WashU weekly Neuroscience publications

Polygenic risk for anxiety influences anxiety comorbidity and suicidal behavior in bipolar disorder
(2020) Translational Psychiatry, 10 (1), art. no. 298, .

Lopes, F.L.^a , Zhu, K.^a , Purves, K.L.^b , Song, C.^a , Ahn, K.^a , Hou, L.^a , Akula, N.^a , Kassem, L.^a , Bergen, S.E.^c , Landen, M.^c d , Veras, A.B.^e , Nardi, A.E.^e , Alliey-Rodriguez, N.^f , Badner, J.A.^f , Berrettini, W.^g , Byerley, W.^h , Coryell, W.ⁱ , Craig, D.W.^j , Edenberg, H.J.^k , Foroud, T.^l , Gershon, E.S.^f , Greenwood, T.A.^m , Guo, Y.ⁿ , Keating, B.J.^o , Koller, D.L.^l , Lawson, W.B.^p , Liu, C.^q , Mahon, P.B.^r , McInnis, M.G.^s , Murray, S.S.^t , Nurnberger, J.L., Jr.^u , Nwulia, E.A.^v , Panganiban, C.B.^j , Rice, J.^w , Schork, N.J.^j x y , Smith, E.N.^z aa , Zhang, P.^ab , Zöllner, S.^s ab , Goes, F.S.^r , Kelsoe, J.R.^m , Nievergelt, C.M.^m , Potash, J.B.^m r , Shekhtman, T.^m , Schilling, P.D.^ac ad , Zandi, P.P.^ae , McMahon, F.J.^a , Bipolar Genome Study Consortium (BiGS)^af

^a Intramural Research Program, National Institute of Mental Health, National Institutes of Health, US Department of Health & Human Services, Bethesda, MD, United States
^b King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, London, United Kingdom
^c Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
^d Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
^e Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil
^f Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, United States
^g Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, United States
^h Department of Psychiatry, University of California at San Francisco, San Francisco, CA, United States
ⁱ University of Iowa Hospitals and Clinics, Iowa City, IA (Coryell), United States
^j The Translational Genomics Research Institute, Phoenix, AZ, United States
^k Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
^l Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^m Department of Psychiatry, University of California San Diego, San Diego, CA, United States
ⁿ Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States
^o Institute for Translational Medicine and Therapeutics, School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^p Dell Medical School, University of Texas at Austin, Austin, TX, United States
^q Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, United States
^r Department of Psychiatry and Behavioral Sciences, John Hopkins School of Medicine, Baltimore, MD, United States
^s Department of Psychiatry, University of Michigan, Ann Arbor, MI, United States
^t Department of Pathology, University of California San Diego, La Jolla, United States
^u Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^v Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, United States
^w Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^x University of California, San Diego, La Jolla, CA, United States
^y J. Craig Venter Institute, La Jolla, CA, United States
^z Scripps Genomic Medicine & The Scripps Translational Sciences Institute (STSI), La Jolla, CA, United States
^aa Department of Pediatrics and Rady’s Children’s Hospital, School of Medicine, University of California San Diego, La Jolla, CA, United States
^ab Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, United States
^ac Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
^ad Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden
^ae Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States

Abstract
Bipolar disorder is often comorbid with anxiety, which is itself associated with poorer clinical outcomes, including suicide. A better etiologic understanding of this comorbidity could inform diagnosis and treatment. The present study aims to test whether comorbid anxiety in bipolar disorder reflects shared genetic risk factors. We also sought to assess the contribution of genetic risk for anxiety to suicide attempts in bipolar disorder. Polygenic risk scores (PRS) were calculated from published genome-wide association studies of samples of controls and cases with anxiety (n = 83,566) or bipolar disorder (n = 51,710), then scored in independent target samples (total n = 3369) of individuals with bipolar disorder who reported or denied lifetime anxiety disorders or suicidal attempts in research interviews. Participants were recruited from clinical and nonclinical settings and genotyped for common genetic variants. The results show that polygenic risk for anxiety was associated with comorbid anxiety disorders and suicide attempts in bipolar disorder, while polygenic risk for bipolar disorder was not associated with any of these variables. Our findings point out that comorbid anxiety disorders in bipolar disorder reflect a dual burden of bipolar and anxiety-related genes; the latter may also contribute to suicide attempts. Clinical care that recognizes and addresses this dual burden may help improve outcomes in people living with comorbid bipolar and anxiety disorders. © 2020, The Author(s).

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

Using electrodiagnostics to define injury patterns amenable to nerve transfer surgery in tetraplegia: an illustrative case report
(2020) Spinal Cord Series and Cases, 6 (1), art. no. 78, .

Hill, E.J.R.^a , El-Haj, M.^b , Giles, J.A.^c , Fox, I.K.^a

^a Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b Hand and Microvascular Surgery Unit, Hadassah University Hospital, Jerusalem, Israel
^c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Introduction: Spinal cord injury is a devastating condition affecting a person’s independence and quality of life. Nerve transfers are increasingly used to restore critical upper extremity function. Electrodiagnostic studies guide operative planning but the implications for clinical outcomes is not well defined. This case study delineates how clinical examination and electrodiagnostics can define the varying patterns of neuronal injury to guide timing and strategy for optimal outcomes in nerve transfers. Case presentation: We discuss a 20-year-old man with a C6–7 spinal cord injury (SCI). We illustrate how history, physical examination, and electrodiagnostic studies predicted patterns of upper and lower motor neuron injury, confirmed intraoperatively via direct nerve stimulation. We undertook brachialis nerve transfer to the median fascicles supplying flexor digitorum superficialis and anterior interosseous nerve (to restore digit flexion), and supinator nerve transfer to posterior interosseous nerve (to restore digit extension). Preoperative electrodiagnostics of the right upper extremity demonstrated a pure upper motor neuron injury to median innervated muscles, and mixed upper and lower motor neuron injury to radial innervated muscles. These findings were confirmed via intraoperative direct neuromuscular stimulation. The preoperative studies provided important information regarding the anatomic basis and time sensitivity of the proposed nerve transfers. At 2 years post operatively the reconstructed digit flexion and extension resulted in improved hand function and independence. Discussion: Upper and lower motor neuron injuries can coexist in individuals with SCI. This example provides proof-of-concept that preoperative electrodiagnostic studies predict LMN injury, and surgery can achieve positive outcomes if completed soon after SCI. © 2020, International Spinal Cord Society.

Document Type: Article
Publication Stage: Final
Source: Scopus

Explosive sensing with insect-based biorobots
(2020) Biosensors and Bioelectronics: X, 6, art. no. 100050, .

Saha, D.^a , Mehta, D.^a , Altan, E.^a , Chandak, R.^a , Traner, M.^a , Lo, R.^a , Gupta, P.^c , Singamaneni, S.^c , Chakrabartty, S.^a b , Raman, B.^a b

^a Department of Biomedical Engineering, Washington University in St. Louis, United States
^b Department of Electrical and Systems Engineering, Washington University in St. Louis, United States
^c Department of Mechanical Engineering and Material Science, Washington University in St. Louis, United States

Abstract
Stand-off chemical sensing is an important capability with applications in several domains including homeland security. Engineered devices for this task, popularly referred to as electronic noses, have limited capacity compared to the broad-spectrum abilities of the biological olfactory system. Therefore, we propose a hybrid bio-electronic solution that directly takes advantage of the rich repertoire of olfactory sensors and sophisticated neural computational framework available in an insect olfactory system. We show that select subsets of neurons in the locust (Schistocerca americana) brain were activated upon exposure to various explosive chemical species (such as DNT and TNT). Responses from an ensemble of neurons provided a unique, multivariate fingerprint that allowed discrimination of explosive vapors from non-explosive chemical species and from each other. Notably, target chemical recognition could be achieved within a few hundred milliseconds of exposure. In sum, our study provides the first demonstration of how biological olfactory systems (sensors and computations) can be hijacked to develop a cyborg chemical sensing approach. © 2020 The Authors

Author Keywords
Chemical sensing;  Explosives detection;  Insect-based machine olfaction;  Neural engineering;  Neural signals;  Pattern recognition

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

WU-NEAT: A clinically validated, open-source MATLAB toolbox for limited-channel neonatal EEG analysis
(2020) Computer Methods and Programs in Biomedicine, 196, art. no. 105716, .

