^e , Horovitz, S.G.^f , Uddin, L.Q.^c , Whitfield-Gabrieli, S.^a

^a Department of Psychology, 125 Nightingale Hall, Northeastern University, 360 Huntington Ave, Boston, MA 02115, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO 63110, United States
^c Department of Psychology, University of Miami, Miami, FL 33124, United States
^d Institute of Gerontology and Department of Psychology, Wayne State University, Detroit, MI 48202, United States
^e Department of Cognitive Science, University of California San Diego, La Jolla, CA 92093, United States
^f Human Motor Control Section, NINDS, NIH, Bethesda, MD 20892, United States

Abstract
Functional connectivity (FC), or the statistical interdependence of blood-oxygen dependent level (BOLD) signals between brain regions using fMRI, has emerged as a widely used tool for probing functional abnormalities in clinical populations due to the promise of the approach across conceptual, technical, and practical levels. With an already vast and steadily accumulating neuroimaging literature on neurodevelopmental, psychiatric, and neurological diseases and disorders in which FC is a primary measure, we aim here to provide a high-level synthesis of major concepts that have arisen from FC findings in a manner that cuts across different clinical conditions and sheds light on overarching principles. We highlight that FC has allowed us to discover the ubiquity of intrinsic functional networks across virtually all brains and clarify typical patterns of neurodevelopment over the lifespan. This understanding of typical FC maturation with age has provided important benchmarks against which to evaluate divergent maturation in early life and degeneration in late life. This in turn has led to the important insight that many clinical conditions are associated with complex, distributed, network-level changes in the brain, as opposed to solely focal abnormalities. We further emphasize the important role that FC studies have played in supporting a dimensional approach to studying transdiagnostic clinical symptoms and in enhancing the multimodal characterization and prediction of the trajectory of symptom progression across conditions. We highlight the unprecedented opportunity offered by FC to probe functional abnormalities in clinical conditions where brain function could not be easily studied otherwise, such as in disorders of consciousness. Lastly, we suggest high priority areas for future research and acknowledge critical barriers associated with the use of FC methods, particularly those related to artifact removal, data denoising and feasibility in clinical contexts. © 2021

Author Keywords
Brain networks;  Connectomics;  Intrinsic functional connectivity;  Mental health;  Resting state fMRI

Funding details
National Institute of Mental HealthNIMHR01MH107549, R01MH111448-01, R01MH118217, R03MH121668, R61/R33MH113751-01A1
National Institute of Neurological Disorders and StrokeNINDS
Brain and Behavior Research FoundationBBRF
University of MiamiUM
Massachusetts Institute of TechnologyMIT
National Alliance for Research on Schizophrenia and DepressionNARSAD

Enhancing dopamine tone modulates global and local cortical perfusion as a function of COMT val158met genotype
(2021) NeuroImage, 242, art. no. 118472, . 

Furman, D.J.^a b , Pappas, I.^b c , White, R.L., III^d , Kayser, A.S.^a b c , D’Esposito, M.^b c

^a Department of Neurology, University of California, San Francisco, CA, United States
^b Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States
^c Division of Neurology, VA Northern California Health Care System, United States
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The cognitive effects of pharmacologically enhancing cortical dopamine (DA) tone are variable across healthy human adults. It has been postulated that individual differences in drug responses are linked to baseline cortical DA activity according to an inverted-U-shaped function. To better understand the effect of divergent starting points along this curve on DA drug responses, researchers have leveraged a common polymorphism (rs4680) in the gene encoding the enzyme catechol-O-methyltransferase (COMT) that gives rise to greater (Met allele) or lesser (Val allele) extracellular levels of cortical DA. Here we examined the extent to which changes in resting cortical perfusion following the administration of two mechanistically-distinct dopaminergic drugs vary by COMT genotype, and thereby track predictions of the inverted-U model. Using arterial spin labeling (ASL) and a double-blind, within-subject design, perfusion was measured in 75 healthy, genotyped participants once each after administration of tolcapone (a COMT inhibitor), bromocriptine (a DA D2/3 agonist), and placebo. COMT genotype and drug interacted such that COMT Val homozygotes exhibited increased prefusion in response to both drugs, whereas Met homozygotes did not. Additionally, tolcapone-related perfusion changes in the right inferior frontal gyrus correlated with altered performance on a task of executive function. No comparable effects were found for a genetic polymorphism (rs1800497) affecting striatal DA system function. Together, these results indicate that both the directionality and magnitude of drug-induced perfusion change provide meaningful information about individual differences in response to enhanced cortical DA tone. © 2021

Funding details
National Institutes of HealthNIHF32 DA038927, R01 DA034685

Substance use patterns in 9-10 year olds: Baseline findings from the adolescent brain cognitive development (ABCD) study
(2021) Drug and Alcohol Dependence, 227, art. no. 108946, . 

Lisdahl, K.M.^a aa , Tapert, S.^c , Sher, K.J.^ab , Gonzalez, R.ⁿ , Nixon, S.J.^m , Feldstein Ewing, S.W.^o , Conway, K.P.^l , Wallace, A.^a , Sullivan, R.^a , Hatcher, K.^a , Kaiver, C.^a , Thompson, W.^c , Reuter, C.^c , Bartsch, H.^c , Wade, N.E.^c , Jacobus, J.^c , Albaugh, M.D.^p , Allgaier, N.^p , Anokhin, A.P.^b , Bagot, K.^c ag , Baker, F.C.^e , Banich, M.T.^f , Barch, D.M.^b , Baskin-Sommers, A.^g , Breslin, F.J.^j , Brown, S.A.^c , Calhoun, V.^ad , Casey, B.J.^g , Chaarani, B.^p , Chang, L.^k , Clark, D.B.^d , Cloak, C.^k , Constable, R.T.^g , Cottler, L.B.^m , Dagher, R.K.^ah , Dapretto, M.ⁱ , Dick, A.ⁿ , Do, E.K.^h , Dosenbach, N.U.F.^b , Dowling, G.J.^l , Fair, D.A.^x , Florsheim, P.^a , Foxe, J.J.^q , Freedman, E.G.^q , Friedman, N.P.^f , Garavan, H.P.^p , Gee, D.G.^g , Glantz, M.D.^l , Glaser, P.^b , Gonzalez, M.R.^r , Gray, K.M.^s , Grant, S.^l , Haist, F.^c , Hawes, S.ⁿ , Heeringa, S.G.^t , Hermosillo, R.^o , Herting, M.M.^u , Hettema, J.M.^h , Hewitt, J.K.^f , Heyser, C.^c , Hoffman, E.A.^l , Howlett, K.D.^l , Huber, R.S.^v , Huestis, M.A.^c w , Hyde, L.W.^t , Iacono, W.G.^x , Isaiah, A.^k , Ivanova, M.Y.^p , James, R.S.^ae , Jernigan, T.L.^c , Karcher, N.R.^b , Kuperman, J.M.^c , Laird, A.R.ⁿ , Larson, C.L.^a , LeBlanc, K.H.^l , Lopez, M.F.^l , Luciana, M.^x , Luna, B.^d , Maes, H.H.^h , Marshall, A.T.^r , Mason, M.J.^y , McGlade, E.^v , Morris, A.S.^j z , Mulford, C.^l , Nagel, B.J.^o , Neigh, G.^h , Palmer, C.E.^c , Paulus, M.P.^j , Pecheva, D.^c , Prouty, D.^e , Potter, A.^p , Puttler, L.I.^t , Rajapakse, N.^ah , Ross, J.M.^af , Sanchez, M.ⁿ , Schirda, C.^d , Schulenberg, J.^t , Sheth, C.^v , Shilling, P.D.^c , Sowell, E.R.^r , Speer, N.^f , Squeglia, L.^s , Sripada, C.^t , Steinberg, J.^h , Sutherland, M.T.ⁿ , Tomko, R.^s , Uban, K.^ac , Vrieze, S.^x , Weiss, S.R.B.^l , Wing, D.^c , Yurgelun-Todd, D.A.^v , Zucker, R.A.^t , Heitzeg, M.M.^t , ABCD Consortium^ai

