WashU weekly Neuroscience publications

Symptoms of social anxiety disorder and major depressive disorder: A network perspective
(2019) Journal of Affective Disorders, 243, pp. 531-538. 

Langer, J.K.^a , Tonge, N.A.^{a c} , Piccirillo, M.^{a c} , Rodebaugh, T.L.^{a c} , Thompson, R.J.^{a c} , Gotlib, I.H.^{b d}

^a Washington University in St. Louis, 1 Brookings Dr. St Louis, MO, St Louis, MO 63130, United States
^b Stanford University, 450 Serra Mall, Stanford, CA 94305, United States
^c Natasha A. Tonge, Marilyn Piccirillo, Thomas L. Rodebaugh, and Renee J. Thompson are at the Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^d Ian H. Gotlib is at the Department of Psychology, Stanford University. The research was conducted at Stanford University, United States

Abstract
Background: We used network analyses to examine symptoms that may play a role in the co-occurrence of social anxiety disorder (SAD) and major depressive disorder (MDD). Whereas latent variable models examine relations among latent constructs, network analyses have the advantage of characterizing direct relations among the symptoms themselves. Method: We conducted network modeling on symptoms of social anxiety and depression in a clinical sample of 130 women who met criteria for SAD, MDD, both disorders, or had no lifetime history of mental illness. Results: In the resulting network, the core symptoms of social fear and depressed mood appeared at opposite ends of the network and were weakly related; so-called “bridges” between these symptoms appeared to occur via intervening variables. In particular, the worthless variable appeared to play a central role in the network. Limitations: Because our data were cross-sectional, we are unable to draw conclusions about the direction of these effects or whether these variables are related to each other prospectively. Conclusions: Continued testing of these pathways using longitudinal data will help facilitate the development of more effective clinical interventions for these disorders. © 2018

Author Keywords
Anxiety disorders;  Assessment;  Depression;  Diagnosis;  Social anxiety disorder;  Treatment

Document Type: Article
Source: Scopus

Widespread distribution of tauopathy in preclinical Alzheimer’s disease
(2018) Neurobiology of Aging, 72, pp. 177-185. 

Schultz, S.A.^{a b} , Gordon, B.A.^{b c d} , Mishra, S.^b , Su, Y.^b , Perrin, R.J.^{c e} , Cairns, N.J.^{c e f} , Morris, J.C.^{c f} , Ances, B.M.^{a c f} , Benzinger, T.L.S.^{a b c g}

^a Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychological & Brain Sciences, Washington University, St. Louis, MO, United States
^e Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
The objective of this study was to examine the distribution and severity of tau-PET binding in cognitively normal adults with preclinical Alzheimer’s disease as determined by positive beta-amyloid PET. 18F-AV-1451 tau-PET data from 109 cognitively normal older adults were processed with 34 cortical and 9 subcortical FreeSurfer regions and averaged across both hemispheres. Individuals were classified as being beta-amyloid positive (N = 25, A+) or negative (N = 84, A−) based on a 18F-AV-45 beta-amyloid-PET standardized uptake value ratio of 1.22. We compared the tau-PET binding in the 2 groups using covariate-adjusted linear regressions. The A+ cohort had higher tau-PET binding within 8 regions: precuneus, amygdala, banks of the superior temporal sulcus, entorhinal cortex, fusiform gyrus, inferior parietal cortex, inferior temporal cortex, and middle temporal cortex. These findings, consistent with preclinical involvement of the medial temporal lobe and parietal lobe and association regions by tauopathy, emphasize that therapies targeting tauopathy in Alzheimer’s disease could be considered before the onset of symptoms to prevent or ameliorate cognitive decline. © 2018

Author Keywords
Alzheimer’s disease;  Parietal lobe;  Positron emission tomography;  Tau;  Temporal lobe

Document Type: Article
Source: Scopus

Opioid Consumption After Knee Arthroscopy
(2018) The Journal of bone and joint surgery. American volume, 100 (19), pp. 1629-1636. 

Wojahn, R.D., Bogunovic, L., Brophy, R.H., Wright, R.W., Matava, M.J., Green, J.R., 4th, Zalomek, C.A., Haas, A.K., Holloway, W.L., Garofoli, E.A., Smith, M.V.

Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: The opioid epidemic in the United States has placed increased pressure on physicians to engage in responsible opioid prescribing practices. However, surgeons currently have little information to guide their postoperative prescription decision-making. The purpose of this study was to assess opioid consumption after knee arthroscopy and identify preoperative factors that may predict higher opioid usage.

METHODS: A prospective observational study of 221 patients was conducted in patients undergoing outpatient knee arthroscopy for meniscal repair, partial meniscectomy, debridement, chondroplasty, or loose body removal. Participants recorded their daily opioid consumption in a postoperative pain diary. Total opioid consumption was calculated from counts of remaining pills at the 2-week and 6-week postoperative office visits. Variables, including age, sex, body mass index, smoking status, alcohol consumption, preoperative pain severity and duration, preoperative opioid usage, Patient-Reported Outcomes Measurement Information System (PROMIS) scores, and the Connor-Davidson Resilience Scale, were evaluated for an association with opioid consumption.

RESULTS: Total opioid consumption ranged from 0 to 188 pills, with a median of 7 pills (hydrocodone 5-mg equivalents). Forty-six percent of patients took ≤5 pills, 59% took ≤10 pills, and 81% took ≤20 pills. Fifty-six percent of patients had discontinued opioid usage by the third postoperative day. Eighty-eight percent of patients had surplus opioid medication at the time of the final follow-up. Patients undergoing meniscal repair, smokers, and those taking preoperative opioids were significantly more likely to take ≥20 pills (p < 0.05).

CONCLUSIONS: The median number of pills taken after knee arthroscopy is 7, with the majority of patients consuming ≤20 pills. Meniscal repair, smoking, and preoperative opioid usage were associated with higher postoperative opioid consumption.

LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Document Type: Article
Source: Scopus

Regulatory γ1 subunits defy symmetry in functional modulation of BK channels
(2018) Proceedings of the National Academy of Sciences of the United States of America, 115 (40), pp. 9923-9928. 

Gonzalez-Perez, V.^a , Johny, M.B.^b , Xia, X.-M.^a , Lingle, C.J.^a

^a Department of Anesthesiology, School of Medicine, Washington University, St. Louis, MO 63110, United States
^b Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, United States

Abstract
Structural symmetry is a hallmark of homomeric ion channels. Nonobligatory regulatory proteins can also critically define the precise functional role of such channels. For instance, the poreforming subunit of the large conductance voltage and calciumactivated potassium (BK, Slo1, or KCa1.1) channels encoded by a single KCa1.1 gene assembles in a fourfold symmetric fashion. Functional diversity arises from two families of regulatory subunits, β and γ, which help define the range of voltages over which BK channels in a given cell are activated, thereby defining physiological roles. A BK channel can contain zero to four β subunits per channel, with each β subunit incrementally influencing channel gating behavior, consistent with symmetry expectations. In contrast, a γ1 subunit (or single type of γ1 subunit complex) produces a functionally all-or-none effect, but the underlying stoichiometry of γ1 assembly and function remains unknown. Here we utilize two distinct and independent methods, a Forster resonance energy transfer-based optical approach and a functional reporter in single-channel recordings, to reveal that a BK channel can contain up to four γ1 subunits, but a single γ1 subunit suffices to induce the full gating shift. This requires that the asymmetric association of a single regulatory protein can act in a highly concerted fashion to allosterically influence conformational equilibria in an otherwise symmetric K+ channel. © 2018 National Academy of Sciences. All rights reserved.

