WashU weekly Neuroscience publications

Epigenetic regulation in Huntington’s disease
(2021) Neurochemistry International, 148, art. no. 105074, . 

Hyeon, J.W.^a , Kim, A.H.^{a b c d e} , Yano, H.^a b c e

^a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Huntington’s disease (HD) is a devastating and fatal monogenic neurodegenerative disorder characterized by progressive loss of selective neurons in the brain and is caused by an abnormal expansion of CAG trinucleotide repeats in a coding exon of the huntingtin (HTT) gene. Progressive gene expression changes that begin at premanifest stages are a prominent feature of HD and are thought to contribute to disease progression. Increasing evidence suggests the critical involvement of epigenetic mechanisms in abnormal transcription in HD. Genome-wide alterations of a number of epigenetic modifications, including DNA methylation and multiple histone modifications, are associated with HD, suggesting that mutant HTT causes complex epigenetic abnormalities and chromatin structural changes, which may represent an underlying pathogenic mechanism. The causal relationship of specific epigenetic changes to early transcriptional alterations and to disease pathogenesis require further investigation. In this article, we review recent studies on epigenetic regulation in HD with a focus on DNA and histone modifications. We also discuss the contribution of epigenetic modifications to HD pathogenesis as well as potential mechanisms linking mutant HTT and epigenetic alterations. Finally, we discuss the therapeutic potential of epigenetic-based treatments. © 2021 Elsevier Ltd

Author Keywords
DNA methyltransferases (DNMTs);  Epigenetic regulation;  Epigenetic-based therapy;  Huntington’s disease (HD);  Neurodegeneration;  Transcription

Funding details
National Institutes of HealthNIHR01 NS051255, R01 NS111014, R21 NS103509

Examining the patient and caregiver experience with diazepam nasal spray for seizure clusters: Results from an exit survey of a phase 3, open-label, repeat-dose safety study
(2021) Epilepsy and Behavior, 121, art. no. 108013, . 

Penovich, P.^a , Wheless, J.W.^b , Hogan, R.E.^c , Guerra, C.^d , Cook, D.F.^d , Carrazana, E.^d , Rabinowicz, A.L.^d

^a Minnesota Epilepsy Group, 225 Smith Ave N, Suite 201, St. Paul, MN 55102, United States
^b Le Bonheur Children’s Hospital, University of Tennessee Health Science Center, Pediatric Neurology, 49 N Dunlap Ave, 3rd Floor – FOB, Memphis, TN 38105, United States
^c Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, United States
^d Neurelis, Inc., 3430 Carmel Mountain Road, Suite 300, San Diego, CA 92121, United States

Abstract
Background: Ideal rescue treatments for acute treatment of seizure clusters should be easy to administer, so it is important to assess user perceptions of these treatments. Diazepam nasal spray is designed to have a rapid, noninvasive, and socially acceptable route of administration. Patient and caregiver (including care partner) responses to surveys from a phase 3 safety study of diazepam nasal spray are reported. Methods: The study enrolled patients aged 6–65 years with seizure clusters. Surveys distributed to patients and caregivers at study end, completion, or discontinuation collected data on comfort using diazepam nasal spray outside the home, timing of administration and return to their usual selves, and comfort of use compared with rectal diazepam. Safety was assessed. Results: Of 175 patients enrolled at the October 31, 2019, interim cutoff, 158 received diazepam nasal spray. Sixty-seven (42.4%) patients and 84 (53.2%) caregivers responded to the surveys (including 35 matched pairs). Most patients (78.8%, 52/66) responded that they were very comfortable doing activities outside the home with diazepam nasal spray available; 59.4% of patients returned to their usual selves within an hour of administration. Twenty-seven (40.3%) of these patients reported self-administration, 48% doing so at the first sign of a seizure. Administration of diazepam nasal spray was rated extremely or very easy by 93.8% of caregivers. Safety profile was consistent with diazepam rectal gel; no patient discontinued owing to treatment-emergent adverse events. Nasal discomfort was typically mild and transient. Among patients who had used diazepam rectal gel, most were not at all comfortable using it outside the home (86.7%) or at home (64.5%) compared with diazepam nasal spray, whereas caregivers reported that diazepam rectal gel was not at all easy to use compared with diazepam nasal spray. Conclusions: This survey from the phase 3 safety study of diazepam nasal spray shows that patients and caregivers were satisfied with, and more comfortable using, diazepam nasal spray than rectal diazepam in public. NCT02721069. © 2021 The Author(s)

Author Keywords
Care partner;  Caregiver;  Diazepam nasal spray;  Patient;  Seizure cluster;  Survey

Results of the First GNAO1-Related Neurodevelopmental Disorders Caregiver Survey
(2021) Pediatric Neurology, 121, pp. 28-32. 

Axeen, E.^a , Bell, E.^b , Robichaux Viehoever, A.^c , Schreiber, J.M.^d , Sidiropoulos, C.^e , Goodkin, H.P.^f

^a Department of Neurology, University of Virginia, Charlottesville, VA, United States
^b The Bow Foundation, Springfield, VA, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Department of Neurology, Children’s National Medical Center, Washington, DC, United States
^e Department of Neurology, Michigan State University, East Lansing, MI, United States
^f Department of Neurology and Pediatrics, University of Virginia, Charlottesville, VA, United States

Abstract
Background: We sought to expand our knowledge of the clinical spectrum of GNAO1-related neurodevelopmental disorders through a caregiver survey reviewing medical and developmental history and development of epilepsy and movement disorders. Methods: An online survey was administered to caregivers of individuals diagnosed with GNAO1 pathogenic variants. Results: Eighty-two surveys were completed. Nearly all (99%) reported the first symptom of concern by age one year with the most frequently identified concerns as hypotonia (68%), developmental delay (67%), seizures (29%), difficulty feeding (23%), and abnormal movements (20%). All caregivers reported developmental delays with a spectrum of severity. Movement disorders (76%) were more common than epilepsy (52%), although 33% reported both. The onset of seizures tended to be earlier than abnormal movements. Nearly half (48%) of those with any seizures, reported they were no longer having recurrent seizures. No single most effective medication for movement disorders or epilepsy was noted. Ten participants have had deep brain stimulator for their movement disorder, and all indicated positive effects. Conclusions: GNAO1-related neurodevelopmental disorders most often present within the first year of life with nonspecific symptoms of hypotonia or developmental delay. Although associated epilepsy and movement disorders can be severe, GNAO1-associated epilepsy may not always be medically refractory or lifelong. © 2021 Elsevier Inc.

Author Keywords
Developmental and epileptic encephalopathy;  Epilepsy;  Genetic;  GNAO1;  Movement disorder;  Neurodevelopmental disorder

Funding details
AbbVie
Medtronic
Michigan State UniversityMSU

Subdural hemorrhage in a cohort with cerebral sinovenous thrombosis: Application to abusive head trauma
(2021) Child Abuse and Neglect, 117, art. no. 105119, . 

Anderst, J.^a , Carpenter, S.^a , Frazier, T.^a , Appavu, B.^b , Noetzel, M.^c , Beslow, L.A.^d , Sharma, M.^a , International Pediatric Stroke Study Investigators^e

^a Department of Pediatrics, Children’s Mercy Hospital, University of Missouri-Kansas City School of Medicine, Kansas City, MO, United States
^b Department of Pediatrics, University of Arizona College of Medicine, Phoenix Children’s Hospital, Phoenix, AZ, United States
^c Department of Neurology, St. Louis Children’s Hospital, Washington University, St. Louis, MO, United States
^d Departments of Neurology and Pediatrics, Perelman School of Medicine, University of Pennsylvania, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States

Abstract
Background: Cerebral sinovenous thrombosis (CSVT) is a postulated cause of subdural hemorrhage (SDH) that is hypothesized to mimic abusive head trauma (AHT). Minimal data exists directly investigating this relationship. Objectives: To evaluate the frequency of SDH in children with CSVT, identify factors associated with CSVT and SDH, and to assess if any association supports the hypothesis that CSVT causes SDH. Participants and setting: The International Pediatric Stroke Study (IPSS) prospectively collects data on subjects birth to 19 years of age with intracranial thrombosis. Methods: IPSS subjects with CSVT and SDH were compared to those with CSVT and no SDH. For subjects with CSVT and SDH, neuroimaging reports further characterized the findings. In any case with no known risk factors for SDH, neuroimaging studies were reviewed by a pediatric neuroradiologist. Results: Of 216 subjects with CSVT, 20 (9.3%) had SDH. Those with SDH (median age 0.3 years) were younger than those without SDH (median age 4.2 years), p < 0.001. Subjects with CSVT and SDH more frequently had anoxia (OR = 10.8; 95% CI: 1.4, 81.1), head/neck injury (OR = 4.0; 95% CI: 1.3, 12.6), or abnormal consciousness (OR = 3.0; 95% CI: 1.2, 7.6). Of 20 subjects with CSVT and SDH, 19 had known risk factors for SDH. The remaining subject had a chronic SDH identified concomitantly to a newly symptomatic CSVT with accompanying venous infarctions. Conclusions: SDH in the setting of CSVT is typically identified in children with independent risk factors for SDH. This study does not support the hypothesis that CSVT causes SDH. © 2021 Elsevier Ltd

Author Keywords
Abusive head trauma;  Cerebral sinovenous thrombosis;  Child abuse;  Subdural hemorrhage

Chronic hypoxia in pregnant mice impairs the placental and fetal vascular response to acute hypercapnia in BOLD-MRI hemodynamic response imaging
(2021) Placenta, 110, pp. 29-38. 