^a University of Wisconsin, Milwaukee, WI, United States
^b Washington University, St. Louis, MO, United States
^c University of California, San Diego, CA, United States
^d University of Pittsburgh, Pittsburgh, PA, United States
^e SRI International, Menlo Park, CA, United States
^f University of Colorado BoulderCO, United States
^g Yale University, New Haven, CT, United States
^h Virginia Commonwealth University, Richmond, VA, United States
ⁱ University of California, Los Angeles, CA, United States
^j Laureate Institute for Brain Research, Tulsa, OK, United States
^k University of Maryland School of Medicine, Baltimore, MD, United States
^l National Institute on Drug Abuse, NIH, Bethesda, MD, United States
^m University of Florida, Gainesville, FL, United States
ⁿ Florida International University, Miami, FL, United States
^o Oregon Health & Science University, Portland, OR, United States
^p University of Vermont, Burlington, VT, United States
^q University of Rochester, Rochester, NY, United States
^r Children’s Hospital Los Angeles, Los Angeles, CA, United States
^s Medical University of South Carolina, Charleston, SC, United States
^t University of Michigan, Ann Arbor, MI, United States
^u University of Southern California, Los Angeles, CA, United States
^v University of Utah, Salt Lake City, UT, United States
^w Thomas Jefferson University, Philadelphia, PA, United States
^x University of Minnesota, Minneapolis, MN, United States
^y University of Tennessee, Knoxville, TN, United States
^z Oklahoma State University, Stillwater, OK, United States
^aa Medical College of Wisconsin, Milwaukee, WI, United States
^ab University of Missouri, Columbia, MO, United States
^ac University of California, Irvine, CA, United States
^ad Georgia State University, Atlanta, GA, United States
^ae American Psychistric Association, United States
^af University of Colorado Anschutz Medical Campus, Aurora, CO, United States
^ag Icahn School of Medicine at Mount Sinai, United States
^ah National Institute of Minority Health and Health Disparities, Bethesda, MD, United States

Abstract
Background: The Adolescent Brain Cognitive Development ™ Study (ABCD Study®) is an open-science, multi-site, prospective, longitudinal study following over 11,800 9- and 10-year-old youth into early adulthood. The ABCD Study aims to prospectively examine the impact of substance use (SU) on neurocognitive and health outcomes. Although SU initiation typically occurs during teen years, relatively little is known about patterns of SU in children younger than 12. Methods: This study aims to report the detailed ABCD Study® SU patterns at baseline (n = 11,875) in order to inform the greater scientific community about cohort’s early SU. Along with a detailed description of SU, we ran mixed effects regression models to examine the association between early caffeine and alcohol sipping with demographic factors, externalizing symptoms and parental history of alcohol and substance use disorders (AUD/SUD). Primary Results: At baseline, the majority of youth had used caffeine (67.6 %) and 22.5 % reported sipping alcohol (22.5 %). There was little to no reported use of other drug categories (0.2 % full alcohol drink, 0.7 % used nicotine, <0.1 % used any other drug of abuse). Analyses revealed that total caffeine use and early alcohol sipping were associated with demographic variables (p’s<.05), externalizing symptoms (caffeine p = 0002; sipping p = .0003), and parental history of AUD (sipping p = .03). Conclusions: ABCD Study participants aged 9–10 years old reported caffeine use and alcohol sipping experimentation, but very rare other SU. Variables linked with early childhood alcohol sipping and caffeine use should be examined as contributing factors in future longitudinal analyses examining escalating trajectories of SU in the ABCD Study cohort. © 2021 Elsevier B.V.

Author Keywords
ABCD study;  Alcohol;  Alcohol sipping;  Caffeine;  Cannabis;  Children;  Externalizing behaviors;  Nicotine

Funding details
National Institutes of HealthNIHU01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA051016, U01DA051018, U01DA051037, U01DA051038, U01DA051039, U24DA041123, U24DA041147
National Institute of Mental HealthNIMH
GE Healthcare

Using error-estimation to probe the psychological processes underlying contextual interference effects
(2021) Human Movement Science, 79, art. no. 102854, . 

Thomas, J.L.^a , Fawver, B.^a b , Taylor, S.^a , Miller, M.W.^c , Williams, A.M.^a , Lohse, K.R.^d

