Neurology Commons^™

Clinical Exome Sequencing Data Reveal High Diagnostic Yields For Congenital Diaphragmatic Hernia Plus (Cdh+) And New Phenotypic Expansions Involving Cdh, Tiana M Scott, Ian M Campbell, Andres Hernandez-Garcia, Seema R Lalani, Pengfei Liu, Chad A Shaw, Jill A Rosenfeld, Daryl A Scott

Duncan NRI Faculty and Staff Publications

Background: Congenital diaphragmatic hernia (CDH) is a life-threatening birth defect that often co-occurs with non-hernia-related anomalies (CDH+). While copy number variant (CNV) analysis is often employed as a diagnostic test for CDH+, clinical exome sequencing (ES) has not been universally adopted.

Methods: We analysed a clinical database of ~12 000 test results to determine the diagnostic yields of ES in CDH+ and to identify new phenotypic expansions.

Results: Among the 76 cases with an indication of CDH+, a molecular diagnosis was made in 28 cases for a diagnostic yield of 37% (28/76). A provisional diagnosis was made in seven other …

Response Of Astrocyte Subpopulations Following Spinal Cord Injury., R Vivian Allahyari, Nicolette M Heinsinger, Daniel Hwang, David A Jaffe, Javad Rasouli, Stephanie Shiers, Samantha J Thomas, Theodore J Price, Abdolmohamad Rostami, Angelo C Lepore

Farber Institute for Neuroscience Faculty Papers

There is growing appreciation for astrocyte heterogeneity both across and within central nervous system (CNS) regions, as well as between intact and diseased states. Recent work identified multiple astrocyte subpopulations in mature brain. Interestingly, one subpopulation (Population C) was shown to possess significantly enhanced synaptogenic properties in vitro, as compared with other astrocyte subpopulations of adult cortex and spinal cord. Following spinal cord injury (SCI), damaged neurons lose synaptic connections with neuronal partners, resulting in persistent functional loss. We determined whether SCI induces an enhanced synaptomodulatory astrocyte phenotype by shifting toward a greater proportion of Population C cells and/or increasing …

Blood–Brain Barrier Disruption Mediated By Ffa1 Receptor—Evidence Using Miniscope, Kristen L Lindenau, Jeffrey L Barr, Christopher R Higgins, Kevin T Sporici, Eugen Brailoiu, Gabriela C Brailoiu

Faculty, Staff and Student Publications

Omega-3 polyunsaturated fatty acids (n-3 PUFAs), obtained from diet and dietary supplements, have been tested in clinical trials for the prevention or treatment of several diseases. n-3 PUFAs exert their effects by activation of free fatty acid (FFA) receptors. FFA1 receptor, expressed in the pancreas and brain, is activated by medium- to long-chain fatty acids. Despite some beneficial effects on cognition, the effects of n-3 PUFAs on the blood-brain barrier (BBB) are not clearly understood. We examined the effects of FFA1 activation on BBB permeability in vitro, using rat brain microvascular endothelial cells (RBMVEC), and in vivo, by assessing Evans …

Seizure Prediction In Epilepsy Patients, Gary Dean Cravens

NSU REACH and IPE Day

Purpose/Objective: Characterize rigorously the preictal period in epilepsy patients to improve the development of seizure prediction techniques. Background/Rationale: 30% of epilepsy patients are not well-controlled on medications and would benefit immensely from reliable seizure prediction. Methods/Methodology: Computational model consisting of in-silico Hodgkin-Huxley neurons arranged in a small-world topology using the Watts-Strogatz algorithm is used to generate synthetic electrocorticographic (ECoG) signals. ECoG data from 18 epilepsy patients is used to validate the model. Unsupervised machine learning is used with both patient and synthetic data to identify potential electrophysiologic biomarkers of the preictal period. Results/Findings: The model has shown states corresponding to …

Recent Insights Into The Role Of Glia And Oxidative Stress In Alzheimer’S Disease Gained From Drosophila, Lindsey D Goodman, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Here, we discuss findings made using Drosophila on Alzheimer's disease (AD) risk and progression. Recent studies have investigated the mechanisms underlying glia-mediated neuroprotection in AD. First, we discuss a novel mechanism of glial lipid droplet formation that occurs in response to elevated reactive oxygen species in neurons. The data suggest that disruptions to this process contribute to AD risk. We further discuss novel mechanistic insights into glia-mediated Aβ42-clearance made using the fly. Finally, we highlight work that provides evidence that the aberrant accumulation of reactive oxygen species in AD may not just be a consequence of disease but contribute to …

Disruption Of Mecp2-Tcf20 Complex Underlies Distinct Neurodevelopmental Disorders, Jian Zhou, Hamdan Hamdan, Hari Krishna Yalamanchili, Kaifang Pang, Amy E Pohodich, Joanna Lopez, Yingyao Shao, Juan A Oses-Prieto, Lifang Li, Wonho Kim, Mark A Durham, Sameer S Bajikar, Donna J Palmer, Philip Ng, Michelle L Thompson, E Martina Bebin, Amelie J Müller, Alma Kuechler, Antje Kampmeier, Tobias B Haack, Alma L Burlingame, Zhandong Liu, Matthew N