Vesoulis, Z.A.^a , Gamble, P.G.^a , Jain, S.^b , Ters, N.M.E.^a , Liao, S.M.^a , Mathur, A.M.^c

^a Department of Pediatrics, Division of Newborn Medicine, Washington University School of Medicine, 1 Children’s Place, Campus Box 8116, St. LouisMO 63110, United States
^b Department of Neurology, Division of Pediatric Neurology, Washington University School of Medicine, United States
^c Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Saint Louis University School of Medicine, United States

Abstract
Background: Limited-channel EEG research in neonates is hindered by lack of open, accessible analytic tools. To overcome this limitation, we have created the Washington University-Neonatal EEG Analysis Toolbox (WU-NEAT), containing two of the most commonly used tools, provided in an open-source, clinically-validated package running within MATLAB. Methods: The first algorithm is the amplitude-integrated EEG (aEEG), which is generated by filtering, rectifying and time-compressing the original EEG recording, with subsequent semi-logarithmic display. The second algorithm is the spectral edge frequency (SEF), calculated as the critical frequency below which a user-defined proportion of the EEG spectral power is located. The aEEG algorithm was validated by three experienced reviewers. Reviewers evaluated aEEG recordings of fourteen preterm/term infants, displayed twice in random order, once using a reference algorithm and again using the WU-NEAT aEEG algorithm. Using standard methodology, reviewers assigned a background pattern classification. Inter/intra-rater reliability was assessed. For the SEF, calculations were made using the same fourteen recordings, first with the reference and then with the WU-NEAT algorithm. Results were compared using Pearson’s correlation coefficient. Results: For the aEEG algorithm, intra- and inter-rater reliability was 100% and 98%, respectively. For the SEF, the mean±SD Pearson correlation coefficient between algorithms was 0.96±0.04. Conclusion: We have demonstrated a clinically-validated toolbox for generating the aEEG as well as calculating the SEF from EEG data. Open-source access will enable widespread use of common analytic algorithms which are device-independent and unlikely to become outdated as technology changes, thereby facilitating future collaborative research in neonatal EEG. © 2020

Author Keywords
EEG;  MATLAB;  Neonates;  Open source;  Quantitative methods;  Spectral edge frequency

Document Type: Article
Publication Stage: Final
Source: Scopus

Brain connectivity and socioeconomic status at birth and externalizing symptoms at age 2 years
(2020) Developmental Cognitive Neuroscience, 45, art. no. 100811, .

Ramphal, B.^a , Whalen, D.J.^b , Kenley, J.K.^c , Yu, Q.^b , Smyser, C.D.^c d e , Rogers, C.E.^b e , Sylvester, C.M.^b

^a New York State Psychiatric Institute and Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York, NY, 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 Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Low childhood socioeconomic status (SES) predisposes individuals to altered trajectories of brain development and increased rates of mental illness. Brain connectivity at birth is associated with psychiatric outcomes. We sought to investigate whether SES at birth is associated with neonatal brain connectivity and if these differences account for socioeconomic disparities in infant symptoms at age 2 years that are predictive of psychopathology. Resting state functional MRI was performed on 75 full-term and 37 term-equivalent preterm newborns (n = 112). SES was characterized by insurance type, the Area Deprivation Index, and a composite score. Seed-based voxelwise linear regression related SES to whole-brain functional connectivity of five brain regions representing functional networks implicated in psychiatric illnesses and affected by socioeconomic disadvantage: striatum, medial prefrontal cortex (mPFC), ventrolateral prefrontal cortex (vlPFC), and dorsal anterior cingulate cortex. Lower SES was associated with differences in striatum and vlPFC connectivity. Striatum connectivity with frontopolar and medial PFC mediated the relationship between SES and behavioral inhibition at age 2 measured by the Infant-Toddler Social Emotional Assessment (n = 46). Striatum-frontopolar connectivity mediated the relationship between SES and externalizing symptoms. These results, convergent across three SES metrics, suggest that neurodevelopmental trajectories linking SES and mental illness may begin as early as birth. © 2020

Author Keywords
Externalizing;  Functional connectivity;  Neonatal neuroimaging;  Prefrontal cortex;  Socioeconomic status;  Striatum

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

Patient Feedback on the Effectiveness of Auricular Acupuncture on Pain in Routine Clinical Care: The Experience of 11,406 Veterans
(2020) Medical Care, 58 Suppl 2 9S, pp. S101-S107.

Zeliadt, S.B.^a b , Thomas, E.R.^a , Olson, J.^c , Coggeshall, S.^a , Giannitrapani, K.^d , Ackland, P.E.^e f , Reddy, K.P.^g h , Federman, D.G.^i j , Drake, D.F.^k l m , Kligler, B.^l n , Taylor, S.L.^o p

^a Center of Innovation for Veteran-Centered and Value-Driven Care, VA Puget Sound Health Care System
^b Department of Health Services, School of Public Health, University of Washington, Seattle, WA
^c VA Central Iowa Health Care System, IA, Des Moines, United States
^d Center for Innovation to Implementation, Palo Alto VA Health Care System, Palo Alto, CA
^e Center for Care Delivery and Outcomes Research, Minneapolis VA Health Care System
^f Department of Medicine, University of Minnesota, MN, Minneapolis, United States
^g John Cochran Veterans Hospital, VA St. Louis Health Care System
^h Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO
ⁱ VA Connecticut Health Care System
^j Yale University School of Medicine, CT, New Haven, United States
^k Department of Physical Medicine and Rehabilitation, Hunter Holmes McGuire VA Medical Center, VA, Richmond
^l Integrative Health Coordinating Center, Veterans Health Administration, DCWA
^m Department of Physical Medicine and Rehabilitation, Virginia Commonwealth University, VA, Richmond
ⁿ Office of Patient-Centered Care and Cultural Transformation, Veterans Health Administration, DCWA
^o Center for the Study of Healthcare Innovation, Implementation and Policy, Greater Los Angeles VA Health Care System
^p Department of Health Policy and Management, UCLA School of Public Health, Los Angeles, CA

Abstract
OBJECTIVES: Veterans Health Administration (VHA) launched a national initiative to train providers in a specific, protocolized auricular acupuncture treatment (also called Battlefield Acupuncture or BFA) as a nonpharmacological approach to pain management. This evaluation assessed the real-world effectiveness of BFA on immediate pain relief and identified subgroups of patients for whom BFA is most effective. RESEARCH DESIGN: In a cross-sectional cohort study, electronic medical record data for 11,406 Veterans treated with BFA at 57 VHA medical centers between October 2016 and September 2018 was analyzed. The multivariate analysis incorporated data on pain history, change in pain level on an 11-point scale, complications, and demographic information. METHODS: A total of 11,406 Veterans were treated with BFA at 57 VHA medical centers between October 2016 and September 2018 and had effectiveness data recorded in their electronic medical record. RESULTS: More than 3 quarters experienced immediate decreases in pain following administration of BFA, with nearly 60% reported experiencing a minimal clinically important difference in pain intensity. The average decrease in pain intensity was -2.5 points (SD=2.2) at the initial BFA treatment, and -2.2 points (SD=2.0) at subsequent treatments. BFA was effective across a wide range of Veterans with many having preexisting chronic pain, or physical, or psychological comorbid conditions. Veterans with opioid use in the year before BFA experienced less improvement, with pain intensity scores improving more among Veterans who had not recently used opioids. CONCLUSION: VHA’s rapid expansion of training providers to offer BFA as a nonpharmacological approach to pain management has benefited many Veterans.

Document Type: Article
Publication Stage: Final
Source: Scopus

Bilateral Subthalamic Nucleus Deep Brain Stimulation in Elderly Patients With Parkinson Disease: A Case-Control Study
(2020) Operative Neurosurgery (Hagerstown, Md.), 19 (3), pp. 234-240.

Mitchell, K.T.^a , Younce, J.R.^a , Norris, S.A.^a b , Tabbal, S.D.^a c , Dowling, J.L.^d , Rich, K.M.^d , Perlmutter, J.S.^{a b e f g} , Ushe, M.^a

^a Department of Neurology, 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 Department of Neurology, American University of Beirut, Beirut, Lebanon
^d Department of Neurological Surgery, 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 Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
^g Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an effective adjunctive therapy for Parkinson disease. Studies have shown improvement of motor function but often exclude patients older than 75 yr. OBJECTIVE: To determine the safety and effectiveness of STN DBS in patients 75 yr and older. METHODS: A total of 104 patients (52 patients >75 yr old, 52 patients <75 yr old) with STN DBS were paired and retrospectively analyzed. The primary outcome was change in Unified Parkinson Disease Rating Scale (UPDRS) subscale III at 1 yr postoperatively, OFF medication. Secondary outcomes were changes in UPDRS I, II, and IV subscales and levodopa equivalents. Complications and all-cause mortality were assessed at 30 d and 1 yr. RESULTS: Both cohorts had significant improvements in UPDRS III at 6 mo and 1 yr with no difference between cohorts. Change in UPDRS III was noninferior to the younger cohort. The cohorts had similar worsening in UPDRS I at 1 yr, no change in UPDRS II, similar improvement in UPDRS IV, and similar levodopa equivalent reduction. There were similar numbers of postoperative intracerebral hemorrhages (2/52 in each cohort, more severe in the older cohort) and surgical complications (4/52 in each cohort), and mortality in the older cohort was similar to an additional matched cohort not receiving DBS. CONCLUSION: STN DBS provides substantial motor benefit and reduction in levodopa equivalents with a low rate of complications in older patients, which is also noninferior to the benefit in younger patients. STN DBS remains an effective therapy for those over 75 yr. Copyright © 2020 by the Congress of Neurological Surgeons.