^a Department of Health and Kinesiology, University of Utah, Salt Lake City, UT, United States
^b US Army Medical Research Directorate-West, Walter Reed Army Institute of Research, Joint Base Lewis McChordWA, United States
^c School of Kinesiology and Center for Neuroscience, Auburn University, Auburn, AL, United States
^d Program in Physical Therapy, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Although the learning benefits of interleaved practice schedules relative to blocked schedules are well-reported, the mechanisms underlying these effects are not fully understood. Researchers have generally suggested that random schedules of practice increase task-related information processing which arises due to switching between variations of the same task (or switching between different tasks). Thus, one potentially useful way to both probe and manipulate contextual interference is to pair it with error estimation during practice. Forced error estimation increases task-related information processing and recording these estimates provides insight into learners’ self-awareness of their errors. In the present study, 84 participants were randomly allocated to four groups. Participants practiced a timing task under blocked or random schedules, with and without error estimations prior to feedback. During the acquisition phase, three target times were trained (1500, 1700, 1900 ms), with feedback delivered after every trial. We used delayed post-tests (24 hrs later) to evaluate the retention of these target times and their transfer to two new target times (1600, 1800 ms). Participants who practiced with a random schedule performed worse (i.e., greater absolute error) than those with a blocked schedule during acquisition (p = .006); however, randomly scheduled participants also showed reduced error (p = .004) on the retention and transfer tests. Although prompting error estimations led to greater self-reported mental effort being invested on the task (p = .001), error estimation was not reliably associated with superior learning (p = .133). The accuracy of error estimations did not differ as a function of practice structure (p = .070), although the accuracy of error estimations improved during acquisition (p = .006). Findings highlight the robustness of the contextual interference effect, but we did not find evidence that error estimations moderated the effect on this task. It is in some ways surprising that we found an effect of contextual interference, as past-work suggests that interference effects are attenuated (or eliminated) when participants switch between different parameters of the same task. We speculate that this might be due to the difficulty of the task; even though participants switched between parametric variations of the same task, the distinction between parameters was subtle (i.e., tenths of a second). © 2021 Elsevier B.V.

Author Keywords
Contextual interference;  Practice scheduling;  Skill acquisition;  Timing

Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (33), art. no. e2102191118, . 

Wang, H.^a b c , Kulas, J.A.^d e , Wang, C.^f , Holtzman, D.M.^f , Ferris, H.A.^d e , Hansen, S.B.^a b

^a Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL 33458, United States
^b Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, United States
^c Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, FL 33458, United States
^d Division of Endocrinology and Metabolism, University of Virginia, Charlottesville, VA 22908, United States
^e Department of Neuroscience, University of Virginia, Charlottesville, VA 22908, United States
^f Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Alzheimer’s disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, tau tangles, inflammation, and loss of cognitive function. Genetic variation in a cholesterol transport protein, apolipoprotein E (apoE), is the most common genetic risk factor for sporadic AD. In vitro evidence suggests that apoE links to Aβ production through nanoscale lipid compartments (lipid clusters), but its regulation in vivo is unclear. Here, we use superresolution imaging in the mouse brain to show that apoE utilizes astrocyte-derived cholesterol to specifically traffic neuronal amyloid precursor protein (APP) in and out of lipid clusters, where it interacts with β- and γ-secretases to generate Aβpeptide. We find that the targeted deletion of astrocyte cholesterol synthesis robustly reduces amyloid and tau burden in a mouse model of AD. Treatment with cholesterol-free apoE or knockdown of cholesterol synthesis in astrocytes decreases cholesterol levels in cultured neurons and causes APP to traffic out of lipid clusters, where it interacts with α-secretase and gives rise to soluble APP-α (sAPP-α), a neuronal protective product of APP. Changes in cellular cholesterol have no effect on α-, β-, and γ-secretase trafficking, suggesting that the ratio of Aβ to sAPP-α is regulated by the trafficking of the substrate, not the enzymes. We conclude that cholesterol is kept low in neurons, which inhibits Aβ accumulation and enables the astrocyte regulation of Aβ accumulation by cholesterol signaling. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Alzheimer’s;  ApoE;  Cholesterol;  Lipids;  Neurodegeneration

Funding details
AG047644, NS090934, T32DK764627
National Institutes of HealthNIHDP2NS087943, K08, K08DK097293, R01NS112534
Columbia University
JPB Foundation

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome
(2021) JCI Insight, 6 (15), art. no. e145188, . 

Abreu, D.^a b , Stone, S.I.^c , Pearson, T.S.^d , Bucelli, R.C.^d , Simpson, A.N.^e , Hurst, S.^a , Brown, C.M.^a , Kries, K.^a , Onwumere, C.^a , Gu, H.^f , Hoekel, J.^g , Tychsen, L.^g , van Stavern, G.P.^g , White, N.H.^c , Marshall, B.A.^c , Hershey, T.^h , Urano, F.^a i

^a Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, 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
^c Division of Endocrinology and Diabetes, Department of Pediatrics, Washington University, School of Medicine, St. Louis, MO, United States
^d Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
^e Center for Clinical Studies, Washington University, School of Medicine, St. Louis, MO, United States
^f Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
^g Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States
^h Department of Psychiatry and Radiology, Washington University, School of Medicine, St. Louis, MO, United States
ⁱ Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND. Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS. Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS. Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. Copyright: © 2021, Abreu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Funding details
National Institutes of HealthNIH
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKDK020579, DK112921, DK113487
Eli Lilly and Company
National Center for Advancing Translational SciencesNCATSF30DK111070, TR000448, TR002065
Institute of Clinical and Translational SciencesICTSUL1TR002345
Vanderbilt University Medical CenterVUMC

First in-human report of the clinical accuracy of thoracolumbar percutaneous pedicle screw placement using augmented reality guidance
(2021) Neurosurgical Focus, 51 (2), pp. 1-8. 

Yahanda, A.T.^a , Moore, E.^b , Ray, W.Z.^a , Pennicooke, B.^a , Jennings, J.W.^c , Molina, C.A.^a

^a Departments of Neurosurgery and Radiology, Washington University School of Medicine in St. LouisMissouri, United States
^b Wayne State University School of Medicine, Detroit, Michigan, United States
^c Radiology, Washington University School of Medicine in St. LouisMissouri, United States

Abstract
OBJECTIVE Augmented reality (AR) is an emerging technology that has great potential for guiding the safe and accurate placement of spinal hardware, including percutaneous pedicle screws. The goal of this study was to assess the accuracy of 63 percutaneous pedicle screws placed at a single institution using an AR head-mounted display (ARHMD) system. METHODS Retrospective analyses were performed for 9 patients who underwent thoracic and/or lumbar percutaneous pedicle screw placement guided by ARHMD technology. Clinical accuracy was assessed via the Gertzbein-Robbins scale by the authors and by an independent musculoskeletal radiologist. Thoracic pedicle subanalysis was also performed to assess screw accuracy based on pedicle morphology. RESULTS Nine patients received thoracic or lumbar AR-guided percutaneous pedicle screws. The mean age at the time of surgery was 71.9 ± 11.5 years and the mean number of screws per patient was 7. Indications for surgery were spinal tumors (n = 4, 44.4%), degenerative disease (n = 3, 33.3%), spinal deformity (n = 1, 11.1%), and a combination of deformity and infection (n = 1, 11.1%). Presenting symptoms were most commonly low-back pain (n = 7, 77.8%) and lower-extremity weakness (n = 5, 55.6%), followed by radicular lower-extremity pain, loss of lower-extremity sensation, or incontinence/urinary retention (n = 3 each, 33.3%). In all, 63 screws were placed (32 thoracic, 31 lumbar). The accuracy for these screws was 100% overall; all screws were Gertzbein-Robbins grade A or B (96.8% grade A, 3.2% grade B). This accuracy was achieved in the thoracic spine regardless of pedicle cancellous bone morphology. CONCLUSIONS AR-guided surgery demonstrated a 100% accuracy rate for the insertion of 63 percutaneous pedicle screws in 9 patients (100% rate of Gertzbein-Robbins grade A or B screw placement). Using an ARHMS system for the placement of percutaneous pedicle screws showed promise, but further validation using a larger cohort of patients across multiple surgeons and institutions will help to determine the true accuracy enabled by this technology. © AANS 2021

