Arts & Sciences Brown School McKelvey School Medicine Weekly Publications

WashU weekly Neuroscience publications

“Dynamic contrast enhancement and flexible odor codes” (2018) Nature Communications

Dynamic contrast enhancement and flexible odor codes
(2018) Nature Communications, 9 (1), art. no. 3062, . 

Nizampatnam, S.a b , Saha, D.a , Chandak, R.a , Raman, B.a b

a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, United States
b Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, United States

Abstract
Sensory stimuli evoke spiking activities patterned across neurons and time that are hypothesized to encode information about their identity. Since the same stimulus can be encountered in a multitude of ways, how stable or flexible are these stimulus-evoked responses? Here we examine this issue in the locust olfactory system. In the antennal lobe, we find that both spatial and temporal features of odor-evoked responses vary in a stimulus-history dependent manner. The response variations are not random, but allow the antennal lobe circuit to enhance the uniqueness of the current stimulus. Nevertheless, information about the odorant identity is confounded due to this contrast enhancement computation. Notably, predictions from a linear logical classifier (OR-of-ANDs) that can decode information distributed in flexible subsets of neurons match results from behavioral experiments. In sum, our results suggest that a trade-off between stability and flexibility in sensory coding can be achieved using a simple computational logic. © 2018, The Author(s).

Document Type: Article
Source: Scopus
Access Type: Open Access

“Predictors of transitions across stages of heroin use and dependence prior to treatment-seeking among people in treatment for opioid dependence” (2018) Drug and Alcohol Dependence

Predictors of transitions across stages of heroin use and dependence prior to treatment-seeking among people in treatment for opioid dependence
(2018) Drug and Alcohol Dependence, 191, pp. 145-151. 

Larance, B.a , Gisev, N.a , Cama, E.a , Nelson, E.C.b , Darke, S.a , Larney, S.a , Degenhardt, L.a

a National Drug and Alcohol Research Centre, University of New South Wales, 22-32 King Street Randwick, Sydney, NSW, Australia
b Washington University, School of Medicine, Department of Psychiatry, 660 South Euclid Avenue, Campus Box 8134, St. Louis, MO, United States

Abstract
Background and aims: Little is known about transition pathways among heroin users prior to treatment. This study examined the demographic and clinical predictors of transition speed from heroin use, to dependence, to first treatment episode. Methods: 1149 heroin-dependent participants recruited from opioid agonist treatment clinics in Sydney, Australia, underwent a structured interview. Age of onset (AOO) was collected for heroin use, dependence and treatment-seeking, childhood maltreatment, psychiatric history and other substance dependence. Discrete-time survival analyses modelled years from onset of use to dependence, and from dependence to treatment-seeking, including demographic and clinical covariates. Findings: Median AOO for first heroin use, dependence and treatment-seeking was 18 years (inter-quartile range, or IQR = 6), 21 years (IQR = 7), and 24 years (IQR = 10) respectively. In adjusted models, younger birth cohorts (vs. born <1960), greater childhood maltreatment and later AAO of first heroin use were associated with more rapid transitions from heroin use to dependence. Living independently, parental violence, and alcohol dependence were associated with slower transitions. Earlier treatment-seeking was associated with younger birth cohorts, having dependent children and later AOO of dependence. Delayed treatment-seeking was associated with <10 years school education, living independently, depression and alcohol dependence. Conclusions: In this treatment sample, onset of heroin use occurred during late adolescence, suggesting the need for targeted interventions in mid-adolescence. Transitions to heroin dependence, then treatment-seeking, occurred during early adulthood. Rapid transitions from use to dependence were associated with younger birth cohorts, greater exposure to childhood maltreatment, and later onset of use. © 2018 Elsevier B.V.

Author Keywords
Heroin;  Opioid dependence;  Opioid use disorders;  Treatment-seeking

Document Type: Article
Source: Scopus

“Vagus Nerve Stimulation: Changing the Paradigm for Chronic Severe Depression?” (2018) Psychiatric Clinics of North America

Vagus Nerve Stimulation: Changing the Paradigm for Chronic Severe Depression?
(2018) Psychiatric Clinics of North America, 41 (3), pp. 409-418.

Aaronson, S.T.a b , Conway, C.R.c  

a Clinical Research Programs, Sheppard Pratt Health System, 6501 North Charles Street, Towson, MD, United States
b Department of Psychiatry, University of Maryland Medical School, 655 West Baltimore Street, Baltimore, MD, United States
c Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St Louis, MO, United States

Abstract
Vagus nerve stimulation (VNS) has been studied for its effect on treatment-resistant depression. Open-label studies have shown a significant positive effect in an especially treatment-resistant depressive population. Insurance company support for VNS has been limited but may be reviewed given recent positive open-label data. Coming developments in novel external ways to stimulate the vagus nerve may revive interest in this area. This article reviews the clinical development of VNS starting with the first recognition of its potential for treating depression, parses the results of several large clinical trials, and suggests a future path for optimal clinical development and use. © 2018 Elsevier Inc.

Author Keywords
Major depression;  Neurostimulation;  Treatment-resistant major depression;  Vagus nerve stimulation

Document Type: Review
Source: Scopus

“Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors” (2018) Journal of Experimental and Clinical Cancer Research

Reprogramming glioblastoma multiforme cells into neurons by protein kinase inhibitors
(2018) Journal of Experimental and Clinical Cancer Research, 37 (1), art. no. 181, . 