Author Keywords
Bk channels;  Fret;  K+ channels;  Regulatory subunits;  Stoichiometry

Document Type: Article
Source: Scopus

Femoral nerve transfers for restoring tibial nerve function: An anatomical study and clinical correlation: A report of 2 cases
(2018) Journal of Neurosurgery, 129 (4), pp. 1024-1033. 

Moore, A.M., Krauss, E.M., Parikh, R.P., Franco, M.J., Tung, T.H.

Division of Plastic and Reconstructive Surgery, Washington University, St. Louis, MO, United States

Abstract
Sciatic nerve injuries cause debilitating functional impairment, particularly when the injury mechanism and level preclude reconstruction with primary grafting. The purpose of this study was to demonstrate the anatomical feasibility of nerve transfers from the distal femoral nerve terminal branches to the tibial nerve and to detail the successful restoration of tibial function using the described nerve transfers. Six cadaveric legs were dissected for anatomical analysis and the development of tension-free nerve transfers from femoral nerve branches to the tibial nerve. In 2 patients with complete tibial and common peroneal nerve palsies following sciatic nerve injury, terminal branches of the femoral nerve supplying the vastus medialis and vastus lateralis muscles were transferred to the medial and lateral gastrocnemius branches of the tibial nerve. Distal sensory transfer of the saphenous nerve to the sural nerve was also performed. Patients were followed up for lower-extremity motor and sensory recovery up to 18 months postoperatively. Consistent branching patterns and anatomical landmarks were present in all dissection specimens, allowing for reliable identification, neurolysis, and coaptation of donor femoral and saphenous nerve branches to the recipients. Clinically, the patients obtained Medical Research Council Grade 3 and 3+ plantar flexion by 18 months postoperatively. Improved strength was accompanied by improved ambulation in both patients and by a return to competitive sports in 1 patient. Sensory recovery was demonstrated by an advancing Tinel sign in both patients. This study illustrates the clinical success and anatomical feasibility of femoral nerve to tibial nerve transfers after proximal sciatic nerve injury. © AANS 2018.

Author Keywords
ambulation;  lower extremity reconstruction;  nerve injury;  nerve transfer;  peripheral nerve;  sciatic nerve;  tibial nerve

Document Type: Conference Paper
Source: Scopus

White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease
(2018) Brain, 141 (10), pp. 3065-3080. Cited 1 time.

Caballero, M.A.A.^a , Suárez-Calvet, M.^{b c} , Duering, M.^a , Franzmeier, N.^a , Benzinger, T.^{d e} , Fagan, A.M.^{d e f} , Bateman, R.J.^{d e f} , Jack, C.R.^g , Levin, J.^{b h} , Dichgans, M.^{a b i} , Jucker, M.^j , Karch, C.^{e f k} , Masters, C.L.^l , Morris, J.C.^{d e} , Weiner, M.^m , Rossor, M.ⁿ , Fox, N.C.ⁿ , Lee, J.-H.^o , Salloway, S.^p , Danek, A.^{b h} , Goate, A.^{q r} , Yakushev, I.^s , Hassenstab, J.^t , Schofield, P.R.^{u v} , Haass, C.^{b c i} , Ewers, M.^a

^a Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität LMU, Feodor-Lynen-Straße, Munich, D-81377, Germany
^b German Center for Neurodegenerative Diseases (DZNE Munich), Munich, Germany
^c Biomedical Center Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany
^d Department of Radiology, Washington University in St Louis, St Louis, MO, United States
^e Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, MO, United States
^f Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Radiology, Mayo Clinic, Rochester, MN, United States
^h Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
ⁱ Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^j Hertie Institute for Clinical Brain Research, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^k Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^l Florey Institute, University of Melbourne, Parkville, VIC, Australia
^m University of California at San Francisco, San Francisco, CA 94143, United States
ⁿ Dementia Research Centre, University College London, Queen Square, London, United Kingdom
^o Department of Neurology, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, South Korea
^p Department of Neurology, Warren Alpert Medical School, Brown University, Providence, RI, United States
^q Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^r Ronald M. Loeb Center for Alzheimer’s Disease, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^s Department of Nuclear Medicine, Technical University of Munich, Munich, Germany
^t Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^u Neuroscience Research Australia, Barker Street Randwick, Sydney, Australia
^v School of Medical Sciences, University of New South Wales, Sydney, Australia

Abstract
White matter alterations are present in the majority of patients with Alzheimer’s disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer’s disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer’s disease. In early-onset autosomal-dominantly inherited Alzheimer’s disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts’ projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β 1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer’s disease pathology and microglia activity in the brain. © 2018 The Author(s).

Author Keywords
Alzheimer’s disease;  autosomal dominant;  diffusion tensor imaging;  TREM2;  white matter

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

Endoscopic synostosis surgery: Case closed. or open? or in between?
(2018) Journal of Neurosurgery: Pediatrics, 22 (4), pp. 331-334. 

Smyth, M.D.

Department of Neurological Surgery, Washington University, St. Louis Children’s Hospital, St. Louis, MO, United States

Document Type: Editorial
Source: Scopus

PERK regulates glioblastoma sensitivity to ER stress although promoting radiation resistance
(2018) Molecular Cancer Research, 16 (10), pp. 1447-1453. 

Dadey, D.Y.A.^{a b c} , Kapoor, V.^a , Khudanyan, A.^{a d} , Thotala, D.^{a e} , Hallahan, D.E.^{a e}

^a Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, 4511 Forest Park, St. Louis, MO 63108, United States
^b Medical Scientist Training Program, School of Medicine, Washington University in St. Louis, St. Louis, MI, United States
^c Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
^d Oregon Health and Science University, School of Medicine, Portland, OR, United States
^e Siteman Cancer Center, School of Medicine, Washington University in St. Louis, St. Louis, MI, United States

Abstract
The aggressive nature and inherent therapeutic resistance of glioblastoma multiforme (GBM) has rendered the median survival of afflicted patients to 14 months. Therefore, it is imperative to understand the molecular biology of GBM to provide new treatment options to overcome this disease. It has been demonstrated that the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is an important regulator of the endoplasmic reticulum (ER) stress response. PERK signaling has been observed in other model systems after radiation; however, less is known in the context of GBM, which is frequently treated with radiation-based therapies. To investigate the significance of PERK, we studied activation of the PERK- eIF2α-ATF4 pathway inGBMafter ionizing radiation (IR). By inhibiting PERK, it was determined that ionizing radiation (IR)-induced PERK activity led to eIF2a phosphorylation. IR enhanced the prodeath component of PERK signaling in cells treated with Sal003, an inhibitor of phospho-eIF2α phosphatase. Mechanistically, ATF4 mediated the prosurvival activity during the radiation response. The data support the notion that induction of ER stress signaling by radiation contributes to adaptive survival mechanisms during radiotherapy. The data also support a potential role for the PERK/eIF2α/ATF4 axis in modulating cell viability in irradiated GBM. Implications: The dual function of PERK as a mediator of survival and death may be exploited to enhance the efficacy of radiation therapy. © 2018 American Association for Cancer Research.

Document Type: Article
Source: Scopus

Indications for neuromuscular ultrasound: Expert opinion and review of the literature
(2018) Clinical Neurophysiology, . Article in Press. 