Author Keywords
augmented reality;  computer-assisted spine surgery;  mixed reality;  percutaneous pedicle screw;  spine navigation

Neurologic and cognitive outcomes in sickle cell disease from infancy through adolescence
(2021) NeoReviews, 22 (8), pp. e531-e539. 

Mayer, S.L.^a , Fields, M.E.^b , Hulbert, M.L.^b

^a Children’s Hospital of Philadelphia, Philadelphia, PA, United States
^b Division of Pediatric Hematology/Oncology, Department of Pediatrics, Washington University in St Louis, St Louis, MO, United States

Abstract
Children with sickle cell disease (SCD) are at risk for neurologic and cognitive complications beginning in early childhood. Current treatment for SCD focuses on primary prevention of complications, such as hydroxyurea for prevention of pain and acute chest syndrome, and chronic transfusion therapy for children who are at high risk for strokes. In this article, the prevalence, pathophysiology, and available interventions to prevent and treat neurologic and cognitive complications of SCD will be reviewed. © 2021 by the American Academy of Pediatrics. All rights reserved.

Funding details
Pfizer

Extradural decompression versus duraplasty in Chiari malformation type I with syrinx: Outcomes on scoliosis from the Park-Reeves Syringomyelia Research Consortium
(2021) Journal of Neurosurgery: Pediatrics, 28 (2), pp. 167-175. 

Sadler, B.^a , Skidmore, A.^b , Gewirtz, J.^b , Anderson, R.C.E.^q , Haller, G.^b , Ackerman, L.L.^d , Adelson, P.D.^e , Ahmed, R.^f , Albert, G.W.^g , Aldana, P.R.^h , Alden, T.D.ⁱ , Averill, C.^b , Baird, L.C.^j , Bauer, D.F.^k , Bethel-Anderson, T.^b , Bierbrauer, K.S.^l , Bonfield, C.M.^aq , Brockmeyer, D.L.^m , Chern, J.J.ⁿ , Couture, D.E.^o , Daniels, D.J.^p , Dlouhy, B.J.^am , Durham, S.R.^r , Ellenbogen, R.G.^s , Eskandari, R.^t , Fuchs, H.E.^u , George, T.M.^v , Grant, G.A.^w , Graupman, P.C.^x , Greene, S.^y , Greenfield, J.P.^z , Gross, N.L.^aa , Guillaume, D.J.^ab , Hankinson, T.C.^ac , Heuer, G.G.^ad , Iantosca, M.^ae , Iskandar, B.J.^f , Jackson, E.M.^af , Jea, A.H.^d , Johnston, J.M.^ag , Keating, R.F.^ah , Khan, N.^aj , Krieger, M.D.^ak , Leonard, J.R.^al , Maher, C.O.^c , Mangano, F.T.^l , Mapstone, T.B.^aa , McComb, J.G.^ak , McEvoy, S.D.^b , Meehan, T.^b , Menezes, A.H.^am , Muhlbauer, M.^aj , Oakes, W.J.^ag , Olavarria, G.^an , O’Neill, B.R.^ac , Ragheb, J.^ao , Selden, N.R.^j , Shah, M.N.^ap , Shannon, C.N.^aq au , Smith, J.^d , Smyth, M.D.^b , Stone, S.S.D.^ar , Tuite, G.F.^as , Wait, S.D.^at , Wellons, J.C., III^aq au , Whitehead, W.E.^k , Park, T.S.^b , Limbrick, D.D., Jr.^a b , Strahle, J.M.^a b ai

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Neurological Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^c Department of Neurosurgery, University of Michigan, School of Medicine, Ann Arbor, MI, United States
^d Department of Neurological Surgery, Indiana University, School of Medicine, Indianapolis, IN, United States
^e Division of Pediatric Neurosurgery, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United States
^f Department of Neurological Surgery, University of Wisconsin, Madison, WI, United States
^g Division of Neurosurgery, Arkansas Children’s Hospital, Little Rock, AR, United States
^h Division of Pediatric Neurosurgery, University of Florida, College of Medicine, Jacksonville, FL, United States
ⁱ Division of Pediatric Neurosurgery, Ann and Robert H. Lurie Children’s Hospital of ChicagoIL, United States
^j Department of Neurological Surgery, Doernbecher Children’s Hospital, Oregon Health and Science University, Portland, OR, United States
^k Division of Pediatric Neurosurgery, Texas Children’s Hospital, Houston, TX, United States
^l Division of Pediatric Neurosurgery, Cincinnati Children’s Medical Center, Cincinnati, OH, United States
^m Division of Pediatric Neurosurgery, Primary Children’s Hospital, Salt Lake City, UT, United States
ⁿ Division of Pediatric Neurosurgery, Children’s Healthcare of AtlantaGA, United States
^o Department of Neurological Surgery, Wake Forest University, School of Medicine, Winston-Salem, NC, United States
^p Department of Neurosurgery, Mayo Clinic, Rochester, MN, United States
^q Department of Neurosurgery, Columbia University, New York, NY, United States
^r Department of Neurosurgery, University of Vermont, Burlington, VT, United States
^s Division of Pediatric Neurosurgery, Seattle Children’s Hospital, Seattle, WA, United States
^t Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States
^u Department of Neurosurgery, Duke University, Durham, NC, United States
^v Division of Pediatric Neurosurgery, Dell Children’s Medical Center, Austin, TX, United States
^w Division of Pediatric Neurosurgery, Lucile Packard Children’s Hospital, Stanford University, School of Medicine, Palo Alto, CA, United States
^x Division of Pediatric Neurosurgery, Gillette Children’s Hospital, St. Paul, MN, United States
^y Division of Pediatric Neurosurgery, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, United States
^z Department of Neurological Surgery, Weill Cornell Medical College, NewYork-Presbyterian Hospital, New York, NY, United States
^aa Department of Neurosurgery, University of Oklahoma, Oklahoma City, OK, United States
^ab Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, MN, United States
^ac Department of Neurosurgery, Children’s Hospital Colorado, Aurora, CO, United States
^ad Division of Pediatric Neurosurgery, Children’s Hospital of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^ae Department of Neurosurgery, Penn State Milton S. Hershey Medical Center, Hershey, PA, United States
^af Department of Neurosurgery, Johns Hopkins University, School of Medicine, Baltimore, MD, United States
^ag Division of Pediatric Neurosurgery, University of Alabama, Birmingham, AL, United States
^ah Department of Neurosurgery, Children’s National Medical Center, Washington, DC, United States
^ai Department of Orthopedic Surgery, Washington University, School of Medicine, St. Louis, MO, United States
^aj Department of Neurosurgery, Le Bonheur Children’s Hospital, Memphis, TN, United States
^ak Department of Neurosurgery, Children’s Hospital, Los Angeles, CA, United States
^al Division of Pediatric Neurosurgery, Nationwide Children’s Hospital, Columbus, OH, United States
^am Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, United States
^an Division of Pediatric Neurosurgery, Arnold Palmer Hospital for Children, Orlando, FL, United States
^ao Department of Neurological Surgery, University of Miami, School of Medicine, Miami, FL, United States
^ap Division of Pediatric Neurosurgery, McGovern Medical School, Houston, TX, United States
^aq Division of Pediatric Neurosurgery, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States
^ar Division of Pediatric Neurosurgery, Boston Children’s Hospital, Boston, MA, United States
^as Department of Neurosurgery, Neuroscience Institute, All Children’s Hospital, St. Petersburg, FL, United States
^at Carolina Neurosurgery and Spine Associates, Charlotte, NC, United States
^au Surgical Outcomes Center for Kids, Monroe Carell Jr. Children’s Hospital of Vanderbilt University, Nashville, TN, United States