Ginosar, Y.^a b g , Bromberg, Z.^c g g , Nachmanson, N.^c g g , Ariel, I.^d , Skarzinski, G.^d , Hagai, L.^e , Elchalal, U.^f , Shapiro, J.^a , Abramovitch, R.^c g g

^a Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Ein Karem, And the Faculty of Medicine, Hebrew University, Jerusalem, Israel
^b Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^c The Goldyne Savad Institute of Gene Therapy and MRI Laboratory, Human Biology Research Center, Hadassah Hebrew University Medical Center, Ein Karem, And the Faculty of Medicine, Hebrew University, Jerusalem, Israel
^d Perinatal Pathology Unit, Hadassah Hebrew University Medical Center, Mount Scopus, Jerusalem, Israel
^e Medical Student, Hebrew University-Hadassah Medical School, Ein Karem, Jerusalem, Israel
^f Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Ein Karem, And the Faculty of Medicine, Hebrew University, Jerusalem, Israel
^g The Wohl Institute for Translational Medicine, Hadassah Hebrew University Medical Center, Ein Karem, And the Faculty of Medicine, Hebrew University, Jerusalem, Israel

Abstract
Introduction: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model). Methods: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O2;E13.5–17.5) and early-onset hypoxia (12%O2;E10.5–17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO2). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained. Results: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (−44% ± 7%; p &lt; 0.0001), fetal liver (−32% ± 7%; p &lt; 0.0001) and fetal heart (−54% ± 12%; p &lt; 0.002), with relative fetal brain sparing (−12% ± 5%; p &lt; 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only. Conclusions: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury. © 2021

Author Keywords
Animals;  Fetal asphyxia;  Fetal growth restriction;  Hypercapnia;  Hypoxia;  Magnetic resonance imaging;  MESH terms): mice;  Placenta;  Pregnancy

Funding details
International Anesthesia Research SocietyIARS
Hadassah Medical OrganizationHMO
Israel Science FoundationISF1243/10, 1817/13

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression
(2021) Science Translational Medicine, 13 (597), art. no. eabe1376, . 

Nagele, P.^a , Palanca, B.J.^b , Gott, B.^c , Brown, F.^a , Barnes, L.^c , Nguyen, T.^b , Xiong, W.^c , Salloum, N.C.^c , Espejo, G.D.^c , Lessov-Schlaggar, C.N.^c , Jain, N.^a , Cheng, W.W.L.^b , Komen, H.^b , Yee, B.^b , Bolzenius, J.D.^b , Janski, A.^c , Gibbons, R.^d , Zorumski, C.F.^c e , Conway, C.R.^c e

^a Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL 60637, United States
^b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Center for Health Statistics, University of Chicago, Chicago, IL 60637, United States
^e Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects. © 2021 The Authors, some rights reserved;

Intrinsic connectivity reveals functionally distinct cortico-hippocampal networks in the human brain
(2021) PLoS Biology, 19 (6), art. no. e3001275, . 

Barnett, A.J.^a , Reilly, W.^a , Dimsdale-Zucker, H.R.^b , Mizrak, E.^a c , Reagh, Z.^a d e , Ranganath, C.^a

^a Center for Neuroscience, University of California at Davis, Davis, CA, United States
^b Department of Psychology, Columbia University, New York, NY, United States
^c Department of Psychology, University of Zurich, Zürich, Switzerland
^d Department of Neurology, University of California at Davis, Sacramento, CA, United States
^e Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Episodic memory depends on interactions between the hippocampus : and interconnected neocortical regions. Here, using data-driven analyses of resting-state functional magnetic resonance imaging (fMRI) data, we identified the networks that interact with the hippocampus-the default mode network (DMN) and a “medial temporal network” (MTN) that included regions in the medial temporal lobe (MTL) and precuneus. We observed that the MTN plays a critical role in connecting the visual network to the DMN and hippocampus. The DMN could be further divided into 3 subnetworks: a “posterior medial” (PM) subnetwork comprised of posterior cingulate and lateral parietal cortices; an “anterior temporal” (AT) subnetwork comprised of regions in the temporopolar and dorsomedial prefrontal cortex; and a “medial prefrontal” (MP) subnetwork comprised of regions primarily in the medial prefrontal cortex (mPFC). These networks vary in their functional connectivity (FC) along the hippocampal long axis and represent different kinds of information during memory-guided decision-making. Finally, a Neurosynth meta-analysis of fMRI studies suggests new hypotheses regarding the functions of the MTN and DMN subnetworks, providing a framework to guide future research on the neural architecture of episodic memory. © 2021 Barnett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Postnatal expression profiles of atypical cadherin FAT1 suggest its role in autism
(2021) Biology Open, 10 (6), art. no. bio056457, . 

Frei, J.A.^a , Brandenburg, C.J.^a b , Nestor, J.E.^a , Hodzic, D.M.^c , Plachez, C.^a d , McNeill, H.^c , Dykxhoorn, D.M.^e , Nestor, M.W.^a , Blatt, G.J.^a , Lin, Y.-C.^a

^a Program in Neuroscience, Hussman Institute for Autism, Baltimore, MD 21201, United States
^b Graduate Program in Neuroscience, University of Maryland, School of Medicine, Baltimore, MD 21201, United States
^c Department of Developmental Biology, Washington University, School of Medicine, St Louis, MO 63110, United States
^d Department of Anatomy and Neurobiology, University of Maryland, School of Medicine, Baltimore, MD 21201, United States
^e Hussman Institute for Human Genomics and John T. Macdonald Foundation, Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL 33136, United States

Abstract
Genetic studies have linked FAT1 (FATatypical cadherin 1) with autism spectrum disorder (ASD); however, the role that FAT1 plays in ASD remains unknown. In mice, the function of Fat1 has been primarily implicated in embryonic nervous system development with less known about its role in postnatal development. We show for the first time that FAT1 protein is expressed in mouse postnatal brains and is enriched in the cerebellum, where it localizes to granule neurons and Golgi cells in the granule layer, as well as inhibitory neurons in the molecular layer. Furthermore, subcellular characterization revealed FAT1 localization in neurites and soma of granule neurons, as well as being present in the synaptic plasma membrane and postsynaptic densities. Interestingly, FAT1 expression was decreased in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) from individuals with ASD. These findings suggest a novel role for FAT1 in postnatal development and may be particularly important for cerebellum function. As the cerebellum is one of the vulnerable brain regions in ASD, our study warrants further investigation of FAT1 in the disease etiology. © 2021. Published by The Company of Biologists Ltd.

Author Keywords
Autism;  Cadherin;  Cerebellum;  FAT1;  Granule cells;  Neural precursor cells

Funding details
15003, 18004, 18005
Hussman Foundation15007

Restless Legs Syndrome Shows Increased Silent Postmortem Cerebral Microvascular Disease With Gliosis
(2021) Journal of the American Heart Association, 10 (11), p. e019627. 

Walters, A.S.^a , Paueksakon, P.^b , Adler, C.H.^c , Moussouttas, M.^d , Weinstock, L.B.^e , Spruyt, K.^f , Bagai, K.^a

^a Sleep Division Department of Neurology Vanderbilt University Medical Center Nashville TN
^b Department of Pathology, Microbiology, Immunology Vanderbilt University Medical Center Nashville TN
^c Department of Neurology Mayo Clinic College of Medicine Scottsdale AZ
^d Cerebrovascular Division Department of Neurology Rutgers Medical School New Brunswick NJ
^e Specialists in Gastroenterology and Washington University Saint Louis MO
^f INSERM Neurocampus Lyon France

Abstract
Background Patients with restless legs syndrome (RLS) have increased silent microvascular disease by magnetic resonance imaging. However, there has been no previous autopsy confirmation of these magnetic resonance imaging findings. RLS is also frequently associated with inflammatory and immunologically mediated medical disorders. The postmortem cortex in patients with RLS was therefore evaluated for evidence of microvascular and immunological changes. Methods and Results Ten microvascular injury samples of precentral gyrus in 5 patients with RLS (3 men, 2 women; mean age, 81 years) and 9 controls (2 men, 7 women; mean age, 90 years) were studied by hematoxylin and eosin stains in a blinded fashion. None of the subjects had a history of stroke or neurologic insults. In a similar manner, the following immunohistochemistry stains were performed: (1) glial fibrillary acidic protein (representing gliosis, reactive change of glial cells in response to damage); (2) CD3 (a T-cell marker); (3) CD19 (a B-cell marker); (4) CD68 (a macrophage marker); and (5) CD117 (a mast cell marker). Patients with RLS had significantly greater silent microvascular disease (P=0.015) and gliosis (P=0.003). T cells were increased in RLS compared with controls (P=0.009) and tended to colocalize with microvascular disease (P=0.003). Other markers did not differ. There was no correlation between microvascular lesion load and RLS severity or duration. Conclusions Patients with RLS had statistically significantly more silent cerebral microvascular disease and gliosis than controls compatible with previous magnetic resonance imaging studies and with studies showing a link between RLS and hypertension, clinical stroke, and cardiovascular disease. T-cell invasion may be a secondary phenomenon.

Author Keywords
cortex;  gliosis;  microvascular disease;  restless legs syndrome;  T cells

Scalable Bio Marker Combinations for Early Stroke Diagnosis: A Systematic Review
(2021) Frontiers in Neurology, 12, art. no. 638693, . 