Walker, F.O.^a , Cartwright, M.S.^a , Alter, K.E.^b , Visser, L.H.^c , Hobson-Webb, L.D.^d , Padua, L.^{e f} , Strakowski, J.A.^{g h i} , Preston, D.C.^j , Boon, A.J.^k , Axer, H.^l , van Alfen, N.^m , Tawfik, E.A.ⁿ , Wilder-Smith, E.^{o p q} , Yoon, J.S.^r , Kim, B.-J.^s , Breiner, A.^t , Bland, J.D.P.^u , Grimm, A.^v , Zaidman, C.M.^w

^a Department of Neurology at Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, United States
^b Department of Rehabilitation Medicine, National INeurolnstitutes of Health, Bethesda, MD 20892, United States
^c Departments of Neurology and Clinical Neurophysiology, Elisabeth-Tweesteden Hospital, Tilburg, Netherlands
^d Department of Neurology, Neuromuscular Division, Duke University School of Medicine, Durham, NC, United States
^e Don Carlo Gnocchi ONLUS Foundation, Piazzale Rodolfo Morandi, 6, Milan, 20121, Italy
^f Department of Geriatrics, Neurosciences and Orthopaedics, Universita Cattolica del Sacro Cuore, Rome, Italy
^g Department of Physical Medicine and Rehabilitation, The Ohio State University, Columbus, OH, United States
^h Department of Physical Medicine and Rehabilitation, OhioHealth Riverside Methodist Hospital, Columbus, OH, United States
ⁱ OhioHealth McConnell Spine, Sport and Joint Center, Columbus, OH, United States
^j Neurological Institute, University Hospitals, Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, United States
^k Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, United States
^l Hans Berger, Department of Neurology, Jena University Hospital, Jena, 07747, Germany
^m Department of Neurology and Clinical Neurophysiology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
ⁿ Department of Physical Medicine & Rehabilitation, Faculty of Medicine, Ain Shams University, Cairo, Egypt
^o Department of Neurology, Yong Loo Lin School of Medicine, National University Singapore, Singapore
^p Department of Neurology, Kantonsspital Lucerne, Switzerland
^q Department of Neurology, Inselspital Berne, Switzerland
^r Department of Physical Medicine and Rehabilitation, Korea University Guro Hospital, Seoul, South Korea
^s Department of Neurology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea
^t Division of Neurology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Canada
^u Deparment of Clinical Neurophysiology, East Kent Hospitals University NHS Foundation Trust, Canterbury, Kent, United Kingdom
^v Department of Neurology, University Hospital Tuebingen, Tuebingen, Germany
^w Division of Neuromuscular Medicine, Department of Neurology, Washington University in St. Louis, 660 S. Euclid Ave, Box 8111, St. Louis, MO 63110, United States

Abstract
Over the last two decades, dozens of applications have emerged for ultrasonography in neuromuscular disorders. We wanted to measure its impact on practice in laboratories where the technique is in frequent use. After identifying experts in neuromuscular ultrasound and electrodiagnosis, we assessed their use of ultrasonography for different indications and their expectations for its future evolution. We then identified the earliest papers to provide convincing evidence of the utility of ultrasound for particular indications and analyzed the relationship of their date of publication with expert usage. We found that experts use ultrasonography often for inflammatory, hereditary, traumatic, compressive and neoplastic neuropathies, and somewhat less often for neuronopathies and myopathies. Usage significantly correlated with the timing of key publications in the field. We review these findings and the extensive evidence supporting the value of neuromuscular ultrasound. Advancement of the field of clinical neurophysiology depends on widespread translation of these findings. © 2018

Author Keywords
Diaphragm;  Electromyography;  Motor neuron disease;  Myopathy;  Nerve conduction studies;  Neuropathy

Document Type: Article in Press
Source: Scopus

The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders
(2018) Pediatric Research, . Article in Press. 

Warner, B.B.

Department of Pediatrics, School of Medicine, Washington University in St Louis, Saint Louis, MO, United States

Abstract
Bidirectional communication between the gut and brain is well recognized, with data now accruing for a specific role of the gut microbiota in that link, referred to as the microbiome–gut–brain axis. This review will discuss the emerging role of the gut microbiota in brain development and behavior. Animal studies have clearly demonstrated effects of the gut microbiota on gene expression and neurochemical metabolism impacting behavior and performance. Based on these changes, a modulating role of the gut microbiota has been demonstrated for a variety of neuropsychiatric disorders, including depression, anxiety, and movement including Parkinson’s, and importantly for the pediatric population autism. Critical developmental windows that influence early behavioral outcomes have been identified that include both the prenatal environment and early postnatal colonization periods. The clearest data regarding the role of the gut microbiota on neurodevelopment and psychiatric disorders is from animal studies; however, human data have begun to emerge, including an association between early colonization patterns and cognition. The importance of understanding the contribution of the gut microbiota to the development and functioning of the nervous system lies in the potential to intervene using novel microbial-based approaches to treating neurologic conditions. While pathways of communication between the gut and brain are well established, the gut microbiome is a new component of this axis. The way in which organisms that live in the gut influence the central nervous system (CNS) and host behavior is likely to be multifactorial in origin. This includes immunologic, endocrine, and metabolic mechanisms, all of which are pathways used for other microbial–host interactions. Germ-free (GF) mice are an important model system for understanding the impact of gut microbes on development and function of the nervous system. Alternative animal model systems have further clarified the role of the gut microbiota, including antibiotic treatment, fecal transplantation, and selective gut colonization with specific microbial organisms. Recently, researchers have started to examine the human host as well. This review will examine the components of the CNS potentially influenced by the gut microbiota, and the mechanisms mediating these effects. Links between gut microbial colonization patterns and host behavior relevant to a pediatric population will be examined, highlighting important developmental windows in utero or early in development. © 2018, International Pediatric Research Foundation, Inc.

Document Type: Article in Press
Source: Scopus

A competitive model for striatal action selection
(2018) Brain Research, . Article in Press. 

Bariselli, S.^a , Fobbs, W.C.^a , Creed, M.C.^b , Kravitz, A.V.^{a c}

^a National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
^b Washington University in St Louis, Department of Anesthesiology, St Louis, MO, United States
^c National Institute on Drug Abuse, Baltimore, MD, United States

Abstract
The direct and indirect pathway striatal medium spiny neurons (dMSNs and iMSNs) have long been linked to action selection, but the precise roles of these neurons in this process remain unclear. Here, we review different models of striatal pathway function, focusing on the classic “go/no-go” model which posits that dMSNs facilitate movement while iMSNs inhibit movement, and the “complementary” model, which argues that dMSNs facilitate the selection of specific actions while iMSNs inhibit potentially conflicting actions. We discuss the merits and shortcomings of these models and propose a “competitive” model to explain the contribution of these two pathways to behavior. The “competitive” model argues that rather than inhibiting conflicting actions, iMSNs are tuned to the same actions that dMSNs facilitate, and the two populations “compete” to determine the animal’s behavioral response. This model provides a theoretical explanation for how these pathways work together to select actions. In addition, it provides a link between action selection and behavioral reinforcement, via modulating synaptic strength at inputs onto dMSNs and iMSNs. Finally, this model makes predictions about how imbalances in the activity of these pathways may underlie behavioral traits associated with psychiatric disorders. Understanding the roles of these striatal pathways in action selection may help to clarify the neuronal mechanisms of decision-making under normal and pathological conditions. © 2018

Author Keywords
Approach;  Avoidance;  Dopamine;  Drug-seeking;  Repetitive behavior;  Striatum

Document Type: Article in Press
Source: Scopus

Prevalence and sociodemographic factors associated with depression among hospitalized patients with head and neck cancer—Results from a national study
(2018) Psycho-Oncology, . Article in Press. 