Yuan, J.a b c , Zhang, F.a , Hallahan, D.a , Zhang, Z.d , He, L.d , Wu, L.-G.d , You, M.a , Yang, Q.a

a Cancer Biology Division, Department of Radiation Oncology, Washington University, School of Medicine, 4511 Forest Park, St. Louis, MO, United States
b Medical Center of Stomatology, First Affiliated Hospital, Jinan University, Guangzhou, China
c School of Stomatology, Jinan University, Guangzhou, China
d Synaptic Transmission Section, National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States

Abstract
Background: Reprogramming of cancers into normal-like tissues is an innovative strategy for cancer treatment. Recent reports demonstrate that defined factors can reprogram cancer cells into pluripotent stem cells. Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor in humans. Despite multimodal therapy, the outcome for patients with GBM is still poor. Therefore, developing novel therapeutic strategy is a critical requirement. Methods: We have developed a novel reprogramming method that uses a conceptually unique strategy for GBM treatment. We screened a kinase inhibitor library to find which candidate inhibitors under reprogramming condition can reprogram GBM cells into neurons. The induced neurons are identified whether functional and loss of tumorigenicity. Results: We have found that mTOR and ROCK kinase inhibitors are sufficient to reprogram GBM cells into neural-like cells and “normal” neurons. The induced neurons expressed neuron-specific proteins, generated action potentials and neurotransmitter receptor-mediated currents. Genome-wide transcriptional analysis showed that the induced neurons had a profile different from GBM cells and were similar to that of control neurons induced by established methods. In vitro and in vivo tumorigenesis assays showed that induced neurons lost their proliferation ability and tumorigenicity. Moreover, reprogramming treatment with ROCK-mTOR inhibitors prevented GBM local recurrence in mice. Conclusion: This study indicates that ROCK and mTOR inhibitors-based reprogramming treatment prevents GBM local recurrence. Currently ROCK-mTOR inhibitors are used as anti-tumor drugs in patients, so this reprogramming strategy has significant potential to move rapidly toward clinical trials. © 2018 The Author(s).

Author Keywords
GBM;  mTOR;  Neuron;  Protein kinase inhibitors;  Reprogramming;  ROCK

Document Type: Article
Source: Scopus

“Characterization of Cellular Immune Responses in Thai Individuals with and Without HIV-Associated Neurocognitive Disorders” (2018) AIDS Research and Human Retroviruses

Characterization of Cellular Immune Responses in Thai Individuals with and Without HIV-Associated Neurocognitive Disorders
(2018) AIDS Research and Human Retroviruses, 34 (8), pp. 685-689. 

Ratto-Kim, S.a b , Schuetz, A.a b c , Sithinamsuwan, P.d , Barber, J.e , Hutchings, N.f , Lerdlum, S.g , Fletcher, J.L.K.h , Phuang-Ngern, Y.c , Chuenarom, W.c , Tipsuk, S.h , Pothisri, M.g , Jadwattanakul, T.i , Jirajariyavej, S.j , Sajjaweerawan, C.c , Akapirat, S.c , Chalermchai, T.h , Suttichom, D.h , Kaewboon, B.c , Prueksakaew, P.h , Karnsomlap, P.h , Clifford, D.k , Paul, R.H.k , De Souza, M.S.h , Kim, J.H.l , Ananworanich, J.a b h , Valcour, V.m

a U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, United States
b Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States
c Department of Retrovirology, Armed Forces Research Institute of Medical Sciences-United States Component, 315/6 Rajvithi Road, Bangkok, Thailand, Thailand
d Division of Neurology, Department of Medicine, Phramongkutklao Hospital, Bangkok, Thailand
e Clinical and Molecular Retrovirology Section/Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
f Columbia University College of Phys. and Surg., New York, NY, United States
g Department of Radiology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
h SEARCH, Thai Red Cross AIDS Research Center, Bangkok, Thailand
i Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
j HIV Clinic, Taksin Hospital, Bangkok, Thailand
k Department of Psychology, University of Missouri, St. LouisMO, United States
l International Vaccine Institute, Seoul, South Korea
m Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States

Abstract
HIV-Associated neurocognitive disorder (HAND) remains a challenge despite antiretroviral therapy (ART), and has been linked to monocyte/macrophage (M/M) migration to the brain. Due to the potential impact of T cell effector mechanisms in eliminating activated/HIV-infected M/M, T cell activation may play a role in the development of HAND. We sought to investigate the relationship between cognition and both CD8+ T cell activation (HLA-DR+/CD38+) and HIV-specific CD8+ T cell responses at the time of HIV diagnosis and 12 months postinitiation of ART. CD8+ T cell activation was increased in HAND compared to cognitive normal (NL) individuals and correlated directly with plasma viral load and inversely with the cognitive status. In addition, Gag-specific cytolytic activity (CD107a/b+) was decreased in HAND compared with NL individuals and correlated with their neurological testing, suggesting a potential role of cytotoxic CD8+ T cells in the mechanism of HAND development. © Copyright 2018, Mary Ann Liebert, Inc.

Author Keywords
CD8+ T cell activation;  HIV-Associated neurocognitive disorders;  HIV-specific cytolytic T cells

Document Type: Article
Source: Scopus

“Assessment of the prodromal questionnaire-brief child version for measurement of self-reported psychoticlike experiences in childhood” (2018) JAMA Psychiatry

Assessment of the prodromal questionnaire-brief child version for measurement of self-reported psychoticlike experiences in childhood
(2018) JAMA Psychiatry, 75 (8), pp. 853-861. 

Karcher, N.R.a , Barch, D.M.a , Avenevoli, S.b , Savill, M.c , Huber, R.S.d , Simon, T.J.e , Leckliter, I.N.e , Sher, K.J.f , Loewy, R.L.c

a Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
b National Institute of Mental Health, Bethesda, MD, United States
c Department of Psychiatry, University of California, San Francisco, United States
d Department of Psychiatry, University of Utah, Salt Lake City, United States
e Department of Psychiatry and Behavioral Sciences, University of California, Davis, Sacramento, United States
f Department of Psychology, University of Missouri, Columbia, United States