Abstract
OBJECTIVE Scoliosis is common in patients with Chiari malformation type I (CM-I)-associated syringomyelia. While it is known that treatment with posterior fossa decompression (PFD) may reduce the progression of scoliosis, it is unknown if decompression with duraplasty is superior to extradural decompression. METHODS A large multicenter retrospective and prospective registry of 1257 pediatric patients with CM-I (tonsils ≥ 5 mm below the foramen magnum) and syrinx (≥ 3 mm in axial width) was reviewed for patients with scoliosis who underwent PFD with or without duraplasty. RESULTS In total, 422 patients who underwent PFD had a clinical diagnosis of scoliosis. Of these patients, 346 underwent duraplasty, 51 received extradural decompression alone, and 25 were excluded because no data were available on the type of PFD. The mean clinical follow-up was 2.6 years. Overall, there was no difference in subsequent occurrence of fusion or proportion of patients with curve progression between those with and those without a duraplasty. However, after controlling for age, sex, preoperative curve magnitude, syrinx length, syrinx width, and holocord syrinx, extradural decompression was associated with curve progression > 10°, but not increased occurrence of fusion. Older age at PFD and larger preoperative curve magnitude were independently associated with subsequent occurrence of fusion. Greater syrinx reduction after PFD of either type was associated with decreased occurrence of fusion. CONCLUSIONS In patients with CM-I, syrinx, and scoliosis undergoing PFD, there was no difference in subsequent occurrence of surgical correction of scoliosis between those receiving a duraplasty and those with an extradural decompression. However, after controlling for preoperative factors including age, syrinx characteristics, and curve magnitude, patients treated with duraplasty were less likely to have curve progression than patients treated with extradural decompression. Further study is needed to evaluate the role of duraplasty in curve stabilization after PFD. © AANS 2021, except where prohibited by US copyright law

Author Keywords
Chiari I malformation;  Posterior fossa decompression;  Scoliosis;  Spine;  Syringomyelia

Protein phosphatase 4 controls circadian clock dynamics by modulating CLOCK/BMAL1 activity
(2021) Genes and Development, 35 (15-16), pp. 1161-1174. Cited 1 time.

Klemz, S.^a , Wallach, T.^a , Korge, S.^a , Rosing, M.^b , Klemz, R.^a , Maier, B.^a , Fiorenza, N.C.^a , Kaymak, I.^a , Fritzsche, A.K.^a , Herzog, E.D.^c , Stanewsky, R.^b , Kramer, A.^a

^a Laboratory of Chronobiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, 10117, Germany
^b Institute of Neuro and Behavioral Biology, Westfälische Wilhelms University, Münster, 48149, Germany
^c Department of Biology, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
In all organisms with circadian clocks, post-translational modifications of clock proteins control the dynamics of circadian rhythms, with phosphorylation playing a dominant role. All major clock proteins are highly phosphorylated, and many kinases have been described to be responsible. In contrast, it is largely unclear whether and to what extent their counterparts, the phosphatases, play an equally crucial role. To investigate this, we performed a systematic RNAi screen in human cells and identified protein phosphatase 4 (PPP4) with its regulatory subunit PPP4R2 as critical components of the circadian system in both mammals and Drosophila. Genetic depletion of PPP4 shortens the circadian period, whereas overexpression lengthens it. PPP4 inhibits CLOCK/BMAL1 transactivation activity by binding to BMAL1 and counteracting its phosphorylation. This leads to increased CLOCK/BMAL1DNA occupancy and decreased transcriptional activity, which counteracts the “kamikaze” properties of CLOCK/BMAL1. Through this mechanism, PPP4 contributes to the critical delay of negative feedback by retarding PER/CRY/CK1δ- mediated inhibition of CLOCK/BMAL1. © 2021 Cold Spring Harbor Laboratory Press. All rights reserved.

Author Keywords
BMAL1;  Circadian clock;  Circadian rhythm;  CLOCK;  Phosphorylation;  Protein phosphatase 4

Funding details
Deutsche ForschungsgemeinschaftDFG278001972, SFB740, TRR186

OCD Influences Evidence Accumulation During Decision Making in Males but Not Females During Perceptual and Value-Driven Choice
(2021) Frontiers in Psychiatry, 12, art. no. 687680, . 