Baez, S.D.L.C.^a b , García del Barco, D.^b , Hardy-Sosa, A.^a b , Guillen Nieto, G.^a b , Bringas-Vega, M.L.^a c , Llibre-Guerra, J.J.^d e , Valdes-Sosa, P.^a c

^a The Clinical Hospital of Chengdu Brain Sciences Institute, University Electronic Sciences and Technology of China UESTC, Chengdu, China
^b Center for Genetic Engineering and Biotechnology, Havana, Cuba
^c Cuban Neurosciences Center, Havana, Cuba
^d Department of Neurology, National Institute of Neurology, Neurosurgery of Cuba, Havana, Cuba
^e Department of Neurology, Washington University School of Medicine in St. Louis, St. LouisMO, United States

Abstract
Background: Acute stroke treatment is a time-critical process in which every minute counts. Laboratory biomarkers are needed to aid clinical decisions in the diagnosis. Although imaging is critical for this process, these biomarkers may provide additional information to distinguish actual stroke from its mimics and monitor patient condition and the effect of potential neuroprotective strategies. For such biomarkers to be effectively scalable to public health in any economic setting, these must be cost-effective and non-invasive. We hypothesized that blood-based combinations (panels) of proteins might be the key to this approach and explored this possibility through a systematic review. Methods: We followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines for systematic review. Initially, the broader search for biomarkers for early stroke diagnosis yielded 704 hits, and five were added manually. We then narrowed the search to combinations (panels) of the protein markers obtained from the blood. Results: Twelve articles dealing with blood-based panels of protein biomarkers for stroke were included in the systematic review. We observed that NR2 peptide (antibody against the NR2 fragment) and glial fibrillary acidic protein (GFAP) are brain-specific markers related to stroke. Von Willebrand factor (vWF), matrix metalloproteinase 9 (MMP-9), and S100β have been widely used as biomarkers, whereas others such as the ischemia-modified albumin (IMA) index, antithrombin III (AT-III), and fibrinogen have not been evaluated in combination. We herein propose the following new combination of biomarkers for future validation: panel 1 (NR2 + GFAP + MMP-9 + vWF + S100β), panel 2 (NR2 + GFAP + MMP-9 + vWF + IMA index), and panel 3 (NR2 + GFAP + AT-III + fibrinogen). Conclusions: More research is needed to validate, identify, and introduce these panels of biomarkers into medical practice for stroke recurrence and diagnosis in a scalable manner. The evidence indicates that the most promising approach is to combine different blood-based proteins to provide diagnostic precision for health interventions. Through our systematic review, we suggest three novel biomarker panels based on the results in the literature and an interpretation based on stroke pathophysiology. © Copyright © 2021 Baez, García del Barco, Hardy-Sosa, Guillen Nieto, Bringas-Vega, Llibre-Guerra and Valdes-Sosa.

Author Keywords
biomarker panels;  diagnosis;  neuroprotection;  serum biomarkers;  stroke

Funding details
National Natural Science Foundation of ChinaNSFC61871105, 81871446
National Natural Science Foundation of ChinaNSFC81861128001
University of Electronic Science and Technology of ChinaUESTCY0301902610100201

Spontaneous neural synchrony links intrinsic spinal sensory and motor networks during unconsciousness
(2021) eLife, 10, . 

McPherson, J.G.^a b c d , Bandres, M.F.^a e

^a Program in Physical Therapy, Washington University School of Medicine, St. Louis, United States
^b Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^c Washington University Pain Center, Washington University School of Medicine, St. Louis, United States
^d Program in Neurosciences, Washington University School of Medicine, St. Louis, United States
^e Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, United States

Abstract
Non-random functional connectivity during unconsciousness is a defining feature of supraspinal networks. However, its generalizability to intrinsic spinal networks remains incompletely understood. Previously, Barry et al., 2014 used fMRI to reveal bilateral resting state functional connectivity within sensory-dominant and, separately, motor-dominant regions of the spinal cord. Here, we record spike trains from large populations of spinal interneurons in vivo in rats and demonstrate that spontaneous functional connectivity also links sensory- and motor-dominant regions during unconsciousness. The spatiotemporal patterns of connectivity could not be explained by latent afferent activity or by populations of interconnected neurons spiking randomly. We also document connection latencies compatible with mono- and disynaptic interactions and putative excitatory and inhibitory connections. The observed activity is consistent with the hypothesis that salient, experience-dependent patterns of neural transmission introduced during behavior or by injury/disease are reactivated during unconsciousness. Such a spinal replay mechanism could shape circuit-level connectivity and ultimately behavior. © 2021, McPherson and Bandres.

Author Keywords
neural circuit;  neural plasticity;  neuroscience;  rat;  sensorimotor integration;  spinal cord

Cellular, circuit and transcriptional framework for modulation of itch in the central amygdala
(2021) eLife, 10, . 

Samineni, V.K.^a , Grajales-Reyes, J.G.^a b c , Grajales-Reyes, G.E.^d , Tycksen, E.^e , Copits, B.A.^a , Pedersen, C.^f , Ankudey, E.S.^a , Sackey, J.N.^a , Sewell, S.B.^a , Bruchas, M.R.^a g h , Gereau, R.W.^a f h

^a Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^b Medical Scientist Training Program, Washington University School of Medicine, St. Louis, United States
^c Neuroscience Program, Washington University School of Medicine, St. Louis, United States
^d Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, United States
^e Genome Technology Access Center, Washington University School of Medicine, Seattle, United States
^f Department of Biomedical Engineering, University of Washington, Seattle, United States
^g Departments of Anesthesiology and Pharmacology, University of Washington, Seattle, United States
^h Departmentsof Neuroscience and Biomedical Engineering, Washington University School of Medicine, United States

Abstract
Itch is an unpleasant sensation that elicits robust scratching and aversive experience. However, the identity of the cells and neural circuits that organize this information remains elusive. Here, we show the necessity and sufficiency of chloroquine-activated neurons in the central amygdala (CeA) for both itch sensation and associated aversion. Further, we show that chloroquine-activated CeA neurons play important roles in itch-related comorbidities, including anxiety-like behaviors, but not in some aversive and appetitive behaviors previously ascribed to CeA neurons. RNA-sequencing of chloroquine-activated CeA neurons identified several differentially expressed genes as well as potential key signaling pathways in regulating pruritis. Finally, viral tracing experiments demonstrate that these neurons send projections to the ventral periaqueductal gray that are critical in modulation of itch. These findings reveal a cellular and circuit signature of CeA neurons orchestrating behavioral and affective responses to pruritus in mice. © 2021, Samineni et al.

Author Keywords
affect;  anxiety;  central amygdala;  itch;  mouse;  neuroscience;  pain;  RNAseq

Emerging Nanotechnology for Treatment of Alzheimer’s and Parkinson’s Disease
(2021) Frontiers in Bioengineering and Biotechnology, 9, art. no. 672594, . 

Li, A.^a , Tyson, J.^b , Patel, S.^c d , Patel, M.^c d , Katakam, S.^c d , Mao, X.^c d , He, W.^e

^a Washington University School of Medicine, St. Louis, MO, United States
^b Department of Chemical, Biochemical and Environmental Engineering, University of Maryland Baltimore County, Baltimore, MD, United States
^c Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^d Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^e Key Laboratory of Micro-Nano Materials for Energy Storage and Conversion of Henan Province, Henan Joint International Research Laboratory of Nanomaterials for Energy and Catalysis, College of Chemical and Materials Engineering, Institute of Surface Micro and Nano Materials, Xuchang University, Xuchang, China

Abstract
The prevalence of the two most common neurodegenerative diseases, Parkinson’s disease (PD) and Alzheimer’s Disease (AD), are expected to rise alongside the progressive aging of society. Both PD and AD are classified as proteinopathies with misfolded proteins α-synuclein, amyloid-β, and tau. Emerging evidence suggests that these misfolded aggregates are prion-like proteins that induce pathological cell-to-cell spreading, which is a major driver in pathogenesis. Additional factors that can further affect pathology spreading include oxidative stress, mitochondrial damage, inflammation, and cell death. Nanomaterials present advantages over traditional chemical or biological therapeutic approaches at targeting these specific mechanisms. They can have intrinsic properties that lead to a decrease in oxidative stress or an ability to bind and disaggregate fibrils. Additionally, nanomaterials enhance transportation across the blood-brain barrier, are easily functionalized, increase drug half-lives, protect cargo from immune detection, and provide a physical structure that can support cell growth. This review highlights emergent nanomaterials with these advantages that target oxidative stress, the fibrillization process, inflammation, and aid in regenerative medicine for both PD and AD. © Copyright © 2021 Li, Tyson, Patel, Patel, Katakam, Mao and He.

Author Keywords
Alzheimer’s disease;  nanotechnology/nanomaterials;  nanozymes;  oxidative stress;  Parkinson’s disease

Funding details
204200510016
National Natural Science Foundation of ChinaNSFC51772256

Label-Free Macroscopic Fluorescence Lifetime Imaging of Brain Tumors
(2021) Frontiers in Oncology, 11, art. no. 666059, . 

Lukina, M.^a , Yashin, K.^a , Kiseleva, E.E.^a , Alekseeva, A.^b , Dudenkova, V.^a , Zagaynova, E.V.^a c , Bederina, E.^a , Medyanic, I.^a , Becker, W.^d , Mishra, D.^e , Berezin, M.^e , Shcheslavskiy, V.I.^a d , Shirmanova, M.^a

^a Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod, Russian Federation
^b Department of Neuromorphology, Research Institute of Human Morphology, Moscow, Russian Federation
^c Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russian Federation
^d BeckerHickl GmbH, Berlin, Germany
^e Department of Radiology, Washington University School of Medicine, St LouisMO, United States

Abstract
Advanced stage glioma is the most aggressive form of malignant brain tumors with a short survival time. Real-time pathology assisted, or image guided surgical procedures that eliminate tumors promise to improve the clinical outcome and prolong the lives of patients. Our work is focused on the development of a rapid and sensitive assay for intraoperative diagnostics of glioma and identification of optical markers essential for differentiation between tumors and healthy brain tissues. We utilized fluorescence lifetime imaging (FLIM) of endogenous fluorophores related to metabolism of the glioma from freshly excised brains tissues. Macroscopic time-resolved fluorescence images of three intracranial animal glioma models and surgical samples of patients’ glioblastoma together with the white matter have been collected. Several established and new algorithms were applied to identify the imaging markers of the tumors. We found that fluorescence lifetime parameters characteristic of the glioma provided background for differentiation between the tumors and intact brain tissues. All three rat tumor models demonstrated substantial differences between the malignant and normal tissue. Similarly, tumors from patients demonstrated statistically significant differences from the peritumoral white matter without infiltration. While the data and the analysis presented in this paper are preliminary and further investigation with a larger number of samples is required, the proposed approach based on the macroscopic FLIM has a high potential for diagnostics of glioma and evaluation of the surgical margins of gliomas. © Copyright © 2021 Lukina, Yashin, Kiseleva, Alekseeva, Dudenkova, Zagaynova, Bederina, Medyanic, Becker, Mishra, Berezin, Shcheslavskiy and Shirmanova.