Abstract
IMPORTANCE Childhood psychoticlike experiences (PLEs) are associated with greater odds of a diagnosis of a psychotic disorder during adulthood. However, no known, well-validated self-report tools have been designed to measure childhood PLEs. OBJECTIVE To examine the construct validity and psychometric properties of a measure of PLEs, the Prodromal Questionnaire-Brief Child Version (PQ-BC). DESIGN, SETTING, AND PARTICIPANTS This validation study used data from the first wave of the Adolescent Brain and Cognitive Development (ABCD) Study, a prospective longitudinal study aimed at assessing risk factors associated with adverse physical and mental health outcomes from ages 9 to 10 years into late adolescence and early adulthood. The population-based sample of 3984 children within the ABCD data set was recruited from 20 research sites across the United States. Data for this study were collected from June 1, 2016, through August 31, 2017. MAIN OUTCOMES AND MEASURES The PQ-BC Total and Distress scores were analyzed for measurement invariance across race/ethnicity and sex, their associations with measures of PLEs, and their associations with known correlates of PLEs, including internalizing and externalizing symptoms, neuropsychological test performance, and developmental milestones. RESULTS The study analyses included 3984 participants (1885 girls [47.3%] and 2099 boys [52.7%]; mean [SE] age, 10.0 [0.01] years). The results demonstrated measurement invariance across race/ethnicity and sex. A family history of psychotic disorder was associated with higher mean (SE) PQ-BC Total (3.883 [0.352]; β = 0.061; 95% CI, 0.027-0.094) and Distress (10.210 [1.043]; β = 0.051; 95% CI, 0.018-0.084) scores, whereas a family history of depression or mania was not. Higher PQ-BC scores were associated with higher rates of child-rated internalizing symptoms (Total score: β range, 0.218 [95% CI, 0.189-0.246] to 0.273 [95% CI, 0.245-0.301]; Distress score: β range, 0.248 [95% CI, 0.220-0.277] to 0.310 [95% CI, 0.281-0.338]), neuropsychological test performance deficits such as working memory (Total score: β = −0.042 [95% CI, −0.077 to −0.008]; Distress score: β = −0.051 [95% CI, −0.086 to −0.017]), and motor and speech developmental milestone delays (Total score: β = 0.057 [95% CI, 0.026-0.086] for motor; β = 0.042 [95% CI, 0.010-0.073] for speech; Distress score: β = 0.048 [95% CI, 0.017-0.079] for motor; β = 0.049 [95% CI, 0.018-0.081] for speech). CONCLUSIONS AND RELEVANCE These results provide support for the construct validity and demonstrate adequate psychometric properties of a self-report instrument designed to measure childhood PLEs, providing evidence that the PQ-BC may be a useful measure of early risk for psychotic disorders. Furthermore, these data suggest that PLEs at school age are associated with many of the same familial, cognitive, and emotional factors associated with psychotic symptoms in older populations, consistent with the dimensionality of psychosis across the lifespan. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

“Relationship between patient safety indicator events and comprehensive stroke center volume status in the treatment of unruptured cerebral aneurysms” (2018) Journal of Neurosurgery

Relationship between patient safety indicator events and comprehensive stroke center volume status in the treatment of unruptured cerebral aneurysms
(2018) Journal of Neurosurgery, 129 (2), pp. 471-479. 

Washington, C.W.a , Taylor, L.I.a , Dambrino, R.J.a , Clark, P.R.a , Zipfel, G.J.b

a Department of Neurosurgery, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, United States
b Department of Neurosurgery, Washington University in St. LouisMO, United States

Abstract
OBJECTIVE The Agency of Healthcare Research and Quality (AHRQ) has defined Patient Safety Indicators (PSIs) for assessments in quality of inpatient care. The hypothesis of this study is that, in the treatment of unruptured cerebral aneurysms (UCAs), PSI events are less likely to occur in hospitals meeting the volume thresholds defined by The Joint Commission for Comprehensive Stroke Center (CSC) certification. METHODS Using the 2002–2011 National (Nationwide) Inpatient Sample, patients treated electively for a nonruptured cerebral aneurysm were selected. Patients were evaluated for PSI events (e.g., pressure ulcers, retained surgical item, perioperative hemorrhage, pulmonary embolism, sepsis) defined by AHRQ-specified ICD-9 codes. Hospitals were categorized by treatment volume into CSC or non-CSC volume status based on The Joint Commission’s annual volume thresholds of at least 20 patients with subarachnoid hemorrhage and performance of 15 or more endovascular coiling or surgical clipping procedures for aneurysms. RESULTS A total of 65,824 patients underwent treatment for an unruptured cerebral aneurysm. There were 4818 patients (7.3%) in whom at least 1 PSI event occurred. The overall inpatient mortality rate was 0.7%. In patients with a PSI event, this rate increased to 7% compared with 0.2% in patients without a PSI event (p < 0.0001). The overall rate of poor outcome was 3.8%. In patients with a PSI event, this rate increased to 23.3% compared with 2.3% in patients without a PSI event (p < 0.0001). There were significant differences in PSI event, poor outcome, and mortality rates between non-CSC and CSC volume-status hospitals (PSI event, 8.4% vs 7.2%; poor outcome, 5.1% vs 3.6%; and mortality, 1% vs 0.6%). In multivariate analysis, all patients treated at a non-CSC volume-status hospital were more likely to suffer a PSI event with an OR of 1.2 (1.1–1.3). In patients who underwent surgery, this relationship was more substantial, with an OR of 1.4 (1.2–1.6). The relationship was not significant in the endovascularly treated patients. CONCLUSIONS In the treatment of unruptured cerebral aneurysms, PSI events occur relatively frequently and are associated with significant increases in morbidity and mortality. In patients treated at institutions achieving the volume thresholds for CSC certification, the likelihood of having a PSI event, and therefore the likelihood of poor outcome and mortality, was significantly decreased. These improvements are being driven by the improved outcomes in surgical patients, whereas outcomes and mortality in patients treated endovascularly were not sensitive to the CSC volume status of the hospital and showed no significant relationship with treatment volumes. © AANS 2018.

Author Keywords
Aneurysm;  Comprehensive stroke center;  National (Nationwide) Inpatient Sample;  Patient safety;  Vascular disorders

Document Type: Article
Source: Scopus

“Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths a randomized clinical trial” (2018) JAMA Psychiatry

Metabolic effects of antipsychotics on adiposity and insulin sensitivity in youths a randomized clinical trial
(2018) JAMA Psychiatry, 75 (8), pp. 788-796. Cited 1 time.