Author Keywords
Deep brain stimulation;  Parkinson disease

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

Should Aspirin Be Prescribed to Prevent Recurrence in Nonarteritic Anterior Ischemic Optic Neuropathy?
(2020) Journal of Neuro-Ophthalmology: The Official Journal of the North American Neuro-Ophthalmology Society, 40 (3), pp. 428-433.

Egan, R.A., Arnold, A.C., Lee, A.G., Van Stavern, G.P.

MultiCare Rockwood Clinic (RE), Spokane, Washington; Department of Ophthalmology (ACA), Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, California; Blanton Eye Institute (AGL), Houston Methodist Hospital, Houston, Texas; and Department of Ophthalmology and Visual Sciences (GVS), Washington University in St. Louis, St. Louis, Missouri

Document Type: Article
Publication Stage: Final
Source: Scopus

Indentation and Transverse Diameter of the Meckel Cave: Imaging Markers to Diagnose Idiopathic Intracranial Hypertension
(2020) AJNR. American Journal of Neuroradiology, 41 (8), pp. 1487-1494.

Kamali, A.^a , Sullivan, K.C.^b , Rahmani, F.^c , Gandhi, A.^d , Aein, A.^a , Arevalo, O.^a , Rabiei, P.^a , Choi, S.J.^b , Zhang, X.^a , Gabr, R.E.^a , Riascos, R.F.^a

^a From the Department of Diagnostic Radiology (A.K., A.A., O.A., P.R., R.E.G., University of Texas at Houston, Houston, TX
^b University of Texas Medical School Health Science Center Houston (K.C.S., Houston, TX
^c Neuroimaging Laboratory at Mallinckrodt Institute of Radiology (F.R.), Washington University School of Medicine, St. Louis, MO, United States
^d Rice University (A.G.), Houston, TX

Abstract
BACKGROUND AND PURPOSE: Clinical and imaging manifestations of idiopathic intracranial hypertension should prompt early diagnosis and treatment to avoid complications. Multiple diagnostic imaging criteria are reported to suggest the diagnosis of idiopathic intracranial hypertension with questionable sensitivity and/or specificity. Increased intracranial pressure results in dilation of the perineural cisternal spaces such as the optic nerve sheaths and the Meckel cave. It may also cause protrusion of cisternal structures of the Meckel cave through the skull base foramina, which could result in indentation or a bilobed appearance of the Meckel cave. We investigated the changes in the Meckel cave in patients with proved idiopathic intracranial hypertension versus healthy controls. MATERIALS AND METHODS: We studied 75 patients with a diagnosis of idiopathic intracranial hypertension and 75 age-and sex-matched healthy controls. The transverse diameter of Meckel cave was measured in the axial and coronal planes of T2-weighted MR imaging sequences, and comparison was made between the 2 groups. RESULTS: The mean diameters of the Meckel cave on the coronal T2 plane in patients with idiopathic intracranial hypertension were 5.21  ± 1.22 mm on the right side and 5.16  ± 0.90 mm on the left side, while in the control group, they measured 3.89  ± 0.62 mm and 4.09  ± 0.68 mm, respectively (P value < .001). Of 75 patients with an approved diagnosis of idiopathic intracranial hypertension, 57 (76%) showed an indented Meckel cave as opposed to 21 (28%) in the control group. CONCLUSIONS: Our results confirm for the first time that the shape and size of the Meckel cave can be used as sensitive and specific diagnostic imaging markers for the diagnosis of idiopathic intracranial hypertension. © 2020 by American Journal of Neuroradiology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of Isolated Congenital Heart Disease with Fetal Brain Maturation
(2020) AJNR. American Journal of Neuroradiology, 41 (8), pp. 1525-1531.

Jaimes, C.^a b , Rofeberg, V.^a , Stopp, C.^a , Ortinau, C.M.^c , Gholipour, A.^a b , Friedman, K.G.^a b , Tworetzky, W.^a b , Estroff, J.^a b , Newburger, J.W.^a b , Wypij, D.^a b d , Warfield, S.K.^a b , Yang, E.^a b , Rollins, C.K.^a b

^a From the Departments of Radiology (C.J., A.G., Cardiology (V.R., C.S., K.G.F., Neurology (C.K.R.), Fetal-Neonatal Neuroimaging and Developmental Science Center (C.J.), Boston Children’s Hospital, Boston, MA
^b Radiology (C.J., A.G., Pediatrics (K.G.F., Neurology (C.K.R.), Harvard Medical School, Boston, MA
^c Pediatrics (C.M.O.), Washington University in St. Louis, St. Louis, MO, United States
^d Biostatistics (D.W.), Harvard T.H. Chan School of Public Health, Boston, MA

Abstract
BACKGROUND AND PURPOSE: Brain MRI of newborns with congenital heart disease show signs of immaturity relative to healthy controls. Our aim was to determine whether the semiquantitative fetal total maturation score can detect abnormalities in brain maturation in fetuses with congenital heart disease in the second and third trimesters. MATERIALS AND METHODS: We analyzed data from a prospective study of fetuses with and without congenital heart disease who underwent fetal MR imaging at 25-35 weeks’ gestation. Two independent neuroradiologists blinded to the clinical data reviewed and scored all images using the fetal total maturation score. Interrater reliability was evaluated by the intraclass correlation coefficient using the individual reader scores, which were also used to calculate an average score for each subject. Comparisons of the average and individual reader scores between affected and control fetuses and relationships with clinical variables were evaluated using multivariable linear regression. RESULTS: Data from 69 subjects (48 cardiac, 21 controls) were included. High concordance was observed between readers with an intraclass correlation coefficient of 0.98 (95% CI, 0.97-0.99). The affected group had significantly lower fetal total maturation scores than the control group (β-estimate, -0.9 [95% CI, -1.5 to -0.4], P = .002), adjusting for gestational age and sex. Averaged fetal total maturation, germinal matrix, myelination, and superior temporal sulcus scores were significantly delayed in fetuses with congenital heart disease versus controls (P < .05 for each). The fetal total maturation score was not significantly associated with any cardiac, anatomic, or physiologic variables. CONCLUSIONS: The fetal total maturation score is sensitive to differences in brain maturation between fetuses with isolated congenital heart disease and healthy controls. © 2020 by American Journal of Neuroradiology.

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

Higher Cortical Dysfunction Presenting as Visual Symptoms in Neurodegenerative Diseases
(2020) Frontiers in Neurology, 11, art. no. 679, .

Liu, Y.^a b , Pelak, V.S.^c , van Stavern, G.^d , Moss, H.E.^a e

^a Department of Ophthalmology, Stanford University, Palo Alto, CA, United States
^b Department of Ophthalmology and Vision Science, UC Davis Eye Center, University of California, Davis, Sacramento, CA, United States
^c Departments of Neurology and Ophthalmology, University of Colorado, UCHealth Sue Anschutz-Rodgers Eye Center, Aurora, CO, United States
^d Department of Ophthalmology, Washington University, St. Louis, MO, United States
^e Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA, United States

Abstract
Introduction: As the population ages, increasing prevalence of neurodegenerative diseases will have profound implications for the health care system. Recognizing visual symptoms from neurodegenerative diseases can be challenging, especially in the presence of co-existing eye diseases. Methods: A seven-question survey was completed by attendees at the “neurodegenerative diseases in neuro-ophthalmology” symposium during the 2017 North American Neuro-ophthalmology Society annual meeting using a web-based audience response system. Content included demographics, patient prevalence, and perceived barriers. Results: Fifty-five practicing neuro-ophthalmologists (thirty-three ophthalmology-trained, twenty-two neurology-trained) participated in the survey. Twenty (36%) had <5 years of experience, and 19 (32%) had >15 years of experience. Forty-one (75%) reported seeing patients more than five half-day/week. Thirty (55%) reported that at least 1 of 10 or 1 of 20 new patients referred have a prior diagnosis of a neurodegenerative disease. Twenty-one (40%) of the respondents reported attributing visual complaints to higher order effects in at least 25% of patients with a prior diagnosis of neurodegenerative disease vs. five (9%) without a prior diagnosis. For those diagnosed with neurodegenerative disease by the neuro-ophthalmologist, reasons for referral were unknown cause of visual symptom (56%), to confirm diagnosis and/or treat visual complaint due to neurodegeneration (29%), and functional disorder (5%). Perceived barriers to diagnosing visual dysfunction due to neurodegenerative disease included difficulty making a referral to neuropsychologists or behavioral neurologists (73%), lack of time for in-depth assessment (62%), lack of tools to assess visual dysfunction due to neurodegenerative disease (40%), and lack of knowledge about presenting signs and symptoms (31%). Conclusion: Visual symptoms from neurodegenerative disease in patients with and without prior diagnoses of neurodegenerative disease are evaluated by neuro-ophthalmologists. Lack of time, resources, and knowledge are barriers to diagnosis. A larger study is warranted to guide programs to improve diagnosis of visual consequences of neurodegenerative disease. © Copyright © 2020 Liu, Pelak, van Stavern and Moss.