Author Keywords
autofluorescence;  FLIM;  fluorescence lifetime imaging;  glioblastoma;  image processing;  rat glioma model

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer’s disease
(2021) eLife, 10, . 

Pichet Binette, A.^a b , Theaud, G.^c , Rheault, F.^d , Roy, M.^c , Collins, D.L.^e , Levin, J.^f g , Mori, H.^h , Lee, J.H.ⁱ , Farlow, M.R.^j , Schofield, P.^k l , Chhatwal, J.P.^m , Masters, C.L.ⁿ , Benzinger, T.^o p , Morris, J.^o p , Bateman, R.^o p , Breitner, J.C.^a b , Poirier, J.^a b , Gonneaud, J.^b q , Descoteaux, M.^c , Villeneuve, S.^a b e , DIAN Study Group^r , PREVENT-AD Research Group^s

^a Department of Psychiatry, Faculty of Medicine, McGill University, Montreal, Canada
^b Douglas Mental Health University Institute, Montreal, Canada
^c Sherbrooke Connectivity Imaging Laboratory (SCIL), Université de Sherbrooke, Sherbrooke, Canada
^d Electrical Engineering, Vanderbilt University, Nashville, United States
^e McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, Canada
^f Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^g German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
^h Department of Clinical Neuroscience, Osaka City University Medical SchoolOsaka, Japan
ⁱ Department of Neurology, Asan Medical Center, University of Ulsan College of MedicineSeoul, South Korea
^j Department of Neurology, Indiana University, Bloomington, United States
^k Neuroscience Research Australia, Sydney, Australia
^l School of Medical Sciences, UNSW Sydney, Sydney, Australia
^m Harvard Medical School, Massachusetts General Hospital, Boston, United States
ⁿ University of Melbourne, The Florey Institute of Neuroscience and Mental Health, Parkville, Australia
^o Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, United States
^p Department of Neurology, Washington University School of Medicine, St. Louis, United States
^q Normandie Univ, UNICAEN, INSERM, Institut Blood and Brain @ Caen-Normandie, Caen, France

Abstract
Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer’s disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau burden in both cohorts. Associations were found in the posterior cingulum and uncinate fasciculus in preclinical sporadic AD, and in the anterior and posterior cingulum in presymptomatic mutation carriers. These results suggest that microstructural alterations accompany pathological accumulation as early as the preclinical stage of both sporadic and autosomal dominant AD. © 2021, Pichet Binette et al.

Author Keywords
cingulum;  diffusion MRI;  free-water;  human;  neuroscience;  PET;  uncinate fasciculus

Hierarchical neural network with layer-wise relevance propagation for interpretable multiclass neural state classification
(2021) International IEEE/EMBS Conference on Neural Engineering, NER, 2021-May, art. no. 9441217, pp. 351-354. 

Ellis, C.A.^a , Sendi, M.S.E.^a b , Willie, J.T.^{c d e f g} , Mahmoudi, B.^a h

^a Georgia Institute of Technology and Emory University, Wallace H. Coulter Department of Biomedical Engineering, Atlanta, GA 30332, United States
^b Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA 30332, United States
^c Washington University, Department of Neurology, St. Louis, MO 63110, United States
^d Department of Biomedical Engineering, Washington University, St. Louis, MO 63130, United States
^e Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
^f Department of Neuroscience, Washington University, St. Louis, MO 63130, United States
^g Department of Neurology, Washington University, St. Louis, MO 63110, United States
^h Department of Biomedical Informatics, Emory University, Atlanta, GA 30322, United States

Abstract
Multiclass machine learning classification has many potential applications for both clinical neuroscience and data-driven biomarker discovery. However, to be applicable in these contexts, the machine learning methods must provide a degree of insight into their decision-making processes during training and deployment phases. We propose the use of a hierarchical architecture with layer-wise relevance propagation (LRP) for explainable multiclass classification of neural states. This approach provides both local and global explainability and is suitable for identifying neurophysiological biomarkers, for assessing models based on established domain knowledge during development, and for validation during deployment. We develop a hierarchical classifier composed of multilayer perceptrons (MLP) for sleep stage classification using rodent electroencephalogram (EEG) data and compare this implementation to a standard multiclass MLP classifier with LRP. The hierarchical classifier obtained explainability results that better aligned with domain knowledge than the standard multiclass classifier. It identified α (10-12 Hz), 0 (5-9 Hz), and β (13-30 Hz) and 0 as key features for discriminating awake versus sleep and rapid eye movement (REM) versus non-REM (NREM), respectively. The standard multiclass MLP did not identify any key frequency bands for the NREM and REM classes, but did identify δ (1-4 Hz), 0, and α as more important than β, slow-y (31-55 Hz), and fast-y (65-100Hz) oscillations. The two methods obtained comparable classification performance. These results suggest that LRP with hierarchical classifiers is a promising approach to identifying biomarkers that differentiate multiple neurophysiological states. © 2021 IEEE.

Phase-amplitude coupling between neuronal wideband low-frequency oscillations and broadband gamma activity
(2021) International IEEE/EMBS Conference on Neural Engineering, NER, 2021-May, art. no. 9441250, pp. 95-98. 

Xie, T.^a b , Wu, Z.^c , Chen, L.^c , Zhu, X.^a , Sheng, X.^a , Brunner, P.^b d e

^a National Center for Adaptive Neurotechnologies, Albany, NY, United States
^b National Center for Adaptive Neurotechnologies, Albany, NY, United States
^c Huashan Hospital, Fudan University, Dept. of Neurosurgery, Shanghai, China
^d Dept. of Neurology, Albany Medical College, Albany, NY, United States
^e Dept. of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Phase-amplitude coupling (PAC) between the phase of low-frequency oscillations and the power of high-frequency activity plays a functional role in neuronal computation and information transfer. Traditional Hilbert transform-based PAC methods assume that neuronal activity is narrowband, sinusoidal, and sustained. However, natural neuronal signals often violate these three assumptions, creating a potential confound for the interpretation of PAC results. In this study, we present a new method, called Tau-Modulation, that does not require these assumptions to be met. We use this method to identify task-relevant neuronal networks in human electrocorticographic signals. Our results show that Tau-Modulation can identify these networks and characterize the strength and frequency of wideband low-frequency coupling with broadband gamma activity. Thus, Tau-Modulation might provide for a robust approach to analyzing neuronal signals and pave the way for new insights on brain functions. © 2021 IEEE.

Funding details
18YK1403300
National Institutes of HealthNIH
National Institute of Mental HealthNIMHP50-MH109429
National Institute of Neurological Disorders and StrokeNINDSU01-NS108916, U24-NS109103
National Institute of Biomedical Imaging and BioengineeringNIBIBP41-EB018783, R01-EB026439
National Natural Science Foundation of ChinaNSFC51620105002
Science and Technology Commission of Shanghai MunicipalitySTCSM18JC1410400, 2018SHZDZX01

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration
(2021) Journal of Lipid Research, 62, art. no. 100079, . 

Spears, L.D.^a , Adak, S.^a , Dong, G.^a b , Wei, X.^a , Spyropoulos, G.^c , Zhang, Q.^a , Yin, L.^a , Feng, C.^a , Hu, D.^a , Lodhi, I.J.^a , Hsu, F.-F.^a , Rajagopal, R.^d , Noguchi, K.K.^e , Halabi, C.M.^c , Brier, L.^f , Bice, A.R.^f , Lananna, B.V.^g , Musiek, E.S.^g , Avraham, O.^h , Cavalli, V.^h , Holth, J.K.^g , Holtzman, D.M.^g , Wozniak, D.F.^e , Culver, J.P.^f , Semenkovich, C.F.^a i

^a Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University, St. Louis, MO, United States
^b Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan, China
^c Department of Pediatrics, Washington University, St. Louis, MO, United States
^d Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, United States
^e Department of Psychiatry, Washington University, St. Louis, MO, United States
^f Department of Radiology, Washington University, St. Louis, MO, United States
^g Department of Neurology, Washington University, St. Louis, MO, United States
^h Department of Neuroscience, Washington University, St. Louis, MO, United States
ⁱ Department of Cell Biology and Physiology, Washington University, St. Louis, MO, United States

Abstract
Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice. © 2021 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Funding details
National Institutes of HealthNIHDK20579, NS074969, DK101392, K08HL135400, AG061776, GM103422, DK56341
National Center for Advancing Translational SciencesNCATSUL1 TR000448, U54 HD087011
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Hope Center for Neurological Disorders
American Heart AssociationAHA
China Scholarship CouncilCSC201608420067

Are mobile persons with parkinson disease necessarily more active?
(2021) Journal of Neurologic Physical Therapy, . 