Nicol, G.E.a , Yingling, M.D.a , Flavin, K.S.b , Schweiger, J.A.a , Patterson, B.W.c , Schechtman, K.B.c d , Newcomer, J.W.e

a Department of Psychiatry, Washington University, School of Medicine in St Louis, St Louis, MO, United States
b Department of Internal Medicine, Washington University, School of Medicine in St Louis, St Louis, MO, United States
c Department of Medicine, Washington University, School of Medicine in St Louis, St Louis, MO, United States
d Department of Biostatistics, Washington University, School of Medicine in St Louis, St Louis, MO, United States
e Department of Integrated Medical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, United States

Abstract
IMPORTANCE Antipsychotic medications are commonly used to treat nonpsychotic disruptive behavioral disorders in youths. OBJECTIVE To characterize the metabolic effects of first exposure to antipsychotics in youths using criterion standard assessments of body composition and insulin sensitivity. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial recruited antipsychotic-naive youths aged 6 to 18 years in the St Louis, Missouri, metropolitan area who were diagnosed with 1 or more psychiatric disorders and clinically significant aggression and in whom antipsychotic treatment was considered. Participants were enrolled from June 12, 2006, through November 10, 2010. Enrolled participants were randomized (1:1:1) to 1 of 3 antipsychotics commonly used in children with disruptive behavioral disorders and evaluated for 12 weeks. Data were analyzed from January 17, 2011, through August 9, 2017. INTERVENTIONS Twelve weeks of treatment with oral aripiprazole (n = 49), olanzapine (n = 46), or risperidone (n = 49). MAIN OUTCOMES AND MEASURES Primary outcomes included percentage total body fat measured by dual-energy x-ray absorptiometry (DXA) and insulin sensitivity in muscle measured via hyperinsulinemic clamps with stable isotopically labeled tracers. Secondary outcomes included abdominal adiposity measured by magnetic resonance imaging (MRI) and adipose and hepatic tissue insulin sensitivity measured via clamps with tracers. RESULTS The intention-to-treat sample included 144 participants (98 males [68.1%]; mean [SD] age, 11.3 [2.8] years); 74 (51.4%) were African American, and 43 (29.9%) were overweight or obese at baseline. For the primary outcomes, from baseline to week 12, DXA percentage total body fat increased by 1.18% for risperidone, 4.12% for olanzapine, and 1.66% for aripiprazole and was significantly greater for olanzapine than risperidone or aripiprazole (time by treatment interaction P < .001). From baseline to week 12, insulin-stimulated change in glucose rate of disappearance increased by 2.30% for risperidone and decreased by 29.34% for olanzapine and 30.26% for aripiprazole, with no significant difference across medications (time by treatment interaction, P < .07). This primary measure of insulin sensitivity decreased significantly during 12 weeks in the pooled study sample (effect of time, F = 17.38; P < .001). For the secondary outcomes from baseline to week 12, MRI measured abdominal fat increased, with subcutaneous fat increase significantly greater for olanzapine than risperdone or aripiprazole (time by treatment, P = .003). Behavioral improvements occurred with all treatments. CONCLUSIONS AND RELEVANCE Adverse changes in adiposity and insulin sensitivity were observed during 12 weeks of antipsychotic treatment in youths, with the greatest fat increases on olanzapine. Such changes, likely attributable to treatment, may be associated with risk for premature cardiometabolic morbidity and mortality. The results inform risk-benefit considerations for antipsychotic use in youths. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

“Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models” (2018) Journal of Clinical Investigation

Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models
(2018) Journal of Clinical Investigation, 128 (8), pp. 3558-3567. 

McCampbell, A.a , Cole, T.b , Wegener, A.J.c , Tomassy, G.S.a , Setnicka, A.c , Farley, B.J.a , Schoch, K.M.c , Hoye, M.L.c , Shabsovich, M.c , Sun, L.a , Luo, Y.a , Zhang, M.a , Thankamony, S.a , Salzman, D.W.a , Cudkowicz, M.d , Graham, D.L.a , Bennett, C.F.b , Kordasiewicz, H.B.b , Swayze, E.E.b , Miller, T.M.c

a Biogen, Inc., Cambridge, MA, United States
b Ionis Pharmaceuticals, Carlsbad, CA, United States
c Department of Neurology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, United States
d Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Mutations in superoxide dismutase 1 (SOD1) are responsible for 20% of familial ALS. Given the gain of toxic function in this dominantly inherited disease, lowering SOD1 mRNA and protein is predicted to provide therapeutic benefit. An early generation antisense oligonucleotide (ASO) targeting SOD1 was identified and tested in a phase I human clinical trial, based on modest protection in animal models of SOD1 ALS. Although the clinical trial provided encouraging safety data, the drug was not advanced because there was progress in designing other, more potent ASOs for CNS application. We have developed nextgeneration SOD1 ASOs that more potently reduce SOD1 mRNA and protein and extend survival by more than 50 days in SOD1G93A rats and by almost 40 days in SOD1G93A mice. We demonstrated that the initial loss of compound muscle action potential in SOD1G93A mice is reversed after a single dose of SOD1 ASO. Furthermore, increases in serum phospho-neurofilament heavy chain levels, a promising biomarker for ALS, are stopped by SOD1 ASO therapy. These results define a highly potent, new SOD1 ASO ready for human clinical trial and suggest that at least some components of muscle response can be reversed by therapy. © 2018 American Society for Clinical Investigation. All rights reserved.

Document Type: Article
Source: Scopus

“Low-Burden strategies to promote smoking cessation treatment among patients with serious mental illness” (2018) Psychiatric Services

Low-Burden strategies to promote smoking cessation treatment among patients with serious mental illness
(2018) Psychiatric Services, 69 (8), pp. 849-851. 

Chen, L.-S.a b , Baker, T.B.d , Korpecki, J.M.e , Johnson, K.E.e , Hook, J.P.e , Brownson, R.C.a c , Bierut, L.J.a b

a Siteman Cancer Center and Institute of Public Health Sciences, Washington University School of Medicine in St. Louis, St. Louis, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, United States
c School of Social Work, Washington University, St. Louis, United States
d Center for Tobacco Research and Intervention, Department of Medicine, School of Medicine and Public Health, University of Wisconsin–Madison, United States
e BJC Behavioral Health, BJC Healthcare, St. Louis, United States

Abstract
Patients with serious mental illness have high smoking prevalence and early mortality. Inadequate implementation of evidence-based smoking cessation treatment in community mental health centers (CMHCs) contributes to this disparity. This column describes a study of the effects of quality improvement strategies on treatment and cessation outcomes among patients with serious mental illness at four CMHCs. Two low-burden strategies, decision support and academic detailing with data-driven feedback, were implemented in the CMHCs’ clinics from 2014 to 2016. Pre- and postimplementation data from pharmacy and medical records were analyzed. The percentage of patients receiving cessation medication increased from 5% to 18% (p#.001), and smoking prevalence decreased from 57% to 54% (p#.001). This quality improvement approach holds great potential for increasing the level of smoking cessation care for patients treated in CMHC settings. Decision support and academic detailing with feedback may be effective strategies to promote best practices. © 2018 American Psychiatric Association. All rights reserved.

