WashU weekly Neuroscience publications

Sex may influence motor phenotype in a novel rodent model of cerebral palsy
(2020) Neurobiology of Disease, 134, art. no. 104711, . 

Aravamuthan, B.R.^{a b c} , Gandham, S.^a , Young, A.B.^{c d} , Rutkove, S.B.^{c e}

^a Washington University in St. Louis School of Medicine, St. Louis, MO, United States
^b Boston Children’s Hospital, Boston, MA, United States
^c Harvard Medical School, Boston, MA, United States
^d Massachusetts General Hospital, Boston, MA, United States
^e Beth Israel Deaconess Medical Center, Boston, MA, United States

Abstract
Cerebral palsy (CP) is the most common cause of childhood motor disability, manifesting most often as spasticity and/or dystonia. Spasticity and dystonia are often co-morbid clinically following severe injury at term gestation. Currently available animal CP models have not demonstrated or differentiated between these two motor phenotypes, limiting their clinical relevance. We sought to develop an animal CP model displaying objectively identifiable spasticity and dystonia. We exposed rat pups at post-natal day 7–8 (equivalent to human 37 post-conceptional weeks) to global hypoxia. Since spasticity and dystonia can be difficult to differentiate from each other in CP, objective electrophysiologic markers of motor phenotypes were assessed. Spasticity was inferred using an electrophysiologic measure of hyperreflexia: soleus Hoffman reflex suppression with 2 Hz tibial nerve stimulation. Dystonia was assessed during voluntary isometric hindlimb withdrawal at different levels of arousal by calculating tibialis anterior and triceps surae electromyographic co-activation as a surrogate of overflow muscle activity. Hypoxia affected spasticity and dystonia measures in a sex-dependent manner. Males had attenuated Hoffman reflex suppression suggestive of spasticity but no change in antagonist muscle co-activation. In contrast, females demonstrated increased co-activation suggestive of dystonia but no change in Hoffman reflex suppression. Therefore, there was an unexpected segregation of electrophysiologically-defined motor phenotypes based on sex with males predominantly demonstrating spasticity and females predominantly demonstrating dystonia. These results require human clinical confirmation but suggest that sex could play a critical role in the motor manifestations of neonatal brain injury. © 2019

Author Keywords
Animal models of disease;  Cerebral palsy;  Dystonia;  Neonatal brain injury;  Spasticity

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

Early Detection of Endolymphatic Hydrops using the Auditory Nerve Overlapped Waveform (ANOW)
(2020) Neuroscience, 425, pp. 251-266. 

Lee, C.^a , Valenzuela, C.V.^a , Goodman, S.S.^b , Kallogjeri, D.^a , Buchman, C.A.^a , Lichtenhan, J.T.^a

^a Washington University School of Medicine in St. Louis, Department of Otolaryngology, Saint Louis, MO, United States
^b University of Iowa, Department of Communication Sciences and Disorders, Iowa City, IA, United States

Abstract
Endolymphatic hydrops is associated with low-frequency sensorineural hearing loss, with a large body of research dedicated to examining its putative causal role in low-frequency hearing loss. Investigations have been thwarted by the fact that hearing loss is measured in intact ears, but gold standard assessments of endolymphatic hydrops are made postmortem only; and that no objective low-frequency hearing measure has existed. Yet the association of endolymphatic hydrops with low-frequency hearing loss is so strong that it has been established as one of the important defining features for Ménière’s disease, rendering it critical to detect endolymphatic hydrops early, regardless of whether it serves a causal role or is the result of other disease mechanisms. We surgically induced endolymphatic hydrops in guinea pigs and employed our recently developed objective neural measure of low-frequency hearing, the Auditory Nerve Overlapped Waveform (ANOW). Hearing loss and endolymphatic hydrops were assessed at various time points after surgery. The ANOW detected low-frequency hearing loss as early as the first day after surgery, well before endolymphatic hydrops was found histologically. The ANOW detected low-frequency hearing loss with perfect sensitivity and specificity in all ears after endolymphatic hydrops developed, where there was a strong linear relationship between degree of endolymphatic hydrops and severity of low-frequency hearing loss. Further, histological data demonstrated that endolymphatic hydrops is seen first in the high-frequency cochlear base, though the ANOW demonstrated that dysfunction begins in the low-frequency apical cochlear half. The results lay the groundwork for future investigations of the causal role of endolymphatic hydrops in low-frequency hearing loss. © 2019 IBRO