Zajac, J.A.^a , Cavanaugh, J.T.^c , Baker, T.^a , Colón-Semenza, C.^d , Deangelis, T.R.^a , Duncan, R.P.^e g , Fulford, D.^b , Lavalley, M.^h , Nordahl, T.^a , Rawson, K.S.^e , Saint-Hilaire, M.ⁱ , Thomas, C.A.ⁱ , Earhart, G.M.^e f g , Ellis, T.D.^a

^a Departments of Physical Therapy and Athletic Training, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, United States
^b Departments of Occupational Therapy, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA, United States
^c Department of Physical Therapy, University of New England, Portland, ME, United States
^d Department of Kinesiology, College of Agriculture Health and Natural Resources, University of Connecticut, Storrs, CT, United States
^e Program in Physical Therapy, Washington University in St Louis, School of Medicine, St Louis, MO, United States
^f Department of Neuroscience, Washington University in St Louis, School of Medicine, St Louis, MO, United States
^g Department of Neurology, Washington University in St Louis, School of Medicine, St Louis, MO, United States
^h School of Public Health, Boston University, Boston, MA, United States
ⁱ Department of Neurology, Parkinson’s Disease and Movement Disorders Center, Boston University, Boston, MA, United States

Abstract
Background and Purpose: Walking activity in persons with Parkinson disease (PD) is important for preventing functional decline. The contribution of walking activity to home and community mobility in PD is poorly understood. Methods: Cross-sectional baseline data (N = 69) were analyzed from a randomized controlled PD trial. The Life-Space Assessment (LSA) quantified the extent, frequency, and independence across 5 expanding levels of home and community mobility, producing individual subscores and a total score. Two additional summed scores were used to represent mobility within (Levels 1-3) and beyond (Levels 4-5) neighborhood limits. An accelerometer measured walking activity for 7 days. Regression and correlation analyses evaluated relationships between daily steps and mobility scores. Mann-Whitney U tests secondarily compared differences in mobility scores between the active and sedentary groups. Results: Walking activity contributed significantly to the summed Level 1-3 score (β = 0.001, P = 0.004) but not to the summed Level 4-5 (β = 0.001, P = 0.33) or total (β = 0.002, P = 0.07) scores. Walking activity was significantly related to Level 1 (ρ = 0.336, P = 0.005), Level 2 (ρ = 0.307, P = 0.010), and Level 3 (ρ = 0.314, P = 0.009) subscores. Only the summed Level 1-3 score (P = 0.030) was significantly different between the active and sedentary groups. Discussion and Conclusions: Persons with PD who demonstrated greater mobility beyond the neighborhood were not necessarily more active; walking activity contributed more so to home and neighborhood mobility. Compared with LSA total score, the Level 1-3 summed score may be a more useful participation-level measure for assessing the impact of changes in walking activity. © 2021 Academy of Neurologic Physical Therapy.

Author Keywords
Life space;  Parkinson disease;  Walking activity

Baseline brain function in the preadolescents of the ABCD Study
(2021) Nature Neuroscience, . 

Chaarani, B.^a , Hahn, S.^a , Allgaier, N.^a , Adise, S.^a , Owens, M.M.^a , Juliano, A.C.^a , Yuan, D.K.^a , Loso, H.^a , Ivanciu, A.^a , Albaugh, M.D.^a , Dumas, J.^a , Mackey, S.^a , Laurent, J.^a , Ivanova, M.^a , Hagler, D.J.^b , Cornejo, M.D.^c , Hatton, S.^b , Agrawal, A.^d , Aguinaldo, L.^b , Ahonen, L.^e , Aklin, W.^f , Anokhin, A.P.^d , Arroyo, J.^g , Avenevoli, S.^h , Babcock, D.ⁱ , Bagot, K.^j , Baker, F.C.^k , Banich, M.T.^l , Barch, D.M.^d , Bartsch, H.^m , Baskin-Sommers, A.ⁿ , Bjork, J.M.^o , Blachman-Demner, D.^p , Bloch, M.^q , Bogdan, R.^d , Bookheimer, S.Y.^r , Breslin, F.^s , Brown, S.^b , Calabro, F.J.^e , Calhoun, V.^l t , Casey, B.J.ⁿ , Chang, L.^u , Clark, D.B.^e , Cloak, C.^u , Constable, R.T.ⁿ , Constable, K.^f , Corley, R.^l , Cottler, L.B.^v , Coxe, S.^w , Dagher, R.K.^x , Dale, A.M.^b , Dapretto, M.^r , Delcarmen-Wiggins, R.^y , Dick, A.S.^w , Do, E.K.^o , Dosenbach, N.U.F.^d , Dowling, G.J.^f , Edwards, S.^u , Ernst, T.M.^u , Fair, D.A.^z , Fan, C.C.^d , Feczko, E.^z , Feldstein-Ewing, S.W.^z , Florsheim, P.^aa , Foxe, J.J.^ab , Freedman, E.G.^ab , Friedman, N.P.^l , Friedman-Hill, S.^h , Fuemmeler, B.F.^o , Galvan, A.^r , Gee, D.G.ⁿ , Giedd, J.^b , Glantz, M.^f , Glaser, P.^d , Godino, J.^b , Gonzalez, M.^ac , Gonzalez, R.^w , Grant, S.^f , Gray, K.M.^ad , Haist, F.^b , Harms, M.P.^d , Hawes, S.^w , Heath, A.C.^b , Heeringa, S.^ae , Heitzeg, M.M.^ae , Hermosillo, R.^z , Herting, M.M.^af , Hettema, J.M.^o , Hewitt, J.K.^l , Heyser, C.^b , Hoffman, E.^f , Howlett, K.^f , Huber, R.S.^ag , Huestis, M.A.^ah , Hyde, L.W.^ae , Iacono, W.G.^ai , Infante, M.A.^b , Irfanoglu, O.^aj , Isaiah, A.^u , Iyengar, S.^ak , Jacobus, J.^b , James, R.^o , Jean-Francois, B.^x , Jernigan, T.^b , Karcher, N.R.^d , Kaufman, A.^q , Kelley, B.^al , Kit, B.^am , Ksinan, A.^o , Kuperman, J.^b , Laird, A.R.^w , Larson, C.^aa , LeBlanc, K.^f , Lessov-Schlagger, C.^d , Lever, N.^u , Lewis, D.A.^e , Lisdahl, K.^aa , Little, A.R.^f , Lopez, M.^f , Luciana, M.^ai , Luna, B.^e , Madden, P.A.^d , Maes, H.H.^o , Makowski, C.^b , Marshall, A.T.^ac , Mason, M.J.^an , Matochik, J.^g , McCandliss, B.D.^ao , McGlade, E.^ag , Montoya, I.^f , Morgan, G.^q , Morris, A.^ap , Mulford, C.^f , Murray, P.^g , Nagel, B.J.^z , Neale, M.C.^o , Neigh, G.^o , Nencka, A.^aq , Noronha, A.^g , Nixon, S.J.^v , Palmer, C.E.^b , Pariyadath, V.^f , Paulus, M.P.^s , Pelham, W.E.^w , Pfefferbaum, D.^k , Pierpaoli, C.^ar , Prescot, A.^ag , Prouty, D.^k , Puttler, L.I.^ae , Rajapaske, N.^x , Rapuano, K.M.ⁿ , Reeves, G.^u , Renshaw, P.F.^ag , Riedel, M.C.^w , Rojas, P.^w , de la Rosa, M.^w , Rosenberg, M.D.^as , Ross, M.J.^at , Sanchez, M.^w , Schirda, C.^e , Schloesser, D.^p , Schulenberg, J.^ae , Sher, K.J.^au , Sheth, C.^ag , Shilling, P.D.^b , Simmons, W.K.^s , Sowell, E.R.^ac , Speer, N.^l , Spittel, M.^p , Squeglia, L.M.^ad , Sripada, C.^ae , Steinberg, J.^o , Striley, C.^v , Sutherland, M.T.^w , Tanabe, J.^l , Tapert, S.F.^b , Thompson, W.^b , Tomko, R.L.^ad , Uban, K.A.^av , Vrieze, S.^ai , Wade, N.E.^b , Watts, R.ⁿ , Weiss, S.^f , Wiens, B.A.^v , Williams, O.D.^w , Wilbur, A.^k , Wing, D.^b , Wolff-Hughes, D.^p , Yang, R.^b , Yurgelun-Todd, D.A.^ag , Zucker, R.A.^ae , Potter, A.^a , Garavan, H.P.^a , the ABCD Consortium^aw

^a Department of Psychiatry, University of Vermont, Burlington, VT, United States
^b University of California, San Diego, La Jolla, CA, United States
^c Institute of Physics UC, Pontificia Universidad Catolica de Chile, Pontificia, Chile
^d Department of Psychiatry, Washington University in Saint Louis, St. Louis, MO, United States
^e University of Pittsburgh, Pittsburgh, PA, United States
^f National Institute on Drug Abuse, Bethesda, MD, United States
^g National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States
^h National Institute of Mental Health, Bethesda, MD, United States
ⁱ National Institute of Neurological Disorders and Stroke, Bethesda, MD, United States
^j Icahn School of Medicine at Mount Sinai, New York, NY, United States
^k SRI International, Menlo Park, CA, United States
^l University of Colorado, Boulder, CO, United States
^m Haukeland University Hospital, Bergen, Norway
ⁿ Yale University, New Haven, CT, United States
^o Virginia Commonwealth University, Richmond, VA, United States
^p NIH Office of Behavioral and Social Sciences Research, Bethesda, MD, United States
^q National Cancer Institute, Bethesda, MD, United States
^r University of California, Los Angeles, CA, United States
^s Laureate Institute for Brain Research, Tulsa, OK, United States
^t Tri-institutional Center for Translational Research in Neuroimaging and Data Science, Georgia State University, Georgia Institute of Technology, Emory University, Atlanta, GA, United States
^u University of Maryland School of Medicine, Baltimore, MD, United States
^v University of Florida, Gainesville, FL, United States
^w Florida International University, Miami, FL, United States
^x National Institute on Minority Health and Health Disparities, Bethesda, MD, United States
^y NIH Office of Research on Women’s Health, Bethesda, MD, United States
^z Oregon Health & Science University, Portland, OR, United States
^aa University of Wisconsin, Milwaukee, WI, United States
^ab University of Rochester, Rochester, NY, United States
^ac Children’s Hospital Los Angeles, Los Angeles, CA, United States
^ad Medical University of South Carolina, Charleston, SC, United States
^ae University of Michigan, Ann Arbor, MI, United States
^af University of Southern California, Los Angeles, CA, United States
^ag University of Utah, Salt Lake City, UT, United States
^ah Thomas Jefferson University, Philadelphia, PA, United States
^ai University of Minnesota, Minneapolis, MN, United States
^aj National Institute of Biomedical Imaging and Bioengineering, Bethesda, MD, United States
^ak National Endowment for the Arts, Washington, DC, United States
^al National Institute of Justice, Washington, DC, United States
^am National Heart, Lung, and Blood Institute, Bethesda, MD, United States
^an University of Tennessee, Knoxville, TN, United States
^ao Stanford University, Stanford, CA, United States
^ap Oklahoma State University, Stillwater, OK, United States
^aq Medical College of Wisconsin, Milwaukee, WI, United States
^ar Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, United States
^as University of Chicago, Chicago, IL, United States
^at University of Colorado Anschutz Medical Campus, Aurora, CO, United States
^au University of Missouri, Columbia, MO, United States
^av University of California, Irvine, CA, United States

Abstract
The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHU01DA041022, U01DA041028, U01DA050988, U01DA041174, U01DA041025, U01DA041156, U01DA041093, U01DA041048, U24DA041147, U24DA041123, U01DA041106, U01DA041148, U01DA051038, U01DA041134, U01DA050989, U01DA041117, U01DA051018, U01DA051039, U01DA041089, U01DA041120, U01DA051016, U01DA051037, U01DA050987
National Science FoundationNSFOAC-1827314

“Where are the … Fixations?”: Grammatical number cues guide anticipatory fixations to upcoming referents and reduce lexical competition.
(2021) Journal of Experimental Psychology: Learning Memory and Cognition, . 