Author Keywords
Alzheimer’s disease (AD);  higher cortical dysfunction;  neurodegenerative diseases;  posterior cortical atrophy (PCA);  visual symptoms

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

Learning to Control Neurons using Aggregated Measurements
(2020) Proceedings of the American Control Conference, 2020-July, art. no. 9147426, pp. 4028-4033.

Yu, Y.-C.^a , Narayanan, V.^a , Ching, S.^a b , Li, J.-S.^a b

^a Washington University in St. Louis, Department of Electrical and Systems Engineering, St. Louis, MO 63130, United States
^b Division of Biology and Biomedical Sciences, Washington University in St. Louis, St. Louis, MO 63130, United States

Abstract
Controlling a population of neurons with one or a few control signals is challenging due to the severely underactuated nature of the control system and the inherent nonlinear dynamics of the neurons that are typically unknown. Control strategies that incorporate deep neural networks and machine learning techniques directly use data to learn a sequence of control actions for targeted manipulation of a population of neurons. However, these learning strategies inherently assume that perfect feedback data from each neuron at every sampling instant are available, and do not scale gracefully as the number of neurons in the population increases. As a result, the learning models need to be retrained whenever such a change occurs. In this work, we propose a learning strategy to design a control sequence by using population-level aggregated measurements and incorporate reinforcement learning techniques to find a (bounded, piecewise constant) control policy that fulfills the given control task. We demonstrate the feasibility of the proposed approach using numerical experiments on a finite population of nonlinear dynamical systems and canonical phase models that are widely used in neuroscience. © 2020 AACC.

Document Type: Conference Paper
Publication Stage: Final
Source: Scopus

COVID-19 in Patients With Seizures and Epilepsy: Interpretation of Relevant Knowledge of Presenting Signs and Symptoms
(2020) Epilepsy Currents, .

Hogan, R.E.^a , Grinspan, Z.^b , Axeen, E.^c , Marquis, B.^d , Day, B.K.^e

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Population Health Sciences and Pediatrics, Weill Cornell Medicine, New York, NY, United States
^c University of Virginia HealthVA, United States
^d Pediatrics, Weill Cornell Medicine, New York, NY, United States
^e Epilepsy Fellowship, Washington University School of Medicine, St. Louis, MO, United States

Abstract
There are an increasing number of clinical studies for COVID-19, with several large cohort studies documenting initial signs and symptoms. Realizing the need for current information, this summary provides a focused summary of pertinent clinical diagnostic information about neurological involvement of SARS-CoV-2 virus and clinical presentation of COVID-19, especially in relationship to patients with seizures and epilepsy. There is no evidence from cohort studies in the general population that seizures are worsened in COVID-19. However, relative lack of cohort studies in patients with a history of epileptic seizures limit conclusions about effects of COVID-19 patients with epilepsy. Overall, findings indicate seizures and epilepsy are rare, especially in mild COVID-19 cases, but may occur in more severe cases later in the disease course. Caregivers should be vigilant in assessing for possible seizures, especially in patients with systemic effects of severe COVID-19 infections. © The Author(s) 2020.

Author Keywords
COVID-19;  epilepsy;  seizures;  signs;  symptoms

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

Sleep quality and prostate cancer aggressiveness: Results from the REDUCE trial
(2020) Prostate, .

Wiggins, E.K.^a , Oyekunle, T.^a b , Howard, L.E.^a b , Markt, S.C.^c , Mucci, L.A.^d , Bliwise, D.L.^e , Moreira, D.M.^f , Andriole, G.L.^g , Hopp, M.L.^h , Freedland, S.J.^a h , Allott, E.H.^i j

^a Division of Urology, Durham Veterans Affairs Health Care System, Durham, NC, United States
^b Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, NC, United States
^c Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, United States
^d Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, United States
^e Department of Neurology, Emory University School of Medicine, Atlanta, GA, Georgia
^f Department of Urology, University of Illinois at Chicago, Chicago, IL, United States
^g Division of Urologic Surgery, Department of Surgery, Washington University School of Medicine, St Louis, MO, United States
^h Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
ⁱ Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom
^j Department of Histopathology and Morbid Anatomy, Trinity College Dublin, Trinity Translational Medicine Institute, Dublin, Ireland

Abstract
Background: Disrupted sleep has been associated with increased risk of certain cancers. Little data exist in prostate cancer. We tested the association between sleep quality and prostate cancer diagnosis overall and by tumor grade in the Reduction by Dutasteride of Prostate Cancer Events chemoprevention trial. We hypothesized that worse sleep quality would be associated with increased tumor aggressiveness. Methods: At baseline, 5614 men completed a validated six-item questionnaire on sleep quality. We generated a composite score categorized into tertiles to measure overall sleep quality and assessed each sleep quality question individually. Logistic regression was used to test associations between baseline sleep quality and overall, low-grade and high-grade prostate cancer diagnosis at 2-year study-mandated biopsy. Models were stratified by nocturia. Results: Overall sleep quality was unrelated to overall or low-grade prostate cancer. Worse overall sleep quality was associated with elevated odds of high-grade prostate cancer (odds ratio [OR]T3vsT1 1.15; 95% confidence interval [CI]: 0.83-1.60 and ORT2vsT1 1.39; 95% CI: 1.01-1.92). Men reporting trouble falling asleep at night sometimes vs never had elevated odds of high-grade prostate cancer (OR: 1.51; 95% CI: 1.08-2.09) while trouble staying awake during the day was associated with decreased odds of low-grade prostate cancer (OR: 0.65; 95% CI: 0.49-0.86). Results were similar within strata of nocturia severity. Conclusions: Overall, associations between sleep quality and prostate cancer were inconsistent. However, there was some evidence for a positive association between insomnia and high-grade prostate cancer, and an inverse relationship between daytime sleepiness and low-grade prostate cancer; findings that should be validated by future studies. © 2020 Wiley Periodicals LLC

Author Keywords
insomnia;  prostate biopsy;  prostate cancer;  sleep disturbance;  sleep quality;  tumor grade

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

Massively Parallel Reporter Assays: Defining Functional Psychiatric Genetic Variants Across Biological Contexts
(2020) Biological Psychiatry, .

Mulvey, B.^a b c , Lagunas, T., Jr.^a b c , Dougherty, J.D.^b c

^a Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Neuropsychiatric phenotypes have long been known to be influenced by heritable risk factors, directly confirmed by the past decade of genetic studies that have revealed specific genetic variants enriched in disease cohorts. However, the initial hope that a small set of genes would be responsible for a given disorder proved false. The more complex reality is that a given disorder may be influenced by myriad small-effect noncoding variants and/or by rare but severe coding variants, many de novo. Noncoding genomic sequences—for which molecular functions cannot usually be inferred—harbor a large portion of these variants, creating a substantial barrier to understanding higher-order molecular and biological systems of disease. Fortunately, novel genetic technologies—scalable oligonucleotide synthesis, RNA sequencing, and CRISPR (clustered regularly interspaced short palindromic repeats)—have opened novel avenues to experimentally identify biologically significant variants en masse. Massively parallel reporter assays (MPRAs) are an especially versatile technique resulting from such innovations. MPRAs are powerful molecular genetics tools that can be used to screen thousands of untranscribed or untranslated sequences and their variants for functional effects in a single experiment. This approach, though underutilized in psychiatric genetics, has several useful features for the field. We review methods for assaying putatively functional genetic variants and regions, emphasizing MPRAs and the opportunities they hold for dissection of psychiatric polygenicity. We discuss literature applying functional assays in neurogenetics, highlighting strengths, caveats, and design considerations—especially regarding disease-relevant variables (cell type, neurodevelopment, and sex), and we ultimately propose applications of MPRA to both computational and experimental neurogenetics of polygenic disease risk. © 2020 Society of Biological Psychiatry

Author Keywords
Enhancer;  GWAS;  Noncoding variants;  Polygenicity;  Reporter assay;  UTR

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

Adverse event profile differences between rituximab and ocrelizumab: Findings from the FDA Adverse Event Reporting Database
(2020) Multiple Sclerosis Journal, .