Rohde, R.L.^a , Adjei Boakye, E.^b , Challapalli, S.D.^a , Patel, S.H.^a , Geneus, C.J.^c , Tobo, B.B.^d , Simpson, M.C.^e , Mohammed, K.A.^f , Deshields, T.^g , Varvares, M.A.^e , Osazuwa-Peters, N.^{d h i}

^a Saint Louis University School of Medicine, St Louis, MO, United States
^b Saint Louis University Center for Health Outcomes Research, St Louis, MO, United States
^c Department of Biostatistics and Bioinformatics, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, United States
^d Department of Epidemiology and Biostatistics, Saint Louis University College for Public Health and Social Justice, St Louis, MO, United States
^e Department of Otolaryngology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA, United States
^f Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO, United States
^g Department of Medicine, Washington University School of Medicine, St Louis, MO, United States
^h Department of Otolaryngology—Head and Neck Surgery, Saint Louis University School of Medicine, St Louis, MO, United States
ⁱ Saint Louis University Cancer Center, St Louis, MO, United States

Abstract
Objective: Depression is a significant problem for patients with head and neck cancer (HNC). This study explored the prevalence of and sociodemographic and clinical factors associated with depression, among patients with HNC. Methods: We performed a retrospective analysis of 71 541 cases of HNC using a national dataset, the Nationwide Inpatient Sample, from 2008 to 2013. Weighted, multivariate logistic regression analysis estimated association between sociodemographic/clinical factors and tumor anatomical site with diagnosis of a major depressive disorder. Results: Overall prevalence of major depressive disorder in HNC was 9.3%; highest prevalence was found in patients with laryngeal cancer (28.5%). Compared with laryngeal cancer, there were lower odds of depression among patients with oral cavity cancer (adjusted odds ratio [aOR] = 0.90; 95% CI, 0.84-0.97) and other anatomic sites (aOR = 0.87; 95% CI, 0.81-0.94), except oropharyngeal cancer (aOR = 1.00; 95% CI, 0.93-1.08). For every unit increase in comorbidities, odds of depression increased by 20% (aOR = 1.20; 95% CI, 1.19-1.23). Sociodemographic factors associated with increased odds of depression included being female (aOR = 1.77; 95% CI, 1.68-1.87), white (aOR = 1.75; 95% CI, 1.59-1.92), and having Medicaid (aOR = 1.09; 95% CI, 1.01-1.19) or Medicare insurance (aOR = 1.19; 95% CI, 1.10-1.27). Conclusions: Depression odds vary depending on HNC anatomic site, and one in four patients with laryngeal cancer may be depressed. Since depression is prevalent in this survivor cohort, it is important that psychosocial assessment and intervention are integrated into mainstream clinical care for patients with HNC. © 2018 John Wiley & Sons, Ltd.

Author Keywords
cancer;  cancer survivorship;  depression;  gender differences;  head and neck cancer (HNC);  laryngeal cancer;  major depressive disorder (MDD);  Nationwide Inpatient Sample (NIS);  oncology;  psychosocial morbidity

Document Type: Article in Press
Source: Scopus

Early hypoxemia burden is strongly associated with severe intracranial hemorrhage in preterm infants
(2018) Journal of Perinatology, . Article in Press. 

Vesoulis, Z.A.^a , Bank, R.L.^a , Lake, D.^b , Wallman-Stokes, A.^c , Sahni, R.^c , Moorman, J.R.^b , Isler, J.R.^c , Fairchild, K.D.^d , Mathur, A.M.^a

^a Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Medicine, University of Virginia, Charlottesville, VA, United States
^c Department of Pediatrics, Columbia University, New York, NY, United States
^d Department of Pediatrics, University of Virginia, Charlottesville, VA, United States

Abstract
Objectives:: The objective of this study was to define the association between the burden of severe hypoxemia (SpO2 ≤70%) in the first week of life and development of severe ICH (grade III/IV) in preterm infants. Study design:: Infants born at &lt;32 weeks or weighing &lt;1500 g underwent prospective SpO2 recording from birth through 7 days. Severe hypoxemia burden was calculated as the percentage of the error-corrected recording where SpO2 ≤70%. Binary logistic regression was used to model the relationship between hypoxemia burden and severe ICH. Results:: A total of 163.3 million valid SpO2 data points were collected from 645 infants with mean EGA = 27.7 ± 2.6 weeks, BW = 1005 ± 291 g; 38/645 (6%) developed severe ICH. There was a greater mean hypoxemia burden for infants with severe ICH (3%) compared to those without (0.1%) and remained significant when controlling for multiple confounding factors. Conclusion:: The severe hypoxemia burden in the first week of life is strongly associated with severe ICH. © 2018, Springer Nature America, Inc.

Document Type: Article in Press
Source: Scopus

Wireless bioresorbable electronic system enables sustained nonpharmacological neuroregenerative therapy
(2018) Nature Medicine, . Article in Press. 

Koo, J.^{a b} , MacEwan, M.R.^{c d} , Kang, S.-K.^{e f} , Won, S.M.^g , Stephen, M.^c , Gamble, P.^c , Xie, Z.^{b h} , Yan, Y.^c , Chen, Y.-Y.^g , Shin, J.^g , Birenbaum, N.^{c d} , Chung, S.^g , Kim, S.B.^g , Khalifeh, J.^c , Harburg, D.V.^g , Bean, K.^c , Paskett, M.^c , Kim, J.ⁱ , Zohny, Z.S.^c , Lee, S.M.^{a b} , Zhang, R.^g , Luo, K.^{b h} , Ji, B.^{b h} , Banks, A.^{b g} , Lee, H.M.^j , Huang, Y.^{a b h} , Ray, W.Z.^{c d} , Rogers, J.A.^{a b g h k l m n o}

^a Center for Bio-Integrated Electronics, Northwestern University, Evanston, IL, United States
^b Department of Materials Science Engineering, Northwestern University, Evanston, IL, United States
^c Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^d Department of Biomedical Engineering, Washington University, St Louis, MO, United States
^e Department of Bio and Brain Engineering, Korea Advanced Institute of Science & Technology, Daejeon, South Korea
^f KAIST Institute for Health Science and Technology, Korea Advanced Institute of Science & Technology, Daejeon, South Korea
^g Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL, United States
^h Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL, United States
ⁱ Department of Electronics Convergence Engineering, Kwangwoon University, Nowon-gu, Seoul, South Korea
^j Department of Materials Science and Engineering, Korea Advanced Institute of Science & Technology, Daejeon, South Korea
^k Departments of Electrical Engineering, Computer Science, Chemistry and Biomedical Engineering, Northwestern University, Evanston, IL, United States
^l Simpson Querrey Institute for Nano/biotechnology, Northwestern University, Evanston, IL, United States
^m McCormick School of Engineering, Northwestern University, Evanston, IL, United States
ⁿ Feinberg School of Medicine, Northwestern University, Evanston, IL, United States
^o Department of Neurological Surgery, Northwestern University, Evanston, IL, United States

Abstract
Peripheral nerve injuries represent a significant problem in public health, constituting 2–5% of all trauma cases1. For severe nerve injuries, even advanced forms of clinical intervention often lead to incomplete and unsatisfactory motor and/or sensory function2. Numerous studies report the potential of pharmacological approaches (for example, growth factors, immunosuppressants) to accelerate and enhance nerve regeneration in rodent models3–10. Unfortunately, few have had a positive impact in clinical practice. Direct intraoperative electrical stimulation of injured nerve tissue proximal to the site of repair has been demonstrated to enhance and accelerate functional recovery11,12, suggesting a novel nonpharmacological, bioelectric form of therapy that could complement existing surgical approaches. A significant limitation of this technique is that existing protocols are constrained to intraoperative use and limited therapeutic benefits13. Herein we introduce (i) a platform for wireless, programmable electrical peripheral nerve stimulation, built with a collection of circuit elements and substrates that are entirely bioresorbable and biocompatible, and (ii) the first reported demonstration of enhanced neuroregeneration and functional recovery in rodent models as a result of multiple episodes of electrical stimulation of injured nervous tissue. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.