Brown, V.A.^a , Fox, N.P.^b , Strand, J.F.^c

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Science, Crystal Springs Uplands SchoolCA, United States
^c Department of Psychology, Carleton College, Northfield, MN, United States

Abstract
Listeners make use of contextual cues during continuous speech processing that help overcome the limitations of the acoustic input. These semantic, grammatical, and pragmatic cues facilitate prediction of upcoming words and/or reduce the lexical search space by inhibiting activation of contextually inappropriate words that share phonological information with the target. The current study used the visual world paradigm to assess whether and how listeners use contextual cues about grammatical number during sentence processing by presenting target words in carrier phrases that were grammatically unconstraining (“Click on the …”) or grammatically constraining (“Where is/are the …”). Prior to the onset of the target word, listeners were already more likely to fixate on plural objects in the “Where are the …” context than the “Where is the …” context, indicating that they used the construction of the verb to anticipate the referent. Further, participants showed less interference from cohort competitors when the sentence frame made them contextually inappropriate, but still fixated on those words more than on phonologically unrelated distractor words. These results suggest that listeners rapidly and flexibly make use of contextual cues about grammatical number while maintaining sensitivity to the bottom-up input. (PsycInfo Database Record (c) 2021 APA, all rights reserved) © 2021 American Psychological Association

Author Keywords
contextual cues;  sentence processing;  spoken word recognition;  visual world paradigm

Evaluation of SAMP8 Mice as a Model for Sleep-Wake and Rhythm Disturbances Associated with Alzheimer’s Disease: Impact of Treatment with the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant
(2021) Journal of Alzheimer’s Disease, 81 (3), pp. 1151-1167. 

Beuckmann, C.T.^a , Suzuki, H.^a , Musiek, E.S.^b , Ueno, T.^a , Sato, T.^a , Bando, M.^a , Osada, Y.^a , Moline, M.^c

^a Eisai Co. Ltd., Tsukuba, Ibaraki, Japan
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Eisai Inc., Woodcliff Lake, NJ, United States

Abstract
Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. © 2021-The authors. Published by IOS Press.

Author Keywords
Alzheimer’s disease;  animal models;  dual orexin receptor antagonist;  E2006;  in vivo;  irregular sleep-wake rhythm disorder;  lemborexant;  mouse;  orexin;  running wheel;  sleep

A Brief Early Childhood Screening Tool for Psychopathology Risk in Primary Care: The Moderating Role of Poverty
(2021) Journal of Pediatrics, . 

Silver, J.^a , Barch, D.M.^b , Klein, D.N.^a , Whalen, D.J.^c , Hennefield, L.^c , Tillman, R.^c , Luby, J.^c

^a Department of Psychology, Stony Brook University, Stony Brook, NY, United States
^b Department of Psychological & Brain Science, Washington University in St Louis, St Louis, MO, United States
^c Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States

Abstract
Objectives: To evaluate the Preschool Feeling Checklist (PFC) utility for predicting later mental disorders and functioning for children and assess whether the PFC’s predictive utility differs as a function of childhood poverty. Study design: We analyzed data from a prospective longitudinal study of preschoolers in St Louis. Preschoolers (N = 287) were recruited from primary care sites and were assessed annually for 10-15 years. The PFC screened for depressive symptoms. Later age-appropriate psychiatric diagnostic interviews were used to derive Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnoses. Regression and moderation analyses, and multilevel modeling were used to test the association between the PFC and later outcomes, and whether this relationship was moderated by income-to-needs. Results: The PFC predicted major depressive disorder (OR 1.13, P < .001), attention deficit hyperactivity disorder (OR 1.16, P < .001), and mania (OR 1.18, P < .05) in adolescence and early adulthood. Income-to-needs was a moderator in the predictive pathway between the PFC and later major depressive disorder (OR 1.10, P < .05) and mania (OR 1.19, P < .001) with the measure less predictive for children living in poverty. The PFC predicted worse functioning by the final assessment (b = 1.71, SE = 0.51, P = .001). Conclusions: The PFC served as an indicator of risk for later attention deficit hyperactivity disorder and impairment in all children. It has predictive utility for later mood disorders only in children living above the poverty line. Predicting depression in children living below the poverty line may require consideration of risk factors not covered by the PFC. © 2021 Elsevier Inc.

Author Keywords
income-to-needs;  pediatric;  predictive utility;  preschool depression

Funding details
National Science FoundationNSF
National Institute of Child Health and Human DevelopmentNICHDF32 HD093273
National Institutes of HealthNIHL30 MH108015, K23 MH118426
National Institute of Mental HealthNIMHR01 5R01MH090786
National Science FoundationNSF16-588

Sad, Sadder, Saddest: Recognition of Sad and Happy Emotional Intensity, Adverse Childhood Experiences and Depressive Symptoms in Preschoolers
(2021) Child Psychiatry and Human Development, . 

Sudit, E., Luby, J., Gilbert, K.

Department of Psychiatry, Washington University School of Medicine, 4444 Forest Park, Suite 2100, St. Louis, MO 63108, United States

Abstract
Adverse childhood experiences (ACES) have repeatedly been associated with depression. The ability to differentiate emotional intensity is a protective factor for psychopathology and in the context of life stressors, poor negative emotion differentiation (ED) is associated with depressive symptoms. However, little is known about whether the ability to recognize negative emotional intensity, a theorized developmental prerequisite of ED, influences the relationship between ACES and depressive symptoms in early childhood. The current study examined the interactive effects of ACES, the ability to recognize emotional intensity and depressive symptoms in 249 preschoolers enriched for depression. Findings demonstrated that when experiencing ACES, sad (not happy) emotion recognition was associated with elevated depressive symptoms. Specifically, when facing multiple ACEs, preschoolers with poor and moderate ability to recognize sad emotional intensity exhibited elevated depressive symptoms. Findings demonstrate that when experiencing elevated ACES, sad emotion recognition may be a protective factor for depression in early childhood. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Adverse childhood experiences;  Depression;  Early childhood;  Emotion recognition

Funding details
National Institute of Mental HealthNIMHK23MH115074, R01 MH090786
National Institutes of HealthNIH
Brain and Behavior Research FoundationBBRF

Comparing Simultaneous Electrocochleography and Auditory Brainstem Response Measurements Using Three Different Extratympanic Electrodes
(2021) Journal of the American Academy of Audiology, . 

Lefler, S.M.^a b , Kaf, W.A.^a , Ferraro, J.A.^c

^a Communications Sciences and Disorders Department, Missouri State University, Springfield, MI, United States
^b Department of Otolaryngology, Washington University School of Medicine, Saint Louis, MI, United States
^c Department of Hearing and Speech, University of Kansas, Lawrence, KS, United States

Abstract
Background  Various extratympanic recording electrodes have been used to make electrocochleography (ECochG) and auditory brainstem response (ABR) measurements in clinics, translational research, and basic science laboratories. However, differences may exist in ECochG and ABR measurements depending on the different types of extratympanic electrodes that are used. Purpose  The purpose of this research is to compare simultaneously recorded ECochG and ABR responses using three different extratympanic electrodes. This research helps clinicians and researchers to understand how electrode types and recording sites influence EcochG and ABR results. In addition, our findings could provide more normative data to the ECochG and ABR literature as well as give perspective on a preferred electrode approach when performing simultaneous ECochG and ABR testing. Research Design  Ours was a repeated-measures study with measurements being made from individual participants on two separate sessions. Study Sample  Twenty young adult females with normal hearing. Procedure  A three-channel recording system was used to simultaneously record ECochG and ABR measurements in response to alternating polarity click stimuli. In each session, measurements were simultaneously recorded with a TipTrode electrode and one of the tympanic membrane (TM) electrodes. Data Collection and Analysis  Suprathreshold summating potential (SP) and action potential (AP) of the ECochG and waves I, III, and V of the ABR, and threshold responses (AP and wave V) were identified. Results  Compared with the ear canal TipTrode electrode, TM electrodes yielded suprathreshold amplitudes that were larger than those from the ear canal electrode, smaller SP-AP ratios, lower AP thresholds, and less variability. These findings can help guide choices made by clinicians, translational investigators, and basic science researchers on which type of extra-tympanic electrode to use for their intended purpose. © 2021 GeorgThieme-AIP. All right reserved.

Author Keywords
action potential;  auditory brainstem response;  electrocochleography;  SP/AP ratio;  summating potential

Relations Between the McGurk Effect, Social and Communication Skill, and Autistic Features in Children with and without Autism
(2021) Journal of Autism and Developmental Disorders, . 