Document Type: Article
Source: Scopus

“CRX directs photoreceptor differentiation by accelerating chromatin remodeling at specific target sites” (2018) Epigenetics and Chromatin

CRX directs photoreceptor differentiation by accelerating chromatin remodeling at specific target sites
(2018) Epigenetics and Chromatin, 11 (1), art. no. 42, . 

Ruzycki, P.A.a c , Zhang, X.a , Chen, S.a b c

a Department of Ophthalmology and Visual Sciences, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University, School of Medicine, St. Louis, MO, United States
c Molecular Genetics and Genomics Graduate Program, Division of Biology and Biomedical Sciences, Washington University, School of Medicine, St. Louis, MO, United States

Abstract
Background: Recent technological advances have delivered the genome-wide targets of many important transcription factors (TFs). However, increasing evidence suggests that not all target sites mediate regulatory function, raising the questions of how to determine which sites are active, what are the epigenetic consequences of TF binding at these sites, and how the specificity is coded. To address these questions, we focused on CRX, a disease-associated homeodomain TF required for photoreceptor gene expression and development. Since CRX binds more than 6000 sites across the genome in the retina, we profiled chromatin landscape changes at each binding site during normal development and in the absence of CRX and interpreted the results by thorough investigation of other epigenomic datasets and sequence features. Results: CRX is required for chromatin remodeling at only a subset of its binding sites, which undergo retina or neuronal specific activation during photoreceptor differentiation. Genes near these “CRX Dependent” sites code for proteins important for photoreceptor physiology and function, and their transcription is significantly reduced in Crx deficient retinas. In addition, the nucleotide and motif content distinguish these CRX Dependent sites from other CRX-bound sites. Conclusions: Together, our results suggest that CRX acts only at select, uniquely-coded binding sites to accelerate chromatin remodeling during photoreceptor differentiation. This study emphasizes the importance of connecting TF binding with its functional consequences and provides a framework for making such a connection using comparative analyses of available genomic datasets. Finally, this study prioritizes sets of non-coding DNA sites for future functional interrogation and identification of mutations associated with retinal disease. © 2018 The Author(s).

Author Keywords
Crx deficiency;  Epigenetic regulation;  Photoreceptor development;  Retinal gene expression

Document Type: Article
Source: Scopus

“Special Therapy and Psychosocial Needs Identified in a Multidisciplinary Cancer Predisposition Syndrome Clinic” (2018) Journal of Pediatric Hematology/Oncology

Special Therapy and Psychosocial Needs Identified in a Multidisciplinary Cancer Predisposition Syndrome Clinic
(2018) Journal of Pediatric Hematology/Oncology, . Article in Press. 

Groves, A.P.a , Gettinger, K.b , Druley, T.E.b , A. Kozel, B.d , Shinawi, M.d , Mohrmann, C.b , Henry, J.b , Jacobi, C.b , Trinkaus, K.c , Hayashi, R.J.b

a Division of General Pediatrics, Boston Children’s Hospital, Boston, MA
b Departments of Pediatrics, Division of Pediatric Hematology and Oncology
c Biostatistics
d Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO

Abstract
Identification of patients with cancer predisposition syndromes (CPSs) can provide vital information to guide care of an existing cancer, survey for future malignancy, and counsel families. The same underlying mutation responsible for a CPS may also result in other phenotypic abnormalities amenable to therapeutic intervention. The purpose of this study was to examine patients followed in our multidisciplinary CPS clinic to determine the prevalence and scope of medical and psychosocial needs. Data from a baseline evaluation of a single-center patient registry was reviewed. Eligible patients included those with a known or suspected CPS. Over 3 years, 73 patients consented and had successful follow-up. Utilization rate of special therapies, defined as speech therapy, occupational therapy, and/or physical therapy, in the CPS population was 50.7%, significantly higher than a representative sample of children with special needs. Prevalence of 504/IEP (Individualized Education Program) utilization was 20.5%. Patients with CPSs have a high prevalence of medical and psychosocial needs beyond their risk for cancer, for which early screening for necessary interventions should be offered to maximize the patient’s developmental potential. Future research is needed to further define the developmental and cognitive phenotypes of these syndromes, and to evaluate the effectiveness of subsequent interventions. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Author Keywords
cancer predisposition syndromes;  oncology;  support care

Document Type: Article in Press
Source: Scopus

“Dysregulation of NAD+ metabolism induces a Schwann cell dedifferentiation program” (2018) Journal of Neuroscience

Dysregulation of NAD+ metabolism induces a Schwann cell dedifferentiation program
(2018) Journal of Neuroscience, 38 (29), pp. 6546-6562. 

Sasaki, Y., Hackett, A.R., Kim, S., Strickland, A., Milbrandt, J.

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

Abstract
The Schwann cell (SC) is the major component of the peripheral nervous system (PNS) that provides metabolic and functional support for peripheral axons. The emerging roles of SC mitochondrial function for PNS development and axonal stability indicate the importance of SC metabolism in nerve function and in peripheral neuropathies associated with metabolic disorders. Nicotinamide adenine dinucleotide (NAD+) is a crucial molecule in the regulation of cellular metabolism and redox homeostasis. Here, we investigated the roles of NAD+ metabolism in SC functions in vivo by mutating NAMPT, the rate-limiting enzyme of NAD+ biosynthesis, specifically in SCs. NAMPT SC knock-out male and female mice (NAMPT SCKO mice) had delayed SC maturation in development and developed hypomyelinating peripheral neuropathy without axon degeneration or decreased SC survival. JUN, a master regulator of SC dedifferentiation, is elevated in NAMPT SCKO SCs, suggesting that decreased NAD+ levels cause them to arrest at an immature stage. Nicotinic acid administration rescues the NAD+ decline and reverses the SC maturation defect and the development of peripheral neuropathy, indicating the central role of NAD+ in PNS development. Upon nicotinic acid withdrawal in adulthood, NAMPT SCKO mice showed rapid and severe peripheral neuropathy and activation of ERK/MEK/JUN signaling, which in turn promotes SC dedifferentiation. These data demonstrate the importance of NAD+ metabolism in SC maturation and nerve development and maintenance and suggest that altered SC NAD+ metabolism could underlie neuropathies associated with diabetes and aging. © 2018 the authors.