Document Type: Article in Press
Source: Scopus

A commentary on Parker Jones et al. on Gall’s cortical faculties
(2018) Cortex, . Article in Press. 

Eling, P.^a , Finger, S.^b

^a Department of Psychology, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands
^b Department of Psychological and Brain Sciences, and Program in History of Medicine, Washington University, St. Louis, MO, United States

Document Type: Article in Press
Source: Scopus

TREX1 is expressed by microglia in normal human brain and increases in regions affected by ischemia
(2018) Brain Pathology, . Article in Press. 

Kothari, P.H.^{a b c} , Kolar, G.R.^{d e} , Jen, J.C.^{f g} , Hajj-Ali, R.^h , Bertram, P.ⁱ , Schmidt, R.E.^j , Atkinson, J.P.ⁱ

^a Department of Biology and Biomedical Sciences Human & Statistical Genetics Program, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^c Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^d Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Pathology and Department of Ophthalmology, Saint Louis University School of Medicine, St. Louis, MO, United States
^f Departments of Neurology and Neurobiology, UCLA School of Medicine, Los Angeles, CA, United States
^g Departments of Neurology, Otolaryngology, Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, United States
^h Center for Vasculitis Care and Research, Cleveland Clinic Lerner College of Medicine, Orthopaedic and Rheumatologic Institute, Cleveland, OH, United States
ⁱ Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Mutations in the three-prime repair exonuclease 1 (TREX1) gene have been associated with neurological diseases, including Retinal Vasculopathy with Cerebral Leukoencephalopathy (RVCL). However, the endogenous expression of TREX1 in human brain has not been studied. Methods: We produced a rabbit polyclonal antibody (pAb) to TREX1 to characterize TREX1 by Western blotting (WB) of cell lysates from normal controls and subjects carrying an RVCL frame-shift mutation. Dual staining was performed to determine cell types expressing TREX1 in human brain tissue. TREX1 distribution in human brain was further evaluated by immunohistochemical analyses of formalin-fixed, paraffin-embedded samples from normal controls and patients with RVCL and ischemic stroke. Results: After validating the specificity of our anti-TREX1 rabbit pAb, WB analysis was utilized to detect the endogenous wild-type and frame-shift mutant of TREX1 in cell lysates. Dual staining in human brain tissues from patients with RVCL and normal controls localized TREX1 to a subset of microglia and macrophages. Quantification of immunohistochemical staining of the cerebral cortex revealed that TREX1+ microglia were primarily in the gray matter of normal controls (22.7 ± 5.1% and 5.5 ± 1.9% of Iba1+ microglia in gray and white matter, respectively) and commonly in association with the microvasculature. In contrast, in subjects with RVCL, the TREX1+ microglia were predominantly located in the white matter of normal appearing cerebral cortex (11.8 ± 3.1% and 38.9 ± 5.8% of Iba1+ microglia in gray and white matter, respectively). The number of TREX1+ microglia was increased in ischemic brain lesions in central nervous system of RVCL and stroke patients. Conclusions: TREX1 is expressed by a subset of microglia in normal human brain, often in close proximity to the microvasculature, and increases in the setting of ischemic lesions. These findings suggest a role for TREX1+ microglia in vessel homeostasis and response to ischemic injury. © 2018 The Authors Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology

Author Keywords
brain ischemia;  DNase1;  macrophages;  microglia;  TREX1;  vasculopathy

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

Uncovering the complex genetics of human character
(2018) Molecular Psychiatry, . Article in Press. 

Zwir, I.^{a b} , Arnedo, J.^b , Del-Val, C.^b , Pulkki-Råback, L.^c , Konte, B.^d , Yang, S.S.^e , Romero-Zaliz, R.^b , Hintsanen, M.^f , Cloninger, K.M.^g , Garcia, D.^{h i} , Svrakic, D.M.^a , Rozsa, S.^a , Martinez, M.^a , Lyytikäinen, L.-P.^j , Giegling, I.^{d k} , Kähönen, M.^l , Hernandez-Cuervo, H.^m , Seppälä, I.^j , Raitoharju, E.^j , de Erausquin, G.A.ⁿ , Raitakari, O.^o , Rujescu, D.^d , Postolache, T.T.^{p q} , Sung, J.^e , Keltikangas-Järvinen, L.^c , Lehtimäki, T.^j , Cloninger, C.R.^{a r}

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Computer Science, University of Granada, Granada, Spain
^c Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
^d Department of Psychiatry, Martin-Luther-University Halle-Wittenberg, Halle, Germany
^e Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea
^f University of Oulu, Unit of Psychology, Faculty of Education, Oulu, Finland
^g Anthropedia Foundation, St. Louis, MO, United States
^h Department of Psychology, University of Gothenburg, Gothenburg, Sweden
ⁱ Blekinge Centre of Competence, Blekinge County Council, Karlskrona, Sweden
^j Department of Clinical Chemistry, Fimlab Laboratories, Faculty of Medicine and Life Sciences, Finnish Cardiovascular Research Center-Tampere, University of Tampere, Tampere, Finland
^k Ludwig-Maximilian University, University Clinic, Munich, Germany
^l Department of Clinical Physiology, Tampere University Hospital and Faculty of Medicine and Life Sciences, University of Tampere, Tampere, Finland
^m Departments of Psychiatry and Neurosurgery, University of South Florida, Tampa, FL, United States
ⁿ Institute of Neurosciences, Department of Psychiatry and Neurology, School of Medicine, University of Texas Rio-Grande Valley, Harlingen, TX, United States
^o Research Centre of Applied and Preventive Cardiovascular Medicine, Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, University of Turku, Turku, Finland
^p Department of Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, United States
^q Rocky Mountain Mental Illness, Research, Education, Clinical Center for Veteran Suicide Prevention, Denver, CO, United States
^r Department of Genetics, Department of Psychological and Brain Sciences, and School of Medicine, School of Arts and Sciences, Washington University, St. Louis, MO, United States

Abstract
Human personality is 30–60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic–phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory. © 2018, Springer Nature Limited.

Document Type: Article in Press
Source: Scopus

Viral Encephalitis and Neurologic Diseases: Focus on Astrocytes
(2018) Trends in Molecular Medicine, . Article in Press. 

Soung, A.^a , Klein, R.S.^{a b c}

^a Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, United States
^b Department of Pathology and Immunology, 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

Abstract
Neurotropic RNA virus infections cause a major neurological disease burden. Due to the morbidity and mortality rates of viral encephalitides worldwide, there is a need to develop clinical treatments. Features of the central nervous system (CNS), including interconnected cell types and limited regeneration, provide unique challenges. Viral encephalitis and antiviral immunity can disrupt the CNS environment, leaving patients with poor neurological outcomes despite virologic control. The cellular mechanism(s) underlying neurological recovery are not fully understood, but involve neuroimmune interactions that, until recently, primarily focused on microglia. With increasing evidence that astrocytes also have significant roles in inflammatory responses to viruses, here we summarize recent astrocyte contributions to acute virologic control and neurological impairments during recovery from viral infection. © 2018 Elsevier Ltd

Author Keywords
astrocyte;  blood–brain barrier;  microglia;  neuroinflammation;  RNA virus;  viral encephalitis

Document Type: Article in Press
Source: Scopus

Matrices, scaffolds & carriers for cell delivery in nerve regeneration
(2018) Experimental Neurology, . Article in Press. 