Ma, X.^a , Megli, A.^a d , Pittenger, C.^a b c , Pushkarskaya, H.^a

^a Department of Psychiatry, School of Medicine, Yale University, New Haven, CT, United States
^b Department of Neuroscience, School of Medicine, Yale University, New Haven, CT, United States
^c Yale Child Study Center, School of Medicine, Yale University, New Haven, CT, United States
^d Brown School, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Individuals with obsessive-compulsive disorder (OCD) often have difficulty making decisions. Valuation and value-based judgements are particularly difficult. The mechanisms underlying these impairments are still poorly understood. Previous work has suggested that individuals with OCD require more information prior to making a choice during perceptual discrimination tasks. Little previous work has examined value-guided choice in OCD. Here we examined perceptual and value-based decision making in adults with OCD, using a novel task in which the two types of decision are tested in parallel using the same individually calibrated sets of visual stimuli (Perceptual and Value-based decision-making task, PVDM). Twenty-seven unmedicated participants with OCD (16 female) and thirty-one healthy controls (15 female) were tested. Data were analyzed using hierarchical drift-diffusion modeling (HDDM). Decision formation was altered in OCD, but differentially between genders: males with OCD, but not females, accumulated more information (i.e., were more cautious) and were less effective in evidence accumulation than age- and IQ-matched healthy males. Furthermore, males with OCD, but not females, were less likely than controls to adjust the process of evidence accumulation across decision contexts. These unexpectedly gender-dimorphic effects suggest that more attention should be paid to gender differences in studies of OCD, and of pathophysiology more broadly. © Copyright © 2021 Ma, Megli, Pittenger and Pushkarskaya.

Author Keywords
drift diffusion model of choice;  evidence accumulation;  gender differences;  obsessive compulsive disorder;  perceptual decisions;  value-based decisions

Funding details
National Institute of Mental HealthNIMHR21 MH115394A1

A Sparsity-Driven Backpropagation-Less Learning Framework Using Populations of Spiking Growth Transform Neurons
(2021) Frontiers in Neuroscience, 15, art. no. 715451, . 

Gangopadhyay, A., Chakrabartty, S.

Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Growth-transform (GT) neurons and their population models allow for independent control over the spiking statistics and the transient population dynamics while optimizing a physically plausible distributed energy functional involving continuous-valued neural variables. In this paper we describe a backpropagation-less learning approach to train a network of spiking GT neurons by enforcing sparsity constraints on the overall network spiking activity. The key features of the model and the proposed learning framework are: (a) spike responses are generated as a result of constraint violation and hence can be viewed as Lagrangian parameters; (b) the optimal parameters for a given task can be learned using neurally relevant local learning rules and in an online manner; (c) the network optimizes itself to encode the solution with as few spikes as possible (sparsity); (d) the network optimizes itself to operate at a solution with the maximum dynamic range and away from saturation; and (e) the framework is flexible enough to incorporate additional structural and connectivity constraints on the network. As a result, the proposed formulation is attractive for designing neuromorphic tinyML systems that are constrained in energy, resources, and network structure. In this paper, we show how the approach could be used for unsupervised and supervised learning such that minimizing a training error is equivalent to minimizing the overall spiking activity across the network. We then build on this framework to implement three different multi-layer spiking network architectures with progressively increasing flexibility in training and consequently, sparsity. We demonstrate the applicability of the proposed algorithm for resource-efficient learning using a publicly available machine olfaction dataset with unique challenges like sensor drift and a wide range of stimulus concentrations. In all of these case studies we show that a GT network trained using the proposed learning approach is able to minimize the network-level spiking activity while producing classification accuracy that are comparable to standard approaches on the same dataset. © Copyright © 2021 Gangopadhyay and Chakrabartty.

Author Keywords
domain description;  energy-based learning;  neuromorphic machine learning;  sparsity;  spike rates;  spiking neural network;  supervised leaning;  unsupervised learning

Funding details
National Science FoundationNSF1935073

cAMP binding to closed pacemaker ion channels is non-cooperative
(2021) Nature, 595 (7868), pp. 606-610. 

White, D.S.^a b d , Chowdhury, S.^a e , Idikuda, V.^a f , Zhang, R.^a b , Retterer, S.T.^c , Goldsmith, R.H.^b , Chanda, B.^a f

^a Department of Neuroscience, University of Wisconsin-Madison, Madison, WI, United States
^b Department of Chemistry, University of Wisconsin-Madison, Madison, WI, United States
^c Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, TN, United States
^d Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States
^e Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA, United States
^f Center for Investigation of Membrane Excitability Diseases, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States

Abstract
Electrical activity in the brain and heart depends on rhythmic generation of action potentials by pacemaker ion channels (HCN) whose activity is regulated by cAMP binding1. Previous work has uncovered evidence for both positive and negative cooperativity in cAMP binding2,3, but such bulk measurements suffer from limited parameter resolution. Efforts to eliminate this ambiguity using single-molecule techniques have been hampered by the inability to directly monitor binding of individual ligand molecules to membrane receptors at physiological concentrations. Here we overcome these challenges using nanophotonic zero-mode waveguides4 to directly resolve binding dynamics of individual ligands to multimeric HCN1 and HCN2 ion channels. We show that cAMP binds independently to all four subunits when the pore is closed, despite a subsequent conformational isomerization to a flip state at each site. The different dynamics in binding and isomerization are likely to underlie physiologically distinct responses of each isoform to cAMP5 and provide direct validation of the ligand-induced flip-state model6–9. This approach for observing stepwise binding in multimeric proteins at physiologically relevant concentrations can directly probe binding allostery at single-molecule resolution in other intact membrane proteins and receptors. © 2021, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
National Science FoundationNSFCHE-1856518
National Institutes of HealthNIHGM007507, NS-081293, NS-101723, NS-116850

Principal Component Analysis of Striatal and Extrastriatal D2 Dopamine Receptor Positron Emission Tomography in Manganese-Exposed Workers
(2021) Toxicological Sciences: An Official Journal of the Society of Toxicology, 182 (1), pp. 132-141. 

Criswell, S.R.^a , Searles Nielsen, S.^a , Dlamini, W.W.^a , Warden, M.N.^a , Perlmutter, J.S.^{a b c d e} , Sheppard, L.^f g , Moerlein, S.M.^b h , Lenox-Krug, J.^a , Checkoway, H.^i j , Racette, B.A.^a k

^a Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Radiology, Washington University School of Medicine, St Louis, MO 63110, United States
^c Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110, United States
^d Program in Physical Therapy, Washington University School of Medicine, St Louis, MO 63110, United States
^e Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO 63110, United States
^f Department of Environmental and Occupational Health Sciences, University of Washington, School of Public Health, Seattle, WA 98195, United States
^g Department of Biostatistics, University of Washington, School of Public Health, Seattle, WA 98195, United States
^h Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, MO 63110, United States
ⁱ Department of Family Medicine and Public Health, University of California, School of Medicine, La Jolla, San Diego, CA 92093, United States
^j Department of Neurosciences, University of California, School of Medicine, La Jolla, San Diego, CA 92093, United States
^k School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, South Africa

Abstract
The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p < .05), positively in the substantia nigra, thalamus, amygdala, and medial orbital frontal gyrus and negatively in the nucleus accumbens, anterior putamen, and caudate. PC2 was associated with both Mn exposure status and exposure duration (years). In addition, PC2 was associated with higher Unified Parkinson’s Disease Rating Scale motor subsection 3 (UPDRS3) scores and slower GPT performance. We conclude Mn exposure is associated with both striatal and extrastriatal D2R binding. Multifocal alterations in D2R expression are also associated with motor dysfunction as measured by both the GPT and UPDRS3, demonstrating a link between Mn exposure, striatal and extrastriatal D2R expression, and clinical neurotoxicity. © The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
D2 receptors;  manganese;  PCA;  PET

Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy
(2021) Neurology, 97 (2), pp. e156-e165. 