Author Keywords
Metabolism;  Myelin;  NAD+;  NAMPT;  Peripheral neuropathy;  Schwann cell

Document Type: Article
Source: Scopus

“Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum” (2018) JAMA Neurology

Selective genetic overlap between amyotrophic lateral sclerosis and diseases of the frontotemporal dementia spectrum
(2018) JAMA Neurology, 75 (7), pp. 860-875. 

Karch, C.M.a u , Wen, N.a u , Fan, C.C.b u u , Yokoyama, J.S.c , Kouri, N.d , Ross, O.A.d , Höglinger, G.e f , Müller, U.g , Ferrari, R.h , Hardy, J.h , Schellenberg, G.D.i k , Sleiman, P.M.j k l , Momeni, P.m , Hess, C.P.n , Miller, B.L.c , Sharma, M.o p , Van Deerlin, V.i , Smeland, O.B.q r , Andreassen, O.A.q r s , Dale, A.M.b t , Desikan, R.S.n

a Department of Psychiatry, Washington University in St Louis, 425 S Euclid Ave, Campus Box 8134, St Louis, MO, United States
b Department of Cognitive Sciences, University of California, San Diego, San Diego, United States
c Memory and Aging Center, Department of Neurology, University of California, San Francisco, United States
d Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL, United States
e Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases, Munich, Germany
f Department of Neurology, Technical University of Munich, Munich Cluster for Systems Neurology SyNergy, Munich, Germany
g Institut for Humangenetik, Justus-Liebig-Universität, Giessen, Germany
h Department of Molecular Neuroscience, Institute of Neurology, University College London, London, United Kingdom
i Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
j Center for Applied Genomics, Abramson Research Center, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
k Division of Human Genetics, Abramson Research Center, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
l Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
m Laboratory of Neurogenetics, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, United States
n Neuroradiology Section, Department of Radiology and Biomedical Imaging, University of California, San Francisco, United States
o Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
p Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany
q Norwegian Centre for Mental Disorders Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
r Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway
s Department of Neurosciences, University of California, San Diego, San Diego, United States
t Department of Neurosciences and Radiology, University of California, San Diego, San Diego, United States

Abstract
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. OBJECTIVES: To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. DESIGN, SETTING, AND PARTICIPANTS: In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. MAIN OUTCOMES AND MEASURES: The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. RESULTS: Among 124 876 cases and controls, genome-wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; β = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005). CONCLUSIONS AND RELEVANCE: This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder. © 2018 American Medical Association. All rights reserved.

Document Type: Article
Source: Scopus

“Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness” (2018) American Journal of Physiology – Heart and Circulatory Physiology

Minoxidil improves vascular compliance, restores cerebral blood flow, and alters extracellular matrix gene expression in a model of chronic vascular stiffness
(2018) American Journal of Physiology – Heart and Circulatory Physiology, 315 (1), pp. H18-H32. Cited 1 time.

Knutsen, R.H.a b , Beeman, S.C.c , Broekelmann, T.J.b , Liu, D.a , Tsang, K.M.a , Kovacs, A.d , Ye, L.e , Danback, J.R.e , Watson, A.a , Wardlaw, A.a , Wagenseil, J.E.f g , Garbow, J.R.c , Shoykhet, M.e f g , Kozel, B.A.a e

a National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
b Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
f Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
g Department of Pediatrics, Children’s National Medical Center, Washington, D.C., United States

Abstract
Increased vascular stiffness correlates with a higher risk of cardiovascular complications in aging adults. Elastin (ELN) insufficiency, as observed in patients with Williams-Beuren syndrome or with familial supravalvular aortic stenosis, also increases vascular stiffness and leads to arterial narrowing. We used Eln-/- mice to test the hypothesis that pathologically increased vascular stiffness with concomitant arterial narrowing leads to decreased blood flow to end organs such as the brain. We also hypothesized that drugs that remodel arteries and increase lumen diameter would improve flow. To test these hypotheses, we compared carotid blood flow using ultrasound and cerebral blood flow using MRI-based arterial spin labeling in wild-type (WT) and Eln-/- mice. We then studied how minoxidil, an ATP-sensitive K+ channel opener and vasodilator, affects vessel mechanics, blood flow, and gene expression. Both carotid and cerebral blood flows were lower in Eln-/- mice than in WT mice. Treatment of Eln-/- mice with minoxidil lowered blood pressure and reduced functional arterial stiffness to WT levels. Minoxidil also improved arterial diameter and restored carotid and cerebral blood flows in Eln-/- mice. The beneficial effects persisted for weeks after drug removal. RNA-Seq analysis revealed differential expression of 127 extracellular matrixrelated genes among the treatment groups. These results indicate that ELN insufficiency impairs end-organ perfusion, which may contribute to the increased cardiovascular risk. Minoxidil, despite lowering blood pressure, improves end-organ perfusion. Changes in matrix gene expression and persistence of treatment effects after drug withdrawal suggest arterial remodeling. Such remodeling may benefit patients with genetic or age-dependent ELN insufficiency. NEW &amp; NOTEWORTHY Our work with a model of chronic vascular stiffness, the elastin (Eln)-/- mouse, shows reduced brain perfusion as measured by carotid ultrasound and MRI arterial spin labeling. Vessel caliber, functional stiffness, and blood flow improved with minoxidil. The ATP-sensitive K+ channel opener increased Eln gene expression and altered 126 other matrix-associated genes. © 2018 American Physiological Society. All rights reserved.

Author Keywords
Arterial stiffness;  ATP-sensitive K+channel;  Cerebral blood flow;  Elastin;  Extracellular matrix;  Vascular remodeling

Document Type: Article
Source: Scopus

“Mapping movement, mood, motivation and mentation in the subthalamic nucleus” (2018) Royal Society Open Science

Mapping movement, mood, motivation and mentation in the subthalamic nucleus
(2018) Royal Society Open Science, 5 (7), art. no. 171177, . 