Wang, Z.Z.^{a b} , Sakiyama-Elbert, S.E.^b

^a Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Biomedical Engineering, University of Austin at Texas, Austin, TX, United States

Abstract
Nerve injuries can be life-long debilitating traumas that severely impact patients’ quality of life. While many acellular neural scaffolds have been developed to aid the process of nerve regeneration, complete functional recovery is still very difficult to achieve, especially for long-gap peripheral nerve injury and most cases of spinal cord injury. Cell-based therapies have shown many promising results for improving nerve regeneration. With recent advances in neural tissue engineering, the integration of biomaterial scaffolds and cell transplantation are emerging as a more promising approach to enhance nerve regeneration. This review provides an overview of important considerations for designing cell-carrier biomaterial scaffolds. It also discusses current biomaterials used for scaffolds that provide permissive and instructive microenvironments for improved cell transplantation. © 2018 Elsevier Inc.

Author Keywords
Biomaterials;  Cell-carriers;  Extracellular matrix;  Induced pluripotent stem cells;  Nerve repair;  Neural stem cells;  Olfactory ensheathing cells;  Peripheral nerve injury;  Schwann cells;  Spinal cord injury

Document Type: Article in Press
Source: Scopus

3D Measurements of Acceleration-Induced Brain Deformation via Harmonic Phase Analysis and Finite-Element Models
(2018) IEEE Transactions on Biomedical Engineering, . Article in Press. 

Gomez, A.D.^a , Knutsen, A.^b , Xing, F.^c , Chan, D.^d , Lu, Y.^e , Pham, D.^f , Bayly, P.V.^g , Prince, J.L.^h

^a Electrical and Computer Engineering, Johns Hopkins University, 1466 Baltimore, Maryland United States (e-mail: adgomez@jhu.edu)
^b The Henry M. Jackson Foundation, Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland United States (e-mail: andrew.knutsen@nih.gov)
^c Department of Radiology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts United States (e-mail: fxing1@jhu.edu)
^d The Henry M. Jackson Foundation, Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland United States (e-mail: chand5@rpi.edu)
^e The Henry M. Jackson Foundation, Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland United States (e-mail: yclu@vt.edu)
^f The Henry M. Jackson Foundation, Center for Neuroscience and Regenerative Medicine, Bethesda, Maryland United States (e-mail: pham@jhu.edu)
^g Mechanical Engineering, Washington University in Saint Louis, 7548 Saint Louis, Missouri United States (e-mail: pvb@wustl.edu)
^h Electrical and Computer Engineering, Johns Hopkins University, Baltimore, Maryland United States 21218 (e-mail: prince@jhu.edu)

Abstract
Objective: To obtain dense spatiotemporal measurements of brain deformation from two distinct but complementary head motion experiments: linear and rotational accelerations. Methods: This study introduces a strategy for integrating harmonic phase analysis of tagged magnetic resonance imaging (MRI) and finite element models to extract mechanically representative deformation measurements. The method was calibrated using simulated as well as experimental data, demonstrated in a phantom including data with image artifacts, and used to measure brain deformation in human volunteers undergoing rotational and linear acceleration. Results: Evaluation methods yielded a displacement error of 1.1 mm compared to human observers, and strain errors between 0.1 $pm$ 0.2% (mean $pm$ std. dev.) for linear acceleration and 0.7 $pm$ 0.3% for rotational acceleration. In the presence of inconsistent or missing data, we demonstrate an approach that can provide an error reduction of 86%. Analysis of results shows consistency with 2D motion estimation, agreement with external sensors, and the expected physical behavior of the brain. Conclusion: Mechanical regularization is useful for obtaining dense spatiotemporal measurements of in-vivo brain deformation under different loading regimes. Significance: The measurements suggest that the brain’s 3D response to mild accelerations includes distinct patterns observable using practical MRI resolutions. This type of measurement can provide validation data for computer models for the study of traumatic brain injury (TBI). IEEE

Author Keywords
brain biomechanics;  finite element method;  finite strain;  harmonic phase analysis;  tagged MRI

Document Type: Article in Press
Source: Scopus

A multicomponent approach toward understanding emotion regulation in schizophrenia
(2018) Journal of Clinical Psychology, . Article in Press. 

Painter, J.M.^{a b} , Stellar, J.E.^{a c} , Moran, E.K.^{a d} , Kring, A.M.^a

^a Department of Psychology, University of California, Berkeley, CA, United States
^b Outpatient Mental Health, VA Puget Sound Health Care System, Seattle, WA, United States
^c Department of Psychology, University of Toronto, Mississauga, ON, Canada
^d Department of Psychiatry, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Objectives: Emotion deficits are well documented in people with schizophrenia. Far less is known about their ability to implement emotion regulation strategies. We sought to explore whether people with schizophrenia can modify their emotion responses similar to controls. Methods: People with (n = 25) and without (n = 21) schizophrenia were instructed to amplify positive-emotion expression, reappraise negative emotion experience, and suppress physiological response. Multiple components of emotion response were measured (experience, expression, and physiology). Results: Although people with schizophrenia showed increased positive expressivity following amplification and decreased negative emotion experience following reappraisal, overall, they expressed less positive emotion and experienced more negative emotion compared with controls. Neither group was effective at physiological suppression. Conclusions: Together these findings suggest that people with schizophrenia can engage in amplification and reappraisal when explicitly instructed to do so, albeit additional practice may be necessary to modify emotion responses to levels similar to controls. © 2018 Wiley Periodicals, Inc.

Author Keywords
amplification;  emotion;  reappraisal;  schizophrenia;  suppression

Document Type: Article in Press
Source: Scopus

Linking entropy at rest with the underlying structural connectivity in the healthy and lesioned brain
(2018) Cerebral Cortex, 28 (8), pp. 2948-2958. Cited 1 time.

Saenger, V.M.^a , Ponce-Alvarez, A.^a , Adhikari, M.^a , Hagmann, P.^{b c} , Deco, G.^{a d e f} , Corbetta, M.^g

^a Department of Information and Communication Technologies, Center for Brain and Cognition, Computational Neuroscience Group, Universitat Pompeu Fabra, Barcelona, 08005, Spain
^b Department of Radiology, Centre Hospitalier Universitaire Vaudois (CHUV), University of Lausanne (UNIL), Lausanne, 1011, Switzerland
^c Signal Processing Laboratory 5 (LTS5), École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, 1015, Switzerland
^d Instituci Catalana de la Recerca i Estudis Avanats (ICREA), Universitat Pompeu Fabra, Barcelona, 08010, Spain
^e Department of Neuropsychology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, 04103, Germany
^f School of Psychological Sciences, Monash University, Melbourne, Clayton, VIC 3800, Australia
^g Department of Neurology, Washington University School of Medicine, Saint Louis, MO 63110, United States

Abstract
The brain is a network that mediates information processing through a wide range of states. The extent of state diversity is a reflection of the entropy of the network. Here we measured the entropy of brain regions (nodes) in empirical and modeled functional networks reconstructed from resting state fMRI to address the connection of entropy at rest with the underlying structure measured through diffusion spectrum imaging. Using 18 empirical and 18 modeled stroke networks, we also investigated the effect that focal lesions have on node entropy and information diffusion. Overall, positive correlations between node entropy and structure were observed, especially between node entropy and node strength in both empirical and modeled data. Although lesions were restricted to one hemisphere in all stroke patients, entropy reduction was not only present in nodes from the damaged hemisphere, but also in nodes from the contralesioned hemisphere, an effect replicated in modeled stroke networks. Globally, information diffusion was also affected in empirical and modeled strokes compared with healthy controls. This is the first study showing that artificial lesions affect local and global network aspects in very similar ways compared with empirical strokes, shedding new light into the functional nature of stroke. © The Author 2017.

Author Keywords
Entropy;  Information flow;  Stroke;  Structural connectivity;  Whole-brain modeling

Document Type: Article
Source: Scopus

Prenatal to postnatal trajectory of brain growth in complex congenital heart disease
(2018) NeuroImage: Clinical, 20, pp. 913-922. 