Roda, R.H., Bargiela, D., Chen, W., Perry, K., Ellis, R.J., Clifford, D.B., Bharti, A., Kallianpur, A.R., Oliveira, M.F., Diaz, M.M., Rubin, L.H., Gavegnano, C., McArthur, J.C., Hoke, A., Polydefkis, M.

From the Department of Neurology (R.H.R., W.C., K.P., L.H.R., J.C.M., A.H., M.P.) and Department of Psychiatry (L.H.R.), Johns Hopkins University School of Medicine, Baltimore, MD; Department of Medicine (D.B.), Brigham and Women’s Hospital, Boston, MA; Departments of Neurosciences and Psychiatry (R.J.E., M.M.D.) and Department of Medicine (A.B., M.F.O.), University of California, San Diego; Department of Neurology (D.B.C.), Washington University School of Medicine, St. Louis, MO; Departments of Genomic Medicine, Medicine, and Pediatrics (A.R.K.), Cleveland Clinic/Lerner Research Institute and Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, OH; and Department of Pathology and Laboratory Medicine (C.G.), Joint Appointment in Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA

Abstract
OBJECTIVE: The primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures. METHODS: In this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures. RESULTS: Sixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32-65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3 (SD 97 cells/mm3, range 1-416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147-657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r = -0.344, p = 0.04) and sural nerve amplitude (r = -0.359, p = 0.004). CONCLUSIONS: Both IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy. © 2021 American Academy of Neurology.

Current state of scientific evidence on Internet-based interventions for the treatment of depression, anxiety, eating disorders and substance abuse: an overview of systematic reviews and meta-analyses
(2021) European Journal of Public Health, 31 (1), pp. i3-i10. Cited 1 time.

Taylor, C.B.^a b , Graham, A.K.^c , Flatt, R.E.^a b , Waldherr, K.^d , Fitzsimmons-Craft, E.E.^e

^a Center for m2Health, Palo Alto University, Palo Alto, CA, USA
^b Department of Psychiatry & Behavioral Sciences, Stanford University, Palo Alto, CA, USA
^c Department of Medical Social Sciences, Northwestern University, Chicago, United States
^d FernFH Distance Learning University of Applied Sciences, Wiener Neustadt, Austria
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

Abstract
BACKGROUND: ICare represents a consortium of European Investigators examining the effects of online mental health care for a variety of common mental health disorders provided in a variety of settings. This article provides an overview of the evidence of effectiveness for Internet-based treatment for four common mental health disorders that are the focus of much of this work: depression, anxiety, substance abuse and eating disorders. METHODS: The overview focused primarily on systematic reviews and meta-analyses identified through PubMed (Ovid) and other databases and published in English. Given the large number of reviews specific to depression, anxiety, substance abuse and/or eating disorders, we did not focus on reviews that examined the effects of Internet-based interventions on mental health disorders in general. Each article was reviewed and summarized by one of the senior authors, and this review was then reviewed by the other senior authors. We did not address issues of prevention, cost-effectiveness, implementation or dissemination, as these are addressed in other reviews in this supplement. RESULTS: Across Internet-based intervention studies addressing depression, anxiety, substance abuse and eating disorders primarily among adults, almost all reviews and meta-analyses found that these interventions successfully reduce symptoms and are efficacious treatments. Generally, effect sizes for Internet-based interventions treating eating disorders and substance abuse are lower compared with interventions for depression and anxiety. CONCLUSIONS: Given the effectiveness of Internet-based interventions to reduce symptoms of these common mental health disorders, efforts are needed to examine issues of how they can be best disseminated and implemented in a variety of health care and other settings. © The Author(s) 2020. Published by Oxford University Press on behalf of the European Public Health Association.

A Simpler and Sensitive Mass Spectrometry Method for Quantitation of Plasma Amyloid Peptides?
(2021) The Journal of Applied Laboratory Medicine, 6 (4), pp. 816-819. 

Powers Carson, J.

Department of Medicine; Division of Endocrinology, Metabolism, and Lipid Research, Core Laboratory for Clinical Studies, Washington University, St Louis, MO, USA

Temporal Correlation of CSF and Neuroimaging in the Amyloid-Tau-Neurodegeneration Model of Alzheimer Disease
(2021) Neurology, 97 (1), pp. e76-e87. 

Boerwinkle, A.H., Wisch, J.K., Chen, C.D., Gordon, B.A., Butt, O.H., Schindler, S.E., Sutphen, C., Flores, S., Dincer, A., Benzinger, T.L.S., Fagan, A.M., Morris, J.C., Ances, B.M.

From the Departments of Neurology (A.H.B., J.K.W., O.H.B., S.E.S., C.S., A.M.F., J.C.M., B.M.A.) and Radiology (C.D.C., B.A.G., S.F., A.D., T.L.S.B.), Washington University in St. Louis, MO

Abstract
OBJECTIVE: To evaluate temporal correlations between CSF and neuroimaging (PET and MRI) measures of amyloid, tau, and neurodegeneration in relation to Alzheimer disease (AD) progression. METHODS: A total of 371 cognitively unimpaired and impaired participants enrolled in longitudinal studies of AD had both CSF (β-amyloid [Aβ]42, phosphorylated tau181, total tau, and neurofilament light chain) and neuroimaging (Pittsburgh compound B [PiB] PET, flortaucipir PET, and structural MRI) measures. The pairwise time interval between CSF and neuroimaging measures was binned into 2-year periods. Spearman correlations identified the time bin when CSF and neuroimaging measures most strongly correlated. CSF and neuroimaging measures were then binarized as biomarker-positive or biomarker-negative using Gaussian mixture modeling. Cohen kappa coefficient identified the time bin when CSF measures best agreed with corresponding neuroimaging measures when determining amyloid, tau, and neurodegeneration biomarker positivity. RESULTS: CSF Aβ42 and PiB PET showed maximal correlation when collected within 6 years of each other (R ≈ -0.5). CSF phosphorylated tau181 and flortaucipir PET showed maximal correlation when CSF was collected 4 to 8 years prior to PET (R ≈ 0.4). CSF neurofilament light chain and cortical thickness showed low correlation, regardless of time interval (Ravg ≈ -0.3). Similarly, CSF total tau and cortical thickness had low correlation, regardless of time interval (Ravg < -0.2). CONCLUSIONS: CSF Aβ42 and PiB PET best agree when acquired in close temporal proximity, whereas CSF phosphorylated tau precedes flortaucipir PET by 4 to 8 years. CSF and neuroimaging measures of neurodegeneration have low correspondence and are not interchangeable at any time interval. © 2021 American Academy of Neurology.