Gourisankar, A.a , Eisenstein, S.A.b c , Trapp, N.T.b h , Koller, J.M.b , Campbell, M.C.c d , Ushe, M.d , Perlmutter, J.S.c d e f g , Hershey, T.b c d , Black, K.J.b c d e i

a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Radiology, 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 Department of Neuroscience, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
g Department of Physical Therapy, Washington University, School of Medicine, St. Louis, MO, United States
h University of Iowa, Iowa City, IA, United States
i Department of Psychiatry, Campus Box 8134, 660 S. Euclid Ave, St Louis, MO, United States

Abstract
The anatomical connections of the subthalamic nucleus (STN)have driven hypotheses about its functional anatomy, including the hypothesis that the precise anatomical location of STN deep brain stimulation (DBS)contributes to the variability of motor and non-motor responses across patients with Parkinson’s disease (PD). We previously tested the hypothesis using a three-dimensional (3D)statistical method to interpret the acute effects of unilateral DBS at each patient’s clinically optimized DBS settings and active contact. Here, we report a similar analysis from a new study in which DBS parameters were standardized and DBS locations were chosen blind to clinical response. In 74 individuals with PD and STN DBS, STN contacts were selected near the dorsal and ventral borders of the STN contralateral to the more affected side of the body. Participants were tested off PD medications in each of three unilateral DBS conditions (ventral STN DBS, dorsal STN DBS and DBS off)for acute effects on mood, apathy, working memory, response inhibition and motor function. Voltage, frequency and pulse width were standardized, and participants and raters were blind to condition. In a categorical analysis, both dorsal and ventral STN DBS improved mean motor function without affecting cognitive measures. Ventral STN DBS induced greater improvement in rigidity and anxiety than dorsal STN DBS. In the 3D analysis, contact location was significant for body hypokinesia, rigidity and resting tremor, with the greatest improvement occurring with DBS in dorsal STN and zona incerta. The 3D results provide new, direct functional evidence for the anatomically derived model of STN, in which motor function is best represented in dorsal STN. However, our data suggest that functional segregation between motor and non-motor areas of the STN is limited, because locations that induced improvements in motor function and mood overlapped substantially. © 2018 The Authors.

Author Keywords
Deep brain stimulation;  Emotions;  Inhibition (psychology);  Parkinson’s disease;  Short-term memory;  Subthalamic nucleus

Document Type: Article
Source: Scopus

“Differential effects of adaptation on odor discrimination” (2018) Journal of Neurophysiology

Differential effects of adaptation on odor discrimination
(2018) Journal of Neurophysiology, 120 (1), pp. 171-185. 

Haney, S.a , Saha, D.b , Raman, B.b , Bazhenov, M.a

a Department of Medicine, University of California, San Diego, La Jolla, CA, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Adaptation of neural responses is ubiquitous in sensory systems and can potentially facilitate many important computational functions. Here we examined this issue with a well-constrained computational model of the early olfactory circuits. In the insect olfactory system, the responses of olfactory receptor neurons (ORNs) on the antennae adapt over time. We found that strong adaptation of sensory input is important for rapidly detecting a fresher stimulus encountered in the presence of other background cues and for faithfully representing its identity. However, when the overlapping odorants were chemically similar, we found that adaptation could alter the representation of these odorants to emphasize only distinguishing features. This work demonstrates novel roles for peripheral neurons during olfactory processing in complex environments. NEW & NOTEWORTHY Olfactory systems face the problem of distinguishing salient information from a complex olfactory environment. The neural representations of specific odor sources should be consistent regardless of the background. How are olfactory representations robust to varying environmental interference? We show that in locusts the extraction of salient information begins in the periphery. Olfactory receptor neurons adapt in response to odorants. Adaptation can provide a computational mechanism allowing novel odorant components to be highlighted during complex stimuli. © 2018 the American Physiological Society.

Author Keywords
Adaptation;  Olfaction;  Receptor neurons;  Temporal code

Document Type: Article
Source: Scopus

“Identifying Disruptions in Intrinsic Brain Dynamics due to Severe Brain Injury” (2018) Conference Record of 51st Asilomar Conference on Signals, Systems and Computers, ACSSC 2017

Identifying Disruptions in Intrinsic Brain Dynamics due to Severe Brain Injury
(2018) Conference Record of 51st Asilomar Conference on Signals, Systems and Computers, ACSSC 2017, 2017-October, art. no. 8335197, pp. 344-348. 

Khanmohammadi, S.a b , Kummer, T.T.b , Ching, S.a c d

a Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
d Division of Biology and Biomedical Science, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Recent studies suggest that disruptions in resting state functional connectivity – a measure of stationary statistical association between brain regions – can be used as an objective marker of brain injury. However, fewer characterizations have examined the disruption of intrinsic brain dynamics after brain injury. Here, we examine this issue using electroencephalo-graphic (EEG) data from brain-injured patients, together with a control analysis wherein we quantify the effect of the injury on the ability of intrinsic event responses to traverse their respective state spaces. More specifically, the lability of intrinsically evoked brain activity was assessed by collapsing three sigma event responses in all channels of the obtained EEG signals into a low-dimensional space. The directional derivative of these responses was then used to assay the extent to which brain activity reaches low-variance subspaces. Our findings suggest that intrinsic dynamics extracted from resting state EEG signals can differentiate various levels of consciousness in severe cases of coma. More specifically the cost of moving from one state to another in the state-space trajectories of the underlying dynamics becomes lower as the level of consciousness of patients deteriorates. © 2017 IEEE.

Document Type: Conference Paper
Source: Scopus

“Neonatal brain injury and aberrant connectivity” (2018) NeuroImage

Neonatal brain injury and aberrant connectivity
(2018) NeuroImage, . Article in Press. 