Ortinau, C.M.^a , Mangin-Heimos, K.^b , Moen, J.^c , Alexopoulos, D.^d , Inder, T.E.^e , Gholipour, A.^{f g} , Shimony, J.S.^h , Eghtesady, P.ⁱ , Schlaggar, B.L.^{a d h j k} , Smyser, C.D.^{a d h}

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^c Division of Biostatistics, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^e Department of Pediatric Newborn Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^f Department of Radiology, Boston Children’s Hospital, Boston, MA, United States
^g Department of Radiology, Harvard Medical School, Boston, MA, United States
^h Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Division of Pediatric Cardiothoracic Surgery, Washington University in St. Louis, St. Louis, MO, United States
^j Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^k Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Altered brain development is a common feature of the neurological sequelae of complex congenital heart disease (CHD). These alterations include abnormalities in brain size and growth that begin prenatally and persist postnatally. However, the longitudinal trajectory of changes in brain volume from the prenatal to postnatal environment have not been investigated. We aimed to evaluate the trajectory of brain growth in a cohort of patients with complex CHD (n = 16) and healthy controls (n = 15) to test the hypothesis that patients with complex CHD would have smaller total brain volume (TBV) prenatally, which would become increasingly prominent by three months of age. Participants underwent fetal magnetic resonance imaging (MRI) at a mean of 32 weeks gestation, a preoperative/neonatal MRI shortly after birth, a postoperative MRI (CHD only), and a 3-month MRI to evaluate the trajectory of brain growth. Three-dimensional volumetric analysis was applied to the MRI data to measure TBV, as well as tissue-specific volumes of the cortical gray matter (CGM), white matter (WM), subcortical (deep nuclear) gray matter (SCGM), cerebellum, and cerebrospinal fluid (CSF). A random coefficients model was used to investigate longitudinal changes in TBV and demonstrated an altered trajectory of brain growth in the CHD population. The estimated slope for TBV from fetal to 3-month MRI was 11.5 cm3 per week for CHD infants compared to 16.7 cm3 per week for controls (p = 0.0002). Brain growth followed a similar trajectory for the CGM (p &lt; 0.0001), SCGM (p = 0.002), and cerebellum (p = 0.005). There was no difference in growth of the WM (p = 0.30) or CSF (p = 0.085). Brain injury was associated with reduced TBV at 3-month MRI (p = 0.02). After removing infants with brain injury from the model, an altered trajectory of brain growth persisted in CHD infants (p = 0.006). These findings extend the existing literature by demonstrating longitudinal impairments in brain development in the CHD population and emphasize the global nature of disrupted brain growth from the prenatal environment through early infancy. © 2018 The Authors

Author Keywords
Brain volume;  Congenital heart disease;  Fetal;  Magnetic resonance imaging

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

Uncovering the complex genetics of human temperament
(2018) Molecular Psychiatry, . Article in Press. Cited 1 time.

Zwir, I.^{a b} , Arnedo, J.^{a b} , Del-Val, C.^b , Pulkki-Råback, L.^c , Konte, B.^d , Yang, S.S.^e , Romero-Zaliz, R.^b , Hintsanen, M.^f , Cloninger, K.M.^g , Garcia, D.^{h i} , Svrakic, D.M.^a , Rozsa, S.^a , Martinez, M.^a , Lyytikäinen, L.-P.^j , Giegling, I.^{d k} , Kähönen, M.^l , Hernandez-Cuervo, H.^m , Seppälä, I.^j , Raitoharju, E.^j , de Erausquin, G.A.ⁿ , Raitakari, O.^o , Rujescu, D.^d , Postolache, T.T.^{p q} , Sung, J.^e , Keltikangas-Järvinen, L.^c , Lehtimäki, T.^j , Cloninger, C.R.^{a r}

^a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Computer Science, University of Granada, Granada, Spain
^c Department of Psychology and Logopedics, University of Helsinki, Helsinki, Finland
^d Department of Psychiatry, Martin-Luther-University Halle-Wittenberg, Halle, Germany
^e Department of Epidemiology, School of Public Health, Institute of Health and Environment, Seoul National University, Seoul, South Korea
^f Unit of Psychology, Faculty of Education, University of Oulu, Oulu, Finland
^g Anthropedia Foundation, St. Louis, MO, United States
^h Department of Psychology, University of Gothenburg, Gothenburg, Sweden
ⁱ Blekinge Centre of Competence, Blekinge County Council, Karlskrona, Sweden
^j Fimlab Laboratories, Department of Clinical Chemistry, Faculty of Medicine and Life Sciences, Finnish Cardiovascular Research Center-Tampere, University of Tampere, Tampere, Finland
^k University Clinic, Ludwig-Maximilian University, Munich, Germany
^l Department of Clinical Physiology, Faculty of Medicine and Life Sciences, Tampere University Hospital, University of Tampere, Tampere, Finland
^m Department of Psychiatry and Neurosurgery, University of South Florida, Tampa, FL, United States
ⁿ Department of Psychiatry and Neurology, Institute of Neurosciences, University of Texas Rio-Grande Valley School of Medicine, Harlingen, TX, United States
^o Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland
^p Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, United States
^q Rocky Mountain Mental Illness, Research, Education and Clinical Center for Veteran Suicide Prevention, Denver, CO, United States
^r Department of Psychological and Brain Sciences, School of Arts and Sciences, and Department of Genetics, School of Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic–phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37–53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory. © 2018, Springer Nature Limited.

Document Type: Article in Press
Source: Scopus

TREM2 — a key player in microglial biology and Alzheimer disease
(2018) Nature Reviews Neurology, . Article in Press. 

Ulland, T.K.^a , Colonna, M.^b

^a University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
^b Washington University School of Medicine, St Louis, MO, United States

Abstract
Alzheimer disease (AD) is a debilitating dementia believed to result from the deposition of extracellular amyloid-β (Aβ)-containing plaques followed by the formation of neurofibrillary tangles. Familial AD typically results from mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 or presenilin 2. Variations in triggering receptor expressed on myeloid cells 2 (TREM2), one of several genes for which expression is restricted to microglia in the brain, have now been shown to increase the risk of developing late-onset AD. Microglia have been shown to respond to Aβ accumulation and neurodegenerative lesions, progressively acquiring a unique transcriptional and functional signature and evolving into disease-associated microglia (DAM). DAM attenuate the progression of neurodegeneration in certain mouse models, but inappropriate DAM activation accelerates neurodegenerative disease in other models. TREM2 is essential for maintaining microglial metabolic fitness during stress events, enabling microglial progression to a fully mature DAM profile and ultimately sustaining the microglial response to Aβ-plaque-induced pathology. Here, we review the current data detailing the role of TREM2 in microglial biology and AD. © 2018, Springer Nature Limited.

Document Type: Article in Press
Source: Scopus

Scoping Review: The Trajectory of Recovery of Participation Outcomes following Stroke
(2018) Behavioural neurology, 2018, p. 5472018. 