Caldito, N.G.^a , Shirani, A.^b , Salter, A.^c , Stuve, O.^d e

^a Department of Neurology Neurotherapeutics, Immunology Graduate Program, University of Texas Southwestern Medical C, enter, Dallas, TX, United States
^b Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, United States
^c Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurology Neurotherapeutics, Immunology Graduate Program, University of Texas Southwestern, Medical Center, Dallas, TX, United States
^e /Neurology Section, VA North Texas Health Care System, Dallas, TX, United States

Abstract
Background: Rituximab and ocrelizumab are anti-CD20 monoclonal antibodies that have shown a marked reduction in multiple sclerosis (MS) inflammatory activity. However, their real-world safety profile has not been adequately compared. Objective: To investigate the adverse event (AE) profile of rituximab and ocrelizumab reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Methods: The FAERS database was filtered by indication (MS) and drug (rituximab or ocrelizumab). Disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted to identify drug–AE associations. A signal was detected if the lower limit of the 95% confidence interval of ROR (ROR025) exceeded 1. Results: There were 623 and 7948 reports for rituximab and ocrelizumab, respectively. The most frequent AEs with rituximab and ocrelizumab were infusion-related reaction (4.82%) and urinary tract infection (10.52%), respectively. The strongest drug–AE association for rituximab and ocrelizumab were ear pruritus (ROR025: 47.53) and oral herpes (ROR025: 38.99), respectively. Ocrelizumab was associated with an almost two times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively). Conclusion: This study revealed differences in reporting AEs between rituximab and ocrelizumab. Infections were reported more frequently with ocrelizumab. Although speculative, a potentially different or more extensive B-cell depletion by ocrelizumab might explain these findings. Additional pharmacovigilance studies need to be performed to better characterize differences in the AE profile in B-cell-depleting therapies. © The Author(s), 2020.

Author Keywords
adverse event profile;  CD20;  FAERS;  multiple sclerosis;  ocrelizumab;  Rituximab

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

Beyond the classic extinction network: A wider, comparative view
(2020) Neuroforum, pp. 642-1482.

Güntürkün, O.^a , Stüttgen, M.C.^b , Starosta, S.^c , Pusch, R.^a , Gao, M.^a , Nitsche, M.^d , Ernst, T.M.^e , Ladd, M.E.^f , Quick, H.H.^g h , Timmann, D.^e

^a Department of Biopsychology, Faculty for Psychology, Ruhr-University Bochum, Bochum, 44780, Germany
^b Institute of Pathophysiology, University Medical Center, Johannes Gutenberg University, Mainz, Germany
^c Department of Neuroscience, Washington University St. Louis, St. Louis, MO 63110, United States
^d Department of Psychology and Neurosciences, Leibniz Research Centre for Working Environment and Human Factors, Ardeystr. 67, Dortmund, 44139, Germany
^e Department of Neurology, Essen University Hospital, University of Duisburg Essen, Essen, 45147, Germany
^f Division of Medical Physics in Radiology, German Cancer Research Center, Heidelberg, 69120, Germany
^g Erwin L. Hahn Institute for Magnetic Resonance Imaging, University of Duisburg-Essen, Essen, 45141, Germany
^h High-Field and Hybrid Mr Imaging, Essen University Hospital, Essen, 45147, Germany

Abstract
Extinction learning modifies the dynamics of brain circuits such that a previously learned conditioned response is no longer generated. The majority of extinction studies use fear conditioning in rodents and identified the prefrontal cortex, the hippocampus, and the amygdala as core regions of the extinction circuit. We sought to find answers to two questions: First, do we find a similar functional brain circuit in birds, which underwent a 300-million-year separate evolution from mammals? Second, do we have to incorporate the cerebellum as a key component of the central extinction circuit? We indeed show that the avian extinction pathways are not identical but highly similar to those of mammals. In addition, we reveal that the human cerebellum processes prediction errors, a key element driving extinction of learned fear responses, and contributes to context-related effects of extinction. © 2020 Onur Güntürkün et al.

Author Keywords
cerebellum;  context learning;  eyeblink conditioning;  pigeons;  prediction error

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

Expanding the clinical and genetic spectrum of CAD deficiency: an epileptic encephalopathy treatable with uridine supplementation
(2020) Genetics in Medicine, .

Rymen, D.^a , Lindhout, M.^b , Spanou, M.^c , Ashrafzadeh, F.^d , Benkel, I.^e , Betzler, C.^f g , Coubes, C.^h , Hartmann, H.ⁱ , Kaplan, J.D.^j k , Ballhausen, D.^l , Koch, J.^m , Lotte, J.^f , Mohammadi, M.H.ⁿ , Rohrbach, M.^o , Dinopoulos, A.^c , Wermuth, M.^p , Willis, D.^q , Brugger, K.^m , Wevers, R.A.^r , Boltshauser, E.^s , Bierau, J.^b , Mayr, J.A.^m , Wortmann, S.B.^m t

^a Metabolic Center, University Hospitals Leuven, Leuven, Belgium
^b Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, Netherlands
^c 3rd Paediatric Department, Attikon University Hospital, Athens, Greece
^d Department of Pediatric Neurology, Mashhad University of Medical Sciences, Mashhad, Iran
^e Klinik für Kinderneurologie und Kinderneurologisches Zentrum, EEG, Sana Kliniken Düsseldorf GmbH, Düsseldorf, Germany
^f Clinic for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany
^g Institute for Transition, Rehabilitation and Palliation, Paracelsus Private Medical University of Salzburg, Salzburg, Austria
^h Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU, Montpellier, France
ⁱ Clinic for Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany
^j Nemours A.I. DuPont Hospital for Children, Department of Pediatrics, Division of Medical Genetics, Delaware, Wilmington, DE, United States
^k Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, MS, United States
^l Pediatric unit for metabolic diseases, Woman–Mother–Child Department, University Hospital Lausanne, Lausanne, Switzerland
^m University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austria
ⁿ Department of Pediatrics, Zabol University of Medical Sciences, Zabol, Iran
^o Division of Metabolism and Children’s Research Centre, University Children’s Hospital, 8032, Zürich, Switzerland
^p Department of Pediatrics, Klinikum Links der Weser, Bremen, Germany
^q Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^r Department Laboratory Medicine, Translational Metabolic Laboratory, Radboudumc, Nijmegen, Netherlands
^s Department of Pediatric Neurology, Children’s University Hospital, Zürich, Switzerland
^t Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children’s Hospital, Radboudumc, Nijmegen, Netherlands

Abstract
Purpose: Biallelic CAD variants underlie CAD deficiency (or early infantile epileptic encephalopathy-50, [EIEE-50]), an error of pyrimidine de novo biosynthesis amenable to treatment via the uridine salvage pathway. We further define the genotype and phenotype with a focus on treatment. Methods: Retrospective case series of 20 patients. Results: Our study confirms CAD deficiency as a progressive EIEE with recurrent status epilepticus, loss of skills, and dyserythropoietic anemia. We further refine the phenotype by reporting a movement disorder as a frequent feature, and add that milder courses with isolated developmental delay/intellectual disability can occur as well as onset with neonatal seizures. With no biomarker available, the diagnosis relies on genetic testing and functional validation in patient-derived fibroblasts. Underlying pathogenic variants are often rated as variants of unknown significance, which could lead to underrecognition of this treatable disorder. Supplementation with uridine, uridine monophosphate, or uridine triacetate in ten patients was safe and led to significant clinical improvement in most patients. Conclusion: We advise a trial with uridine (monophosphate) in all patients with developmental delay/intellectual disability, epilepsy, and anemia; all patients with status epilepticus; and all patients with neonatal seizures until (genetically) proven otherwise or proven unsuccessful after 6 months. CAD deficiency might represent a condition for genetic newborn screening. © 2020, American College of Medical Genetics and Genomics.

Author Keywords
anemia;  developmental delay;  early infantile epileptic encephalopathy-50;  EIEE;  epilepsy

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

Creating an appropriate adaptation of a healthy lifestyle intervention for people after stroke
(2020) Brain Injury, .