Association Between Benzodiazepine or Z-Drug Prescriptions and Drug-Related Poisonings Among Patients Receiving Buprenorphine Maintenance: A Case-Crossover Analysis
(2021) The American Journal of Psychiatry, 178 (7), pp. 651-659. 

Xu, K.Y., Borodovsky, J.T., Presnall, N., Mintz, C.M., Hartz, S.M., Bierut, L.J., Grucza, R.A.

Department of Psychiatry, Health and Behavior Research Center, Washington University School of Medicine, St. Louis (Xu, Presnall, Mintz, Hartz, Bierut, Grucza); Department of Biomedical Data Science, Center for Technology and Behavioral Health, Geisel School of Medicine, Dartmouth, Hanover, N.H. (Borodovsky); Alvin J. Siteman Cancer Center, Barnes Jewish Hospital and Washington University School of Medicine, St. Louis (Bierut); and Departments of Family and Community Medicine and Health and Outcomes Research, St. Louis University, St. Louis (Grucza)

Abstract
OBJECTIVE: Persons with opioid use disorder who take benzodiazepines are at high risk for overdose. The objective of this study was to evaluate the association of benzodiazepine and Z-drug use with drug-related poisonings among patients receiving buprenorphine maintenance treatment. METHODS: A case-crossover study design was used to analyze prescription claims among persons ages 12-64 with opioid use disorder who had buprenorphine prescriptions and had claims data in the IBM MarketScan databases (2006-2016), encompassing 14,213,075 person-days of observation time for 23,036 individuals who experienced drug-related poisoning. The exposures were buprenorphine prescriptions and benzodiazepine or Z-drug prescriptions, standardized as daily diazepam-equivalent milligram doses and separated by pharmacologic properties (short-acting or long-acting benzodiazepines, Z-drugs). The outcome of interest was nonfatal drug-related poisoning. Conditional logistic regression was used to evaluate variation in benzodiazepine or Z-drug and buprenorphine use between poisoning and nonpoisoning days. RESULTS: Buprenorphine treatment days were associated with a nearly 40% reduction in the risk of poisoning events (odds ratio=0.63, 95% CI=0.60, 0.66) compared with nontreatment days, whereas benzodiazepine or Z-drug treatment days were associated with an 88% increase in the risk of such events (95% CI=1.78, 1.98). In stratified analyses by dose, we observed a 78% (95% CI=1.67, 1.88) and 122% (95% CI=2.03, 2.43) increase in poisonings associated with low-dose and high-dose benzodiazepine or Z-drug treatment days, respectively. High-dose, but not low-dose, benzodiazepine or Z-drug treatment was associated with increased poisonings in combination with buprenorphine cotreatment (odds ratio=1.64, 95% CI=1.39, 1.93), but this was lower than the odds risk associated with benzodiazepine or Z-drug treatment in the absence of buprenorphine (low-dose: odds ratio=1.69, 95% CI=1.60, 1.79; high-dose: odds ratio=2.23, 95% CI=2.04, 2.45). CONCLUSIONS: Increased risk of nonfatal drug-related poisoning is associated with benzodiazepine or Z-drug treatment in patients with opioid use disorder, but this risk is partially mitigated by buprenorphine treatment. Dose reduction of benzodiazepines or Z-drugs while maintaining buprenorphine treatment may provide the advantage of lowering drug-related poisoning risk.

Author Keywords
Addiction Psychiatry;  Drug Interactions;  Medication-Assisted Treatment;  Sedatives;  Substance-Related and Addictive Disorders

Heel Rise and Non-Weight-Bearing Ankle Plantar Flexion Tasks to Assess Foot and Ankle Function in People With Diabetes Mellitus and Peripheral Neuropathy
(2021) Physical Therapy, 101 (7), . 

Jeong, H.-J.^a , Mueller, M.J.^a , Zellers, J.A.^a , Yan, Y.^b , Hastings, M.K.^a

^a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
OBJECTIVE: The objective of this study was to examine the effects of diabetes mellitus and peripheral neuropathy (DMPN), limited joint mobility, and weight-bearing on foot and ankle sagittal movements and characterize the foot and ankle position during heel rise. METHODS: Sixty people with DMPN and 22 controls participated. Primary outcomes were foot (forefoot on hindfoot) and ankle (hindfoot on shank) plantar-flexion/dorsiflexion angle during 3 tasks: unilateral heel rise, bilateral heel rise, and non-weight-bearing ankle plantar flexion. A repeated-measures analysis of variance and Fisher exact test were used. RESULTS: Main effects of task and group were significant, but not the interaction in both foot and ankle plantar flexion. Foot and ankle plantar flexion were less in people with DMPN compared with controls in all tasks. Both DMPN and control groups had significantly less foot and ankle plantar flexion with greater weight-bearing; however, the linear trend across tasks was similar between groups. The DMPN group had a greater percentage of individuals in foot and/or ankle dorsiflexion at peak unilateral heel rise compared with controls, but the foot and ankle position was similar at peak bilateral heel rise between DMPN and control groups. CONCLUSION: Foot and ankle plantar flexion is less in people with DMPN. Less plantar flexion in non-weight-bearing suggests that people with DMPN have limited joint mobility. However, peak unilateral and bilateral heel rise is less than the available plantar flexion range of motion measured in non-weight-bearing, indicating that limited joint mobility does not limit heel rise performance. A higher frequency of people with DMPN are in foot and ankle dorsiflexion at peak unilateral heel rise compared with controls, but the position improved with lower weight-bearing. IMPACT: Proper resistance should be considered with physical therapist interventions utilizing heel rise because foot and ankle plantar flexion position could be improved by reducing the amount of weight-bearing. © The Author(s) 2021. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Author Keywords
Diabetes;  Foot-ankle Kinematics;  Midfoot;  Plantar Flexion