Engel-Yeger, B.^a , Tse, T.^{b c d} , Josman, N.^a , Baum, C.^e , Carey, L.M.^{b c}

^a Department of Occupational Therapy, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, Israel
^b Occupational Therapy, Department of Community and Clinical Allied Health, School of Allied Health, La Trobe University, Melbourne, VIC, Australia
^c Neurorehabilitation and Recovery, Stroke Division, The Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
^d Occupational Therapy Department, St Vincent’s Hospital Melbourne, Fitzroy, VIC, Australia
^e Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States

Abstract
Participation is a central concept in health and well-being and healthcare, yet operationalizing this concept has been difficult. Its definition, uses in healthcare, and impacts on recovery require ongoing research. Our review question goes like this: from the longitudinal evidence investigating participation among stroke survivors, what are the patterns of participation recovery in stroke survivors over time, and what interventions are used to improve participation? To fully understand these questions, we also ask, how is participation defined in the stroke literature, and what are the measures of participation used in the stroke literature? A systematic scoping review was undertaken using the search terms “stroke,” “longitudinal,” “participation,” and “outcome” in seven databases. Articles included were published until April 2017, written in English, and had at least two longitudinal assessments of participation. Fifty-nine articles met the inclusion criteria. The International Classification of Functioning, Disability and Health was the most frequent definition of participation used (34%). There were 22 different measures of participation. Eight of ten studies demonstrated significant improvements in participation up to 12 months poststroke. Efficacy of interventions and their impact on participation varied. The various definitions, measures, and intervention efficacies of participation highlight the need for further research worldwide into achieving meaningful participation and quality of life among stroke survivors. Future practice should include participation as a main outcome measure.

Document Type: Review
Source: Scopus
Access Type: Open Access

Cognitive Behavioral Therapy for Tinnitus Unbound
(2018) JAMA Otolaryngology – Head and Neck Surgery, . Article in Press. 

Rodebaugh, T.L.

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

Document Type: Article in Press
Source: Scopus

A test of the initiation–termination model of worry
(2018) Journal of Experimental Psychopathology, 9 (1), . 

Berenbaum, H.^a , Chow, P.I.^a , Flores, L.E., Jr.^a , Schoenleber, M.^a , Thompson, R.J.^b , Most, S.B.^c

^a University of Illinois at Urbana-Champaign, United States
^b Washington University in St. Louis, United States
^c University of New South Wales, Australia

Abstract
An initial test of the initiation–termination model of worry was conducted in a sample of 51 individuals (half of whom had at least one anxiety disorder). On multiple occasions each day, participants were prompted to answer a variety of questions regarding their worrying. Worrying about new topics was presumed to reflect ease of worry initiation, whereas continuing to worry about the same topics and the duration of worrying were presumed to reflect difficulty with worry termination. Results aggregated across the sampling period revealed that worry initiation and termination incrementally predicted global worry and anxiety severity and were differentially associated with depression severity and emotion-induced blindness. Multilevel modeling indicated that, within participants, worry initiation and termination were differentially associated with the perceived costs of undesirable outcomes and with worry beliefs. © The Author(s) 2018.

Author Keywords
Anxiety;  ecological momentary assessment;  emotion-induced blindness;  threat perception;  worry

Document Type: Article
Source: Scopus

The Use of Nerve Transfers to Restore Upper Extremity Function in Cervical Spinal Cord Injury
(2018) PM and R, . Article in Press. 

Fox, I.K.^a , Novak, C.B.^b , Krauss, E.M.^c , Hoben, G.M.^d , Zaidman, C.M.^e , Ruvinskaya, R.^e , Juknis, N.^e , Winter, A.C.^f , Mackinnon, S.E.^d

^a Division of Plastic & Reconstructive Surgery, Washington University School of Medicine, 660 South Euclid Avenue, Box 8238, St Louis, MO 63110, United States
^b Division of Plastic & Reconstructive Surgery, University of Toronto, Toronto, ON, Canada
^c Division of Plastic Surgery, University of British Columbia Island Medical Program, Victoria, BC, Canada
^d Division of Plastic & Reconstructive Surgery, Washington University School of Medicine, St Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^f Division of Public Health Sciences, Washington University School of Medicine, St Louis, MO, United States

Abstract
Background: Nerve transfer surgery to restore upper extremity function in cervical spinal cord injury (SCI) is novel and may transform treatment. Determining candidacy even years post-SCI is ill defined and deserves investigation. Objective: To develop a diagnostic algorithm, focusing on electrodiagnostic (EDX) studies, to determine eligibility for nerve transfer surgery. Design: Retrospective descriptive case series. Setting: Tertiary university-based institution. Patients: Individuals with cervical SCI (n = 45). Methods: The electronic medical records of people referred to the Plastic Surgery Multidisciplinary Upper Extremity Surgery in SCI clinic from 2010-2015 were reviewed. People were considered for nerve transfers to restore elbow extension or finger flexion and/or extension. Data including demographic, clinical evaluation, EDX results, surgery, and outcomes were collected and analyzed. Main Outcome Measurements: EDX data, including nerve conduction studies and electromyography, for bilateral upper extremities of each patient examined was used to assess for the presence of lower motor neuron injury, which would preclude late nerve transfer. Results: Based on our criteria and the results of EDX testing, a substantial number of patients presenting even years post-SCI were candidates for nerve transfers. Clinical outcome results are heterogeneous but promising and suggest that further refinement of eligibility, long-term follow-up, and standardized assessment will improve our understanding of the role of nerve transfer surgery to restore function in people with midcervical SCI. Conclusions: Many patients living with SCI are candidates for nerve transfer surgery to restore upper extremity function. Although the ultimate efficacy of these surgeries is not yet determined, this study attempts to report the criteria we are using and may ultimately determine the timing for intervention and which transfers are most useful for this heterogeneous population. Level of Evidence: IV © 2018 American Academy of Physical Medicine and Rehabilitation

Document Type: Article in Press
Source: Scopus

Predictors of self-perceived stigma in Parkinson’s disease
(2018) Parkinsonism and Related Disorders, . Article in Press. 

Salazar, R.D.^a , Weizenbaum, E.^a , Ellis, T.D.^{a b} , Earhart, G.M.^c , Ford, M.P.^d , Dibble, L.E.^e , Cronin-Golomb, A.^a

^a Department of Psychological and Brain Sciences, Boston University, United States
^b Department of Physical Therapy and Athletic Training, Boston University College of Health and Rehabilitation Sciences: Sargent College, United States
^c Program in Physical Therapy, Washington University in St. Louis-School of Medicine, St. Louis, MO, United States
^d Department of Physical Therapy, School of Health Professions, Samford University, Birmingham, AL, United States
^e Department of Physical Therapy, University of Utah, Salt Lake City, UT, United States

Abstract
Objective: The burden of PD extends beyond physical limitations and includes significant psychosocial adjustments as individuals undergo changes to their self-perception and how others perceive them. There is limited quantitative evidence of the factors that contribute to self-perceived stigma, which we addressed in the present study. Methods: In 362 individuals with PD (157 women, 205 men), self-perceived stigma was measured by the four-item stigma subscale of the Parkinson’s Disease Questionnaire (PDQ-39). Hierarchical linear modeling was used to assess predictors of stigma including demographics (age, gender) and disease characteristics: duration, stage (Hoehn & Yahr Scale), motor severity (Unified Parkinson’s Disease Rating Scale, UPDRS, Part 3), activities of daily living (UPDRS Part 2), and depression (Geriatric Depression Scale). Predictor variables were chosen based on their significant correlations with the stigma subscale. Further analyses were conducted for men and women separately. Results: For the total sample, the full model accounted for 14% of the variance in stigma perception (p <.001). Younger age and higher depression scores were the only significant predictors (both p <.001). This pattern was also seen for the men in the sample. For the women, only depression was a significant predictor. Depression mediated the relation between stigma and activities of daily living. Conclusions: Younger age (men) and depression (men and women) were the primary predictors of self-perceived stigma in PD. Disease characteristics (motor and ADL) did not contribute to stigma perception. Depression is a potential treatment target for self-perceived stigma in PD. © 2018 Elsevier Ltd

Author Keywords
Depression;  Parkinson’s disease;  Stigma

Document Type: Article in Press
Source: Scopus