Driver, S.^a , McShan, E.^a , Swank, C.^a , Grobe, K.^a , Calhoun, S.^a , Bailey, R.^b , Kramer, K.^c

^a Physical Medicine and Rehabilitation, Baylor Scott and White Institute for Rehabilitation, Dallas, TX, United States
^b Brown School, Washington University in St. Louis, St. Louis, MO, United States
^c Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
Primary Objective: To describe (1) an evidence-based approach to promoting a healthy lifestyle, the Diabetes Prevention Program Group Lifestyle Balance intervention, and (2) our work with input from an Advisory Board of stakeholders to modify the program to meet the unique needs of people post stroke. Research Design: Community-Based Participatory Research Methods and Procedures: An Advisory Board of stakeholders was convened to modify the Group Lifestyle Balance intervention to meet the unique needs of people post stroke. Main Outcomes and Results: The primary adaptations that emerged from the Advisory Board included (1) curriculum emphasis on heart health after stroke, (2) care partner participation, (3) physical activity, dietary, and weight loss modifications specific to people after stroke, and (4) general programmatic recommendations (e.g., wider age range of participants; eligibility based on time since stroke; alternative modes of delivery). Conclusions: Feedback from the diverse group of stakeholders provides the basis for modifying an evidence-based healthy lifestyle intervention to meet the unique needs of people after stroke. Future research efforts should examine the efficacy and effectiveness of the adapted program to prevent weight gain after stroke and reduce the risk of chronic conditions including diabetes, metabolic syndrome, and heart disease. © 2020 Taylor & Francis Group, LLC.

Author Keywords
Cerebrovascular accident;  exercise;  weight loss

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

Emerging Insights into the Distinctive Neuronal Methylome
(2020) Trends in Genetics, .

Clemens, A.W., Gabel, H.W.

Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110-1093, United States

Abstract
The genomes of mammalian neurons are enriched for unique forms of DNA methylation, including exceptionally high levels of non-CG methylation. Here, we review recent studies defining how non-CG methylation accumulates in neurons and is read out by the critical regulator of neuronal transcription, MeCP2. We discuss the role of gene expression and genome architecture in establishing non-CG methylation and highlight emerging mechanistic insights into how non-CG methylation and MeCP2 control transcription. Further, we describe the cell type-specific functions of this methylation and explore growing evidence that disruption of this regulatory pathway contributes to neurodevelopmental disorders. These findings uncover how the distinctive epigenome in neurons facilitates the development and function of the complex mammalian brain. © 2020 Elsevier Ltd

Author Keywords
DNMT3A;  gene regulation;  mCH;  MeCP2;  neurodevelopmental disorders;  non-CG DNA methylation

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

Development of In-Office Laryngeal Nerve Conduction Studies: Computed Tomography and Cadaveric Study
(2020) Laryngoscope, .

Bhatt, N.K.^a , Wu, F.M.^a , Darki, L.^b , O’Dell, K.^a , Paniello, R.C.^c , Johns, M.M., III^a

^a Tina and Rick Caruso Department of Otolaryngology–Head and Neck Surgery, University of Southern California, Los Angeles, CA, United States
^b Department of Neurology–Neuromuscular Division, University of Southern California, Los Angeles, CA, United States
^c Department of Otolaryngology–Head and Neck Surgery, Washington University in Saint Louis, St. Louis, MO, United States

Abstract
Objectives/Hypothesis: In-office recurrent laryngeal nerve conduction studies (NCSs) are a technique that can potentially provide information about laryngeal innervation. NCS is essential in the management of other neuropathies including carpal tunnel syndrome and spinal cord injury. We hypothesize that laryngeal NCS may have similar utility in managing patients with vocal fold paralysis, atrophy, and neurodegenerative disease. NCSs are technically challenging because they require transcervical stimulation of the recurrent laryngeal nerve (RLN). This study combines radiographic data with cadaveric dissection to describe the anatomic parameters for optimal RLN stimulation. Study Design: Radiographic and Cadaveric Study. Methods: Fifty computed tomography scans were reviewed to determine the dimensions for ideal needle electrode placement. These values were compared to measurements from 12 fresh human cadaveric neck dissections. Ultrasound imaging was utilized in select cases. The neck was dissected to assess the accuracy of electrode placement. Results: Radiographically, the mean transcervical depth to the RLN was 33.2 mm ± 8.3 mm in males versus 29.4 mm ± 9.4 mm in females. The working space between the lateral trachea and carotid artery was 15.3 mm ± 3.6 mm on the right and 14.1 mm ± 2.9 mm on the left. After placement of stimulating electrodes into the cadaveric neck, the electrode tips were consistently within 8 mm of the RLN. Ultrasound guidance improved placement accuracy of the stimulating electrode. Conclusions: Laryngeal NCSs can provide detailed and objective information about laryngeal innervation that could dramatically improve the management of various neuropathies. In-office NCSs require technical precision, and this study describes anatomic factors that may affect the feasibility of performing this technique. Level of Evidence: NA Laryngoscope, 2020. © 2020 The American Laryngological, Rhinological and Otological Society, Inc.

Author Keywords
evoked electromyography;  Nerve conduction studies;  neurolaryngology;  vocal paralysis

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

Microstructure of the Dorsal Anterior Cingulum Bundle in Very Preterm Neonates Predicts the Preterm Behavioral Phenotype at 5 Years of Age
(2020) Biological Psychiatry, .

Brenner, R.G.^a b , Smyser, C.D.^b c d , Lean, R.E.^e , Kenley, J.K.^b , Smyser, T.A.^e , Cyr, P.E.P.^a b , Shimony, J.S.^c , Barch, D.M.^c e f , Rogers, C.E.^d e

^a Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Mallinckrot Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: The cingulum bundle (CB), specifically the dorsal anterior portion of the CB, plays an important role in psychiatric illnesses; however, its role during early development is unclear. This study investigated whether neonatal white matter microstructure in the CB and its subregions is associated with subsequent preterm behavioral phenotype symptoms (internalizing, inattention, and social deficits) in very preterm (VPT) children. Methods: Diffusion magnetic resonance imaging data were obtained on a 3T scanner in 138 sleeping nonsedated neonates: 55 full-term neonates (gestational age ≥ 36 weeks) and 83 VPT neonates (gestational age < 30 weeks). The CB was tracked using probabilistic tractography and split into anterior and posterior portions. When children were 5 years of age, parents (n = 80) and teachers (n = 63) of VPT children completed questionnaires of preterm behavioral phenotype symptoms. Linear regression models were used to relate measures of neonatal CB microstructure and childhood preterm behavioral phenotype symptoms (n = 56 parent report, n = 45 teacher report). Results: Mean diffusivity in the anterior and posterior CB was increased in VPT neonates compared with full-term neonates. Increased fractional anisotropy and decreased mean diffusivity in the right anterior CB, but not in the posterior CB, were related to increased preterm behavioral phenotype symptoms in VPT children as reported by parents and teachers. Conclusions: Aberrations in the anterior portion of the right CB may underlie the early development of the preterm behavioral phenotype. This finding provides the foundation for future mechanistic and therapeutic investigations into the role of the anterior cingulum in the development of psychopathology in VPT infants. © 2020 Society of Biological Psychiatry

Author Keywords
ADHD;  Anxiety;  Autism;  DTI;  Neonatal;  Preterm

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

The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis
(2020) Journal of Neurology, .

Chiaravalloti, N.D.^a b , Amato, M.P.^c d , Brichetto, G.^e f , Chataway, J.^g h , Dalgas, U.ⁱ , DeLuca, J.^a b , Meza, C.^j , Moore, N.B.^a , Feys, P.^k , Filippi, M.^l m n o , Freeman, J.^p , Inglese, M.^q r , Motl, R.^s , Rocca, M.A.^l m , Sandroff, B.M.^a s , Salter, A.^t , Cutter, G.^u , Feinstein, A.^j , on behalf of the CogEx Research Team^v