Smyser, C.D.a , Wheelock, M.D.b , Limbrick, D.D., Jr.c , Neil, J.J.d

a Departments of Neurology, Pediatrics and Radiology, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8111, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8134, St. Louis, MO, United States
c Departments of Neurosurgery and Pediatrics, Washington University School of Medicine, One Children’s Place, Suite S20, St. Louis, MO, United States
d Department of Pediatric Neurology, Boston Children’s Hospital, 300 Longwood Avenue, BCH3443, Boston, MA, United States

Abstract
Brain injury sustained during the neonatal period may disrupt development of critical structural and functional connectivity networks leading to subsequent neurodevelopmental impairment in affected children. These networks can be characterized using structural (via diffusion MRI) and functional (via resting state-functional MRI) neuroimaging techniques. Advances in neuroimaging have led to expanded application of these approaches to study term- and prematurely-born infants, providing improved understanding of cerebral development and the deleterious effects of early brain injury. Across both modalities, neuroimaging data are conducive to analyses ranging from characterization of individual white matter tracts and/or resting state networks through advanced ‘connectome-style’ approaches capable of identifying highly connected network hubs and investigating metrics of network topology such as modularity and small-worldness. We begin this review by summarizing the literature detailing structural and functional connectivity findings in healthy term and preterm infants without brain injury during the postnatal period, including discussion of early connectome development. We then detail common forms of brain injury in term- and prematurely-born infants. In this context, we next review the emerging body of literature detailing studies employing diffusion MRI, resting state-functional MRI and other complementary neuroimaging modalities to characterize structural and functional connectivity development in infants with brain injury. We conclude by reviewing technical challenges associated with neonatal neuroimaging, highlighting those most relevant to studying infants with brain injury and emphasizing the need for further targeted study in this high-risk population. © 2018 Elsevier Inc.

Author Keywords
Brain injury;  Functional connectivity;  Infant;  Magnetic resonance imaging;  Prematurity;  Structural connectivity

Document Type: Article in Press
Source: Scopus

“Three Distinct Sets of Connector Hubs Integrate Human Brain Function” (2018) Cell Reports

Three Distinct Sets of Connector Hubs Integrate Human Brain Function
(2018) Cell Reports, 24 (7), pp. 1687-1695.e4. 

Gordon, E.M.a b c , Lynch, C.J.d n , Gratton, C.e , Laumann, T.O.e , Gilmore, A.W.f m , Greene, D.J.g l , Ortega, M.e , Nguyen, A.L.e , Schlaggar, B.L.e g h k l , Petersen, S.E.e f g h i , Dosenbach, N.U.F.e j k , Nelson, S.M.a b c

a VISN 17 Center of Excellence for Research on Returning War Veterans, Waco, TX, United States
b Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, TX, United States
c Department of Psychology and Neuroscience, Baylor University, Waco, TX, United States
d Department of Psychology, Georgetown University, Washington, DC, United States
e Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
f Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
g Department of Radiology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
i Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
j Department of Occupational Therapy, Washington University in St. Louis, St. Louis, MO, United States
k Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
l Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
m Laboratory of Brain and Cognition, National Institute of Mental Health, NIH, Bethesda, MD, United States
n Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY, United States

Abstract
Control over behavior is enabled by the brain’s control networks, which interact with lower-level sensory motor and default networks to regulate their functions. Such interactions are facilitated by specialized “connector hub” regions that interconnect discrete networks. Previous work has treated hubs as a single category of brain regions, although their unitary nature is dubious when examined in individual brains. Here we investigated the nature of hubs by using fMRI to characterize individual-specific hub regions in two independent datasets. We identified three separable sets of connector hubs that integrate information between specific brain networks. These three hub categories occupy different positions within the brain’s network structure; they affect networks differently when artificially lesioned, and they are differentially engaged during cognitive and motor task performance. This work suggests a model of brain organization in which different connector hubs integrate control functions and enable top-down control of separate processing streams. Gordon et al. identify separable control-processing, control-default, and cross-control connector hubs that integrate specific brain networks. These hub sets are differentially engaged during task performance and affect networks differently when artificially lesioned. Different connector hub sets may separately enable top-down control of sensory motor, emotional, and control of control functions. © 2018

Author Keywords
brain networks;  connector hubs;  fMRI;  functional connectivity

Document Type: Article
Source: Scopus
Access Type: Open Access

“Remote Limb Ischemic Conditioning and Motor Learning: Evaluation of Factors Influencing Response in Older Adults” (2018) Translational Stroke Research

Remote Limb Ischemic Conditioning and Motor Learning: Evaluation of Factors Influencing Response in Older Adults
(2018) Translational Stroke Research, . Article in Press. 

Sutter, E.N.a , Mattlage, A.E.a , Bland, M.D.a , Cherry-Allen, K.M.a , Harrison, E.a , Surkar, S.M.a , Gidday, J.M.b , Chen, L.c , Hershey, T.d , Lee, J.-M.e , Lang, C.E.a

a Program in Physical Therapy, Washington University School of Medicine, Campus Box 8502, 4444 Forest Park, Saint Louis, MO, United States
b Louisiana State University School of Medicine, New Orleans, LA, United States
c Division of Biostatistics, Washington University School of Medicine, Campus Box 8502, 4444 Forest Park, Saint Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine, Campus Box 8502, 4444 Forest Park, Saint Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, Campus Box 8502, 4444 Forest Park, Saint Louis, MO, United States

Abstract
Remote limb ischemic conditioning (RLIC) is a clinically feasible method of promoting tissue protection against subsequent ischemic insult. Recent findings from our lab demonstrated that RLIC robustly enhances motor learning in young, healthy humans. The next step is to determine which individuals would receive maximum benefit from RLIC before applying these findings to clinical rehabilitation populations such as stroke. Numerous factors, such as age, sex, body mass index (BMI), and cardiovascular comorbidities may influence the response. Sixty-nine participants aged 40–80 were randomized to receive either RLIC (n = 33) or sham (n = 36) conditioning. Participants underwent seven consecutive sessions consisting of RLIC or sham conditioning with a blood pressure cuff on the upper extremity and motor training on a stability platform balance task, with two follow-up sessions. Balance change (post-test–pre-test) was compared across participants, groups, and the factors of age, sex, BMI, and comorbidities. Participants in both groups improved their performance on the balance task from pre- to post-test. Overall balance change was independently associated with age and BMI. There was no difference in balance change between RLIC and Sham groups. However, RLIC significantly enhanced balance performance in participants with no comorbidities. Compared with our previous study in young adults, middle-aged and older adults demonstrated smaller improvements on the balance task. RLIC enhanced learning in middle-aged and older adults only in the absence of pre-defined comorbidities. RLIC may be a promising tool for enhancing motor recovery, but the accumulation of comorbidity with age may decrease its effectiveness. © 2018, Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Cardiovascular disease;  Comorbidity;  Ischemic preconditioning;  Psychomotor performance

Document Type: Article in Press
Source: Scopus