Feldman, J.I.^a b c , Conrad, J.G.^d e , Kuang, W.^d f , Tu, A.^d g , Liu, Y.^d h , Simon, D.M.ⁱ , Wallace, M.T.^{a b i j k l m} , Woynaroski, T.G.^b c i j

^a Department of Hearing and Speech Sciences, Vanderbilt University, MCE 8310 South Tower, 1215 21st Avenue South, Nashville, TN 37232, United States
^b Frist Center for Autism & Innovation, Vanderbilt University, Nashville, TN, United States
^c Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
^d Neuroscience Undergraduate Program, Vanderbilt University, Nashville, TN, United States
^e College of Medicine, University of Illinois, Chicago, IL, United States
^f College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, United States
^g College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States
^h Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
^j Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States
^k Department of Psychology, Vanderbilt University, Nashville, TN, United States
^l Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
^m Department of Pharmacology, Vanderbilt University, Nashville, TN, United States

Abstract
Children with autism show alterations in multisensory integration that have been theoretically and empirically linked with the core and related features of autism. It is unclear, however, to what extent multisensory integration maps onto features of autism within children with and without autism. This study, thus, evaluates relations between audiovisual integration and core and related autism features across children with and without autism. Thirty-six children reported perceptions of the McGurk illusion during a psychophysical task. Parents reported on participants’ autistic features. Increased report of illusory percepts tended to covary with reduced autistic features and greater communication skill. Some relations, though, were moderated by group. This work suggests that associations between multisensory integration and higher-order skills are present, but in some instances vary according to diagnostic group. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Author Keywords
Autism spectrum disorder;  Communication skill;  McGurk;  Multisensory integration;  Social skill

Funding details
DGE 19-22697
National Institute on Deafness and Other Communication DisordersNIDCDR21 DC016144
National Institutes of HealthNIHU54 HD083211
National Center for Advancing Translational SciencesNCATSKL2TR000446

Potential surgical therapies for drug-resistant focal epilepsy
(2021) CNS Neuroscience and Therapeutics, . 

Shan, W.^a b c d , Mao, X.^e , Wang, X.^b , Hogan, R.E.^f , Wang, Q.^a b c d

^a Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
^b National Center for Clinical Medicine of Neurological Diseases, Beijing, China
^c Beijing Institute for Brain Disorders, Beijing, China
^d Beijing Key Laboratory of Neuro-modulation, Beijing, China
^e Shandong Key Laboratory of Industrial Control Technology, School of Automation, Qingdao University, Qingdao, China
^f Departments of Neurology and Neurosurgery, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Drug-resistant focal epilepsy (DRFE), defined by failure of two antiepileptic drugs, affects 30% of epileptic patients. Epilepsy surgeries are alternative options for this population. Preoperative evaluation is critical to include potential candidates, and to choose the most appropriate procedure to maximize efficacy and simultaneously minimize side effects. Traditional procedures involve open skull surgeries and epileptic focus resection. Alternatively, neuromodulation surgeries use peripheral nerve or deep brain stimulation to reduce the activities of epileptogenic focus. With the advanced improvement of laser-induced thermal therapy (LITT) technique and its utilization in neurosurgery, magnetic resonance-guided LITT (MRgLITT) emerges as a minimal invasive approach for drug-resistant focal epilepsy. In the present review, we first introduce drug-resistant focal epilepsy and summarize the indications, pros and cons of traditional surgical procedures and neuromodulation procedures. And then, focusing on MRgLITT, we thoroughly discuss its history, its technical details, its safety issues, and current evidence on its clinical applications. A case report on MRgLITT is also included to illustrate the preoperational evaluation. We believe that MRgLITT is a promising approach in selected patients with drug-resistant focal epilepsy, although large prospective studies are required to evaluate its efficacy and side effects, as well as to implement a standardized protocol for its application. © 2021 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Author Keywords
epileptogenic;  laser-induced thermal therapy;  magnetic resonance-guided;  neuromodulation

Funding details
H2018206435
2016‐1‐2011
China Postdoctoral Science Foundation2019M660719
Natural Science Foundation of Beijing MunicipalityZ200024
Beijing Postdoctoral Science FoundationZZ 2019‐09

Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders
(2021) Genetics in Medicine, . 

May, H.J.^a , Jeong, J.^b , Revah-Politi, A.^a c , Cohen, J.S.^d e , Chassevent, A.^d , Baptista, J.^f g , Baugh, E.H.^a , Bier, L.^a , Bottani, A.^h , Carminho A. Rodrigues, M.T.^h , Conlon, C.^d , Fluss, J.ⁱ , Guipponi, M.^h , Kim, C.A.^j , Matsumoto, N.^k , Person, R.^l , Primiano, M.^m , Rankin, J.ⁿ , Shinawi, M.^o , Smith-Hicks, C.^d e , Telegrafi, A.^l , Toy, S.^o , Uchiyama, Y.^k p , Aggarwal, V.^c , Goldstein, D.B.^a , Roche, K.W.^b , Anyane-Yeboa, K.^a m

^a Institute for Genomic Medicine, Columbia University Irving Medical Center, New York, NY, United States
^b National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^c Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, United States
^d Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD, United States
^e Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, United States
^f Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
^g Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, United Kingdom
^h Division of Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland
ⁱ Pediatric Neurology Unit, Pediatrics Subspecialties Service, Geneva Children’s Hospital, Geneva, Switzerland
^j Genetics Unit, Instituto da Crianca, Hospital das Clinicas, Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil
^k Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
^l Clinical Genomics Program, GeneDx, Gaithersburg, MD, United States
^m Division of Clinical Genetics, Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, United States
ⁿ Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom
^o Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University in St. Louis, St. Louis, MO, United States
^p Department of Rare Disease Genomics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

Abstract
Purpose: In this study, we aimed to characterize the clinical phenotype of a SHANK1-related disorder and define the functional consequences of SHANK1 truncating variants. Methods: Exome sequencing (ES) was performed for six individuals who presented with neurodevelopmental disorders. Individuals were ascertained with the use of GeneMatcher and Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER). We evaluated potential nonsense-mediated decay (NMD) of two variants by making knock-in cell lines of endogenous truncated SHANK1, and expressed the truncated SHANK1 complementary DNA (cDNA) in HEK293 cells and cultured hippocampal neurons to examine the proteins. Results: ES detected de novo truncating variants in SHANK1 in six individuals. Evaluation of NMD resulted in stable transcripts, and the truncated SHANK1 completely lost binding with Homer1, a linker protein that binds to the C-terminus of SHANK1. These variants may disrupt protein–protein networks in dendritic spines. Dispersed localization of the truncated SHANK1 variants within the spine and dendritic shaft was also observed when expressed in neurons, indicating impaired synaptic localization of truncated SHANK1. Conclusion: This report expands the clinical spectrum of individuals with truncating SHANK1 variants and describes the impact these variants may have on the pathophysiology of neurodevelopmental disorders. © 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Funding details
HICF-1009-003
WT098051
National Institutes of HealthNIHUL1TR001873
National Institute of Neurological Disorders and StrokeNINDS
Minnesota Department of HealthMDH
National Center for Advancing Translational SciencesNCATS
Japan Agency for Medical Research and DevelopmentAMEDJP20dm0107090, JP20ek0109301, JP20ek0109348, JP20ek0109486, JP20kk0205012
Wellcome TrustWT
National Institute for Health ResearchNIHR
Japan Society for the Promotion of ScienceKAKENJP17H01539, JP19K17865

Oxytocin receptor activation does not mediate associative fear deficits in a Williams Syndrome model
(2021) Genes, Brain and Behavior, . 

Nygaard, K.R.^a b , Swift, R.G.^a b , Glick, R.M.^a b , Wagner, R.E.^b , Maloney, S.E.^b c , Gould, G.G.^d , Dougherty, J.D.^a b c

^a Department of Genetics, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
^c Intellectual and Developmental Disabilities Research Center, Washington University in St. Louis, St. Louis, MO, United States
^d Department of Cellular and Integrative Physiology, University of Texas Health San Antonio, San Antonio, TX, United States

Abstract
Williams Syndrome results in distinct behavioral phenotypes, which include learning deficits, anxiety, increased phobias and hypersociability. While the underlying mechanisms driving this subset of phenotypes is unknown, oxytocin (OT) dysregulation is hypothesized to be involved as some studies have shown elevated blood OT and altered OT receptor expression in patients. A “Complete Deletion” (CD) mouse, modeling the hemizygous deletion in Williams Syndrome, recapitulates many of the phenotypes present in humans. These CD mice also exhibit impaired fear responses in the conditioned fear task. Here, we address whether OT dysregulation is responsible for this impaired associative fear memory response. We show direct delivery of an OT receptor antagonist to the central nervous system did not rescue the attenuated contextual or cued fear memory responses in CD mice. Thus, increased OT signaling is not acutely responsible for this phenotype. We also evaluated OT receptor and serotonin transporter availability in regions related to fear learning, memory and sociability using autoradiography in wild type and CD mice. While no differences withstood correction, we identified regions that may warrant further investigation. There was a nonsignificant decrease in OT receptor expression in the lateral septal nucleus and nonsignificant lowered serotonin transporter availability in the striatum and orbitofrontal cortex. Together, these data suggest the fear conditioning anomalies in the Williams Syndrome mouse model are independent of any alterations in the oxytocinergic system caused by deletion of the Williams locus. © 2021 International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Author Keywords
associative fear;  autoradiography;  behavioral genetics;  conditioned fear;  mouse model;  OXTR;  oxytocin;  oxytocin receptor antagonist;  SERT;  Williams Syndrome

Funding details
National Science FoundationNSFDGE‐1745038
National Institute of Mental HealthNIMH5R01MH107515‐05
National Institute of Child Health and Human DevelopmentNICHD
San Antonio Area FoundationSAAFD
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD103525

Functional Connectivity of Vermis Correlates with Future Gait Impairments in Parkinson’s Disease
(2021) Movement Disorders, . 

Maiti, B.^a , Rawson, K.S.^b , Tanenbaum, A.B.^a , Koller, J.M.^c , Snyder, A.Z.^a d , Campbell, M.C.^a d , Earhart, G.M.^a b e , Perlmutter, J.S.^{a b d e f}

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Radiology, 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 Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Dysfunction of cerebellar vermis contributes to gait abnormalities in multiple conditions and may play a key role in gait impairment in Parkinson’s disease (PD). Objective: The purpose of this study was to investigate whether altered resting-state functional connectivity of the vermis relates to subsequent impairment of specific domains of gait in PD. Methods: We conducted morphometric and resting-state functional connectivity MRI analyses contrasting 45 PD and 32 age-matched healthy participants. Quantitative gait measures were acquired with a GAITRite walkway at varying intervals after functional connectivity data acquisition. Results: At baseline, PD participants had significantly altered functional connectivity between vermis and sensorimotor cortex compared with controls. Altered vermal functional connectivity with bilateral paracentral lobules correlated with subsequent measures of variability in stride length, step time, and single support time after controlling for confounding variables including the interval between imaging and gait measures. Similarly, altered functional connectivity between vermis and left sensorimotor cortex correlated with mean stride length and its variability. Vermis volume did not relate to any gait measure. PD participants did not differ from controls in vermis volume or cortical thickness at the site of significant regional clusters. Only altered lobule V:sensorimotor cortex functional connectivity correlated with subsequent gait measures in exploratory analyses involving all the other cerebellar lobules. Conclusions: These results demonstrate that abnormal vermal functional connectivity with sensorimotor cortex, in the absence of relevant vermal or cortical atrophy, correlates with subsequent gait impairment in PD. Our data reflect the potential of vermal functional connectivity as a novel imaging biomarker of gait impairment in PD. © 2021 International Parkinson and Movement Disorder Society. © 2021 International Parkinson and Movement Disorder Society

Author Keywords
cerebellum;  functional connectivity;  gait impairment;  Parkinson disease;  vermis

Funding details
AT010753, HD092444, NS075321, NS103957, NS107281, NS110456
National Institutes of HealthNIHKL2 TR002346, NS065701, NS097799, NS116025, P30 NS098577‐01, RO1 NS075321‐02, RO1 NS097437
U.S. Department of DefenseDODDOD W81XWH‐217‐1‐0393
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDSTR 001456
National Endowment for the ArtsNEA1880026‐31‐21, AG050263, AG‐64937, ES029524, NS075527, NS092865, NS109487, R61 AT010753, U10NS077384, U19 NS110456, U54NS116025
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Huntington’s Disease Society of AmericaHDSA
Dystonia Medical Research FoundationDMRF1U01DA05103801, 2R01MH0967730A1, 5R01DK06483215, 5R01HD07085508, 5R01MH10403004, 5U01DA04112005, AG063974, AT010753‐01, AT010753‐02S1, NS075321‐02, NS097437, R01 NS097437, R01 NS10728101
American Brain FoundationABF
American Academy of NeurologyAAN
Stanford UniversitySU
CHDI FoundationCHDI
National Center for Advancing Translational SciencesNCATS
American Parkinson Disease AssociationAPDA
University of Pennsylvania
Foundation for Barnes-Jewish Hospital
ParkinsonfondenR01 HD092444, R61 AT114533, R61 AT114533‐S1, U01 NS113851
St. Louis American Parkinson Disease Association
McDonnell Center for Systems Neuroscience
Parkinson Study GroupPSG

Efficacy of Neratinib Plus Capecitabine in the Subgroup of Patients with Central Nervous System Involvement from the NALA Trial
(2021) Oncologist, . 

Hurvitz, S.A.^a , Saura, C.^b , Oliveira, M.^b , Trudeau, M.E.^c , Moy, B.^d , Delaloge, S.^e , Gradishar, W.^f , Kim, S.-B.^g , Haley, B.^h , Ryvo, L.ⁱ , Dai, M.-S.^j , Milovanov, V.^k , Alarcón, J.^l , Kalmadi, S.^m , Cronemberger, E.ⁿ , Souza, C.^o , Landeiro, L.^p , Bose, R.^q , Bebchuk, J.^r , Kabbinavar, F.^r , Bryce, R.^r , Keyvanjah, K.^r , Brufsky, A.M.^s

^a University of California Los Angeles/Jonsson Comprehensive Cancer Center, Los Angeles, CA, United States
^b Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology, SOLTI Breast Cancer Cooperative Group, Barcelona, Spain
^c Sunnybrook Health Sciences Centre, Toronto, ON, Canada
^d Massachusetts General Hospital Cancer Center, Boston, MA, United States
^e Gustave Roussy, Villejuif, France
^f Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
^g Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
^h University of Texas Southwestern, Dallas, TX, United States
ⁱ Sourasky Medical Center (Ichilov), Tel Aviv, Israel
^j Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
^k Tambov Regional Oncology Center, Tambov, Russian Federation
^l Hospital Universitario Son Espases, Palma de MallorcaBalearic Islands, Spain
^m Ironwood Cancer and Research Centers, Chandler, AZ, United States
ⁿ Centro Regional Integrado de Oncologia, Fortaleza, Ceará, Brazil
^o Hospital de Câncer de Barretos, Barretos, São Paulo, Brazil
^p Nucleo de Oncologia Da Bahia, Ondina, Bahia, Brazil
^q Washington University School of Medicine, St Louis, MO, United States
^r Puma Biotechnology, Inc., Los Angeles, CA, United States
^s Magee-Womens Hospital of UPMC, Pittsburgh, PA, United States

Abstract
Background: Neratinib has efficacy in central nervous system (CNS) metastases from HER2-positive metastatic breast cancer (MBC). We report outcomes among patients with CNS metastases at baseline from the phase III NALA trial of neratinib plus capecitabine (N + C) versus lapatinib plus capecitabine (L + C). Materials and Methods: NALA was a randomized, active-controlled trial in patients who received two or more previous HER2-directed regimens for HER2-positive MBC. Patients with asymptomatic/stable brain metastases (treated or untreated) were eligible. Patients were assigned to N + C (neratinib 240 mg per day, capecitabine 750 mg/m2 twice daily) or L + C (lapatinib 1,250 mg per day, capecitabine 1,000 mg/m2 twice daily) orally. Independently adjudicated progression-free survival (PFS), overall survival (OS), and CNS endpoints were considered. Results: Of 621 patients enrolled, 101 (16.3%) had known CNS metastases at baseline (N + C, n = 51; L + C, n = 50); 81 had received prior CNS-directed radiotherapy and/or surgery. In the CNS subgroup, mean PFS through 24 months was 7.8 months with N + C versus 5.5 months with L + C (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.41–1.05), and mean OS through 48 months was 16.4 versus 15.4 months (HR, 0.90; 95% CI, 0.59–1.38). At 12 months, cumulative incidence of interventions for CNS disease was 25.5% for N + C versus 36.0% for L + C, and cumulative incidence of progressive CNS disease was 26.2% versus 41.6%, respectively. In patients with target CNS lesions at baseline (n = 32), confirmed intracranial objective response rates were 26.3% and 15.4%, respectively. No new safety signals were observed. Conclusion: These analyses suggest improved PFS and CNS outcomes with N + C versus L + C in patients with CNS metastases from HER2-positive MBC. Implications for Practice: In a subgroup of patients with central nervous system (CNS) metastases from HER2-positive breast cancer after two or more previous HER2-directed regimens, the combination of neratinib plus capecitabine was associated with improved progression-free survival and CNS outcomes compared with lapatinib plus capecitabine. These findings build on previous phase II and III studies describing efficacy of neratinib in the prevention and treatment of CNS metastases, and support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies. © 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.

Author Keywords
Capecitabine;  Central nervous system neoplasms;  Lapatinib;  Neratinib;  Receptor, ErbB-2

Adult patient preferences for long-acting adhd treatments: A discrete choice experiment
(2021) Patient Preference and Adherence, 15, pp. 1061-1073. 

Cambron-Mellott, M.J.^a , Mikl, J.^b , Matos, J.E.^a , Erensen, J.G.^b , Beusterien, K.^a , Cataldo, M.J.^b , Hallissey, B.^a , Mattingly, G.W.^c d e

^a Kantar Health, New York, NY, United States
^b Purdue Pharma L.P./Adlon Therapeutics, L.P., Stamford, CT, United States
^c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^d Midwest Research Group, St. Charles, MO, United States
^e St. Charles Psychiatric Associates, St. Charles, MO, United States

Abstract
Background and Objective: Treatment for attention deficit hyperactivity disorder (ADHD) requires a multifaceted approach including psychosocial interventions and pharmacological treatment. This study evaluates preferences for specific attributes associated with different long-acting stimulant treatment among US adults with ADHD. Methods: Patients completed an online, cross-sectional survey, incorporating a discrete choice experiment to assess preferences for attributes. Results: Analyses included 200 adults with ADHD (mean age 33.0 years; 60% self-reporting moderate severity); the mean (SD) Adult ADHD Self-Report Scale-v1.1 score was 45.9 (12.4). Overall, patients valued speed of onset most and risk of rebound least. Three population groups with distinct preferences were identified: side effect-driven (n=69, 35%), quick onset-driven (n=47, 24%) and quick onset and long duration-driven (n=84, 42%). Conclusion: This study shows differences in how adults with ADHD value and assess benefit-risk trade-offs when considering the desired attributes of stimulant treatments, high-lighting the importance of patient-physician shared decision-making to optimize the desired benefits of individualized treatment. © 2021 Cambron-Mellott et al.

Author Keywords
Attention deficit hyperactivity disorder;  Choice behavior;  CNS stimulants;  Discrete choice experiment;  Patient preference

Funding details
Purdue Pharma