^a Kessler Foundation, 120 Eagle Rock Avenue, Suite 100, East Hanover, NJ 07936, United States
^b Department of Physical Medicine and Rehabilitation, Rutgers New Jersey Medical School, Newark, NJ, United States
^c Department NEUROFARBA, Section Neurosciences, University of Florence, Largo Brambilla 3, Florence, 50134, Italy
^d IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
^e Scientific Research Area, Italian Multiple Sclerosis Foundation (FISM), via Operai 40, Genoa, 16149, Italy
^f AISM Rehabilitation Service, Italian Multiple Sclerosis Society, Genoa, Italy
^g Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences, Queen Square Multiple Sclerosis Centre, University College London, London, WC1B 5EH, United Kingdom
^h National Institute for Health Research, University College London Hospitals, Biomedical Research Centre, London, United Kingdom
ⁱ Exercise Biology, Department of Public Health, Aarhus University, Dalgas Avenue 4, Aarhus, 8000, Denmark
^j Department of Psychiatry, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, ON M5R 3B6, Canada
^k REVAL, Faculty of Rehabilitation Sciences, Hasselt University, Diepenbeek, Belgium
^l Division of Neuroscience, Neuroimaging Research Unit, Institute of Experimental Neurology, IRCSS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, Milan, 20132, Italy
^m Neurology Unit, IRCSS San Raffaele Scientific Institute, Milan, Italy
ⁿ Neurophysiology Unit, IRCSS San Raffaele Scientific Institute, Milan, Italy
^o Vita-Salute San Raffaele University, Milan, Italy
^p Faculty of Health, School of Health Professions, University of Plymouth, Devon, United Kingdom
^q Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
^r Ospedale Policlinico San Martino-IRCCS, Genoa, Italy
^s Department of Physical Therapy, University of Alabama at Birmingham, Birmingham, United States
^t Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
^u Department of Biostatistics, University of Alabama At Birmingham, Birmingham, United States

Abstract
Objective: Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS). Methods: Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe. Participants included 131 individuals with PMS. Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread. During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with measures of depressive symptoms, anxiety symptoms, quality of life, and MS symptomatology that were previously administered pre-pandemic. Results: 4% of respondents reported COVID-19 infection. No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown. While total HADS-depression scores increased significantly at follow-up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression. No significant relationships were noted between disease duration, processing speed ability or EDSS, and changes in symptoms of depression or anxiety. Most participants reported the impact of the virus on their psychological well-being, with a little impact on financial well-being. The perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of MS symptomatology on daily life, as well as changes in depression. Conclusions: Overall, little change was noted in symptoms of depression or anxiety or overall quality of life. © 2020, Springer-Verlag GmbH Germany, part of Springer Nature.

Author Keywords
Anxiety;  COVID-19;  Depression;  Progressive multiple sclerosis;  Quality of life

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

Autism in neurofibromatosis type 1: misuse of covariance to dismiss autistic trait burden
(2020) Developmental Medicine and Child Neurology, .

Morris, S.M.^a , Acosta, M.T.^b , Garg, S.^c , Green, J.^c , Legius, E.^d , North, K.^e , Payne, J.M.^e , Weiss, L.A.^f , Constantino, J.N.^g , Gutmann, D.H.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
^c Royal Manchester Children’s Hospital, Manchester, United Kingdom
^d Department of Human Genetics, KU Leuven, Leuven, Belgium
^e Department of Pediatrics, Murdoch Children’s Research Institute, University of Melbourne, Melbourne, Vic, Australia
^f Department of Psychiatry, Institute for Human Genetics, University of California, San Francisco, CA, United States
^g Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States

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

Small vessel disease more than Alzheimer’s disease determines diffusion MRI alterations in memory clinic patients
(2020) Alzheimer’s and Dementia, .

Finsterwalder, S.^a , Vlegels, N.^b , Gesierich, B.^a , Araque Caballero, M.Á.^a c , Weaver, N.A.^b , Franzmeier, N.^a , Georgakis, M.K.^a , Konieczny, M.J.^a , Koek, H.L.^d , Karch, C.M.^e , Graff-Radford, N.R.^f , Salloway, S.^g , Oh, H.^h , Allegri, R.F.ⁱ , Chhatwal, J.P.^j , Jessen, F.^k l , Düzel, E.^m n , Dobisch, L.^m n , Metzger, C.^m n o , Peters, O.^p q , Incesoy, E.I.^q , Priller, J.^p q , Spruth, E.J.^p q , Schneider, A.^k r , Fließbach, K.^k r , Buerger, K.^a c , Janowitz, D.^a , Teipel, S.J.^s t , Kilimann, I.^s t , Laske, C.^u v , Buchmann, M.^u v , Heneka, M.T.^k r , Brosseron, F.^k r , Spottke, A.^k w , Roy, N.^k , Ertl-Wagner, B.^x y , Scheffler, K.^z , Seo, S.W.^{aa ab ac ad ae} , Kim, Y.^aa ab af , Na, D.L.^{aa ab ae ag} , Kim, H.J.^aa ab ae , Jang, H.^aa ab ae , Ewers, M.^a , Levin, J.^c ah ai , Schmidt, R.^aj , Pasternak, O.^ak , Dichgans, M.^a ai , Biessels, G.J.^b , Duering, M.^a ai

^a Institute for Stroke and Dementia Research, University Hospital, LMU Munich, Munich, Germany
^b Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
^c German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^d Department of Geriatrics, University Medical Center Utrecht, Utrecht, Netherlands
^e Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^f Department of Neurology, Mayo Clinic Jacksonville, Jacksonville, FL, United States
^g Butler Hospital, Providence, RI, United States
^h Department of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Providence, RI, United States
ⁱ Department of Cognitive Neurology, FLENI Institute for Neurological Research, Buenos Aires, Argentina
^j Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^k German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
^l Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany
^m German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
ⁿ Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
^o Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, Magdeburg, Germany
^p German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
^q Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin, Germany
^r Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
^s German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
^t Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
^u German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
^v Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
^w Department of Neurology, University of Bonn, Bonn, Germany
^x Institute of Clinical Radiology, University Hospital, LMU Munich, Munich, Germany
^y Department of Medical Imaging, University of Toronto, Toronto, Canada
^z Department for Biomedical Magnetic Resonance, University of Tübingen, Tübingen, Germany
^aa Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
^ab Neuroscience Center, Samsung Medical Center, Seoul, South Korea
^ac Department of Clinical Research Design and Evaluation, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
^ad Center for Imaging of Neurodegenerative Diseases, University of California, San Francisco, CA, United States
^ae Samsung Alzheimer Research Center, Samsung Medical Center, Seoul, South Korea
^af Department of Neurology, Kangwon National University Hospital, Kangwon National University College of Medicine, Chuncheon, South Korea
^ag Department of Health Sciences and Technology, Samsung Advanced Institute of Health Sciences and Technology, Sungkyunkwan University, Seoul, South Korea
^ah Department of Neurology, University Hospital, LMU Munich, Munich, Germany
^ai Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^aj Department of Neurology, Medical University of Graz, Graz, Austria
^ak Department of Psychiatry and Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

Abstract
Introduction: Microstructural alterations as assessed by diffusion tensor imaging (DTI) are key findings in both Alzheimer’s disease (AD) and small vessel disease (SVD). We determined the contribution of each of these conditions to diffusion alterations. Methods: We studied six samples (N = 365 participants) covering the spectrum of AD and SVD, including genetically defined samples. We calculated diffusion measures from DTI and free water imaging. Simple linear, multivariable random forest, and voxel-based regressions were used to evaluate associations between AD biomarkers (amyloid beta, tau), SVD imaging markers, and diffusion measures. Results: SVD markers were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analysis across all memory clinic samples. Voxel-wise analyses between tau and diffusion measures were not significant. Discussion: In memory clinic patients, the effect of SVD on diffusion alterations largely exceeds the effect of AD, supporting the value of diffusion measures as markers of SVD. © 2020 the Alzheimer’s Association

Author Keywords
Alzheimer’s disease;  biomarker;  cerebral small vessel disease;  diffusion tensor imaging;  free water imaging;  white matter

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

Surgical Technique for Below-knee Amputation with Concurrent Targeted Muscle Reinnervation
(2020) Plastic and Reconstructive Surgery – Global Open, .

Daugherty, T.H.F.^a , Parikh, R.^b , Mailey, B.A.^a , Felder, J.M.^b , Bueno, R.A.^a

^a Institute for Plastic Surgery, Southern Illinois University, School of Medicine, P.O. Box 19653, Springfield, IL 62794, United States
^b Division of Plastic and Reconstructive Surgery, Washington University, School of Medicine, St. Louis, Mo, United States

Abstract
Summary: Targeted muscle reinnervation (TMR) is beneficial for decreasing pain following below-knee amputation (BKA). While most current literature describes the principles behind primary TMR, they provide few principles key to the amputation, as the BKA is usually performed by another surgeon. When the BKA and TMR are performed by the same surgeon, it can be performed through the same surgical access as needed for both procedures. The purpose of this article is to describe our anatomically based BKA technique in the setting of planned primary TMR as performed by 3, single, peripheral nerve plastic surgeons at 2 institutions. Advantages of the single-surgeon technique include efficiency in dissection, preservation of donor nerve length, limited proximal dissection, early identification of recipient motor nerves for coaptation, ability to stimulate these while still under tourniquet, and decreased tourniquet and operative time. This technique is quick, reliable, and reproducible to help promote widespread adoption of TMR at the time of BKA. © 2020 Lippincott Williams and Wilkins. All rights reserved.