Author Keywords
cochlea;  cochlear action potential;  compound action potential;  low frequency hearing;  Ménière’s disease;  otoacoustic emissions

Document Type: Article
Publication Stage: Final
Source: Scopus

BOLD-MRI demonstrates acute placental and fetal organ hypoperfusion with fetal brain sparing in response to phenylephrine but not ephedrine
(2020) Placenta, 90, pp. 52-57. 

Shapiro, J.^a , Ginosar, Y.^{a b c} , Gielchinsky, Y.^d , Elchalal, U.^d , Bromberg, Z.^e , Corchia-Nachmanson, N.^{c e} , Abramovitch, R.^{c e}

^a Department of Anesthesiology and Critical Care Medicine, Hadassah Hebrew University Medical Center, Ein Karem, Jerusalem, Israel
^b Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
^c Wohl Institute of Translational Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
^d Department of Obstetrics and Gynecology, Hadassah Hebrew University Medical Center, Ein Karem, Jerusalem, Israel
^e The Goldyne Savad Institute of Gene Therapy and MRI Laboratory, Hadassah Hebrew University Medical Center, Ein Karem, Jerusalem, Israel

Abstract
Introduction: We previously reported blood oxygen level dependent MRI (BOLD-MRI) for monitoring placental and fetal hemodynamic changes in mice following maternal hypercapnia. Here we use BOLD-MRI to compare the placental and fetal hemodynamic effects of different maternal vasopressors in mice. Methods: Pregnant ICR mice (n = 16; E17.5) anesthetized with pentobarbital (80 mg/kg i.p.) were placed supine in a 4.7-T Bruker Biospec MRI. Following baseline images, equipotential doses of ephedrine (10 mg/kg) or phenylephrine (10mcg/kg) were administered intravenously. Changes in placental and fetal signal were analyzed from T2*-weighted gradient echo MR images (TR/TE = 147/10 ms). Different regions of interest (placenta, fetal heart, fetal liver and fetal brain) were identified. Percentage change of BOLD-MRI signal intensity (SI) were presented as time curves. Results: Ephedrine and phenylephrine elicited markedly different effects. Phenylephrine caused an approximate 50% reduction in placental, fetal heart and fetal liver BOLD-MRI-SI, but fetal brain BOLD-MRI-SI was unchanged (statistically different from placenta and other fetal organs; p < 0.001), and the fetal brain/liver BOLD-MRI-SI ratio was markedly increased versus baseline (p < 0.001). Following ephedrine, placental BOLD-MRI-SI increased 30% and fetal heart BOLD-MRI-SI was reduced 26%; other fetal organs were unchanged. Blood gases were unchanged. Discussion: Phenylephrine induced BOLD-MRI-SI changes suggestive of placental and fetal hypoperfusion with brain sparing. Ephedrine induced BOLD-MRI-SI changes suggestive of increased cardiac output; we speculate that reduced fetal heart BOLD-MRI-SI may be due to increased fetal myocardial oxygen extraction or metabolic acidosis. The result demonstrates the potential of BOLD-MRI as a non-invasive hemodynamic tool for assessing pharmacodynamics effects in the placental and fetus. © 2019

Author Keywords
Animal models;  Functional MRI;  Pharmacodynamics;  Placental blood flow;  Vasopressors

Document Type: Article
Publication Stage: Final
Source: Scopus