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

Perspective on the “African American participation in Alzheimer disease research: Effective strategies” workshop, 2018
(2020) Alzheimer’s and Dementia, .

Denny, A.^a , Streitz, M.^a , Stock, K.^b , Balls-Berry, J.E.^a , Barnes, L.L.^c , Byrd, G.S.^d , Croff, R.^e , Gao, S.^f , Glover, C.M.^c , Hendrie, H.C.^g , Hu, W.T.^h , Manly, J.J.ⁱ , Moulder, K.L.^a , Stark, S.^j , Thomas, S.B.^k , Whitmer, R.^l , Wong, R.^m , Morris, J.C.ⁿ

^a Knight Alzheimer Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
^b Washington University in Saint Louis, Saint Louis, MO, United States
^c Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^d Maya Angelou Center for Health Equity, Wake Forest University School of Medicine, Winston-Salem, NC, United States
^e Layton Aging & Alzheimer’s Disease Center, Department of Neurology, Oregon Health and Science University, Portland, OR, United States
^f Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
^g Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
^h Emory University, Atlanta, GA, United States
ⁱ Department of Neurology, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, New York, NY, United States
^j Department of Occupational Therapy, Washington University School of Medicine, Saint Louis, MO, United States
^k Maryland Center for Health Equity, University of Maryland College Park, College Park, MD, United States
^l Alzheimer’s Disease Research Center, UC Davis School of Medicine, Sacramento, CA, United States
^m Public Health Sciences Brown School, Washington University in Saint Louis, Saint Louis, MO, United States
ⁿ Knight Alzheimer Disease Research Center, Harvey A & Dorismae Hacker Friedman Distinguished of Neurology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
The Washington University School of Medicine Knight Alzheimer Disease Research Center’s “African American Participation in Alzheimer Disease Research: Effective Strategies” Workshop convened to address a major limitation of the ongoing scientific progress regarding Alzheimer’s disease and related dementias (ADRD): participants in most ADRD research programs overwhelmingly have been limited to non-Hispanic white persons, thus precluding knowledge as to how ADRD may be represented in non-white individuals. Factors that may contribute to successful recruitment and retention of African Americans into ADRD research were discussed and organized into actionable next steps as described within this report. © 2020 the Alzheimer’s Association

Author Keywords
African American;  Alzheimer disease;  disparities;  racial differences;  recruitment;  recruitment strategies

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

Reconstruction of Severe Palm Injury with Sensate Medial Plantar Artery Flap and Nerve Grafting
(2020) Plastic and Reconstructive Surgery – Global Open, art. no. e2944, .

Padovano, W.M., Hill, E.J.R., Felder, J.M.

Division of Plastic and Reconstructive Surgery, Department of Surgery, Washington University, School of Medicine, Northwest Tower, 660 South Euclid Avenue, Campus Box 8238, St. Louis, MO 63110, United States

Abstract
Summary: A 28-year-old, healthy man presented with an abrasion injury of the left palm, including a full-thickness glabrous skin defect, an open injury of the carpal tunnel with 50% transection of the median nerve, and a multilevel traction/avulsion injury of the thenar motor branch. He underwent repair with a free medial plantar artery flap, nerve transfer of the palmar cutaneous nerve to the medial plantar cutaneous nerve, grafting of the median nerve, and direct neurotization of the thenar muscles via an end-to-side nerve graft from the median nerve. At 8 months postoperative, both donor and recipient areas had healed completely, and the patient had regained meaningful 2-point discrimination of the palm and fingers, achieved innervation of the thenar muscles, and returned to work as a cook. © 2020 Lippincott Williams and Wilkins. All rights reserved.

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

A Comprehensive Practice Guideline for Magnetic Resonance Imaging Compatibility in Implanted Neuromodulation Devices
(2020) Neuromodulation, .

Sayed, D.^a , Chakravarthy, K.^b c , Amirdelfan, K.^d , Kalia, H.^e f , Meacham, K.^g , Shirvalkar, P.^h i , Falowski, S.^j , Petersen, E.^k , Hagedorn, J.M.^l , Pope, J.^m , Leever, J.ⁿ , Deer, T.^o p

^a University of Kansas Medical Center, Kansas City, KS, United States
^b University of California San Diego, San Diego, CA, United States
^c VA San Diego Healthcare, San Diego, CA, United States
^d Director of Medical Research, IPM Medical Group, Inc., Walnut Creek, CA, United States
^e Rochester Regional Health System, Rochester, NY, United States
^f Department of Physical Medicine & Rehabilitation, University of RochesterNY, United States
^g Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^h Anesthesiology (Pain Management) and Neurology, University of California San Francisco, San Francisco, CA, United States
ⁱ Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
^j Director of Functional Neurosurgery, Neurosurgical Associates of Lancaster, Lancaster, PA, United States
^k Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^l Department of Anesthesiology and Perioperative Medicine, Division of Pain Medicine, Mayo Clinic, Rochester, MN, United States
^m Evolve Restorative Center, Santa Rosa, CA, United States
ⁿ Radiology and Neurology and Neuroradiology Fellowship Program Director, Kansas University Medical Center, Kansas City, KS, United States
^o The Spine and Nerve Center of The Virginias, Charleston, WV, United States
^p Anesthesiology and Pain Medicine, WVU School of Medicine, Morgantown, WV, United States

Abstract
Objectives: The evolution of neuromodulation devices in order to enter magnetic resonance imaging (MRI) scanners has been one of understanding limitations, engineering modifications, and the development of a consensus within the community in which the FDA could safely administer labeling for the devices. In the initial decades of neuromodulation, it has been contraindicated for MRI use with implanted devices. In this review, we take a comprehensive approach to address all the major products currently on the market in order to provide physicians with the ability to determine when an MRI can be performed for each type of device implant. Materials and Methods: We have prepared a narrative review of MRI guidelines for currently marketed implanted neuromodulation devices including spinal cord stimulators, intrathecal drug delivery systems, peripheral nerve stimulators, deep brain stimulators, vagal nerve stimulators, and sacral nerve stimulators. Data sources included relevant literature identified through searches of PubMed, MEDLINE/OVID, SCOPUS, and manual searches of the bibliographies of known primary and review articles, as well as manufacturer-provided information. Results: Guidelines and recommendations for each device and their respective guidelines for use in and around MR environments are presented. Conclusions: This is the first comprehensive guideline with regards to various devices in the market and MRI compatibility from the American Society of Pain and Neuroscience. © 2020 International Neuromodulation Society

Author Keywords
Deep brain stimulation;  dorsal column stimulation;  dorsal root ganglion stimulation;  guideline;  intrathecal pump;  medical devices;  MRI;  spinal cord stimulation

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

Dopamine D2 receptor signaling on iMSNs is required for initiation and vigor of learned actions
(2020) Neuropsychopharmacology, .

Augustin, S.M.^a , Loewinger, G.C.^a b , O’Neal, T.J.^c d , Kravitz, A.V.^c e , Lovinger, D.M.^a

^a Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD 20852, United States
^b Department of Biostatistics, Harvard TH Chan School of Public Health, Boston, MA 02115, United States
^c National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, United States
^d Graduate Program in Neuroscience and Center for Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA 98195, United States
^e Departments of Psychiatry, Anesthesiology, and Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Striatal dopamine D2 receptors (D2Rs) are important for motor output. Selective deletion of D2Rs from indirect pathway-projecting medium spiny neurons (iMSNs) impairs locomotor activities in a task-specific manner. However, the role of D2Rs in the initiation of motor actions in reward seeking and taking is not fully understood, and there is little information about how receptors contribute under different task demands and with different outcome types. The iMSN-D2Rs modulate neuronal activity and synaptic transmission, exerting control on circuit functions that may play distinct roles in action learning and performance. Selective deletion of D2Rs on iMSNs resulted in slower action initiation and response rate in an instrumental conditioning task, but only when performance demand was increased. The iMSN-Drd2KO mice were also slower to initiate swimming in a T-maze procedural learning task but were unimpaired in cognitive function and behavioral flexibility. In contrast, in a Pavlovian discrimination learning task, iMSN-Drd2KO mice exhibited normal acquisition and extinction of rewarded responding. The iMSN-Drd2KO mice showed performance deficits at all phases of rotarod skill learning. These findings reveal that dopamine modulation through iMSN-D2Rs influences the ability to self-initiate actions, as well as the willingness and/or vigor with which these responses are performed. However, these receptors seem to have little influence on simple associative learning or on stimulus-driven responding. The loss of normal D2R roles may contribute to disorders in which impaired dopamine signaling leads to hypokinesia or impaired initiation of specific voluntary actions. © 2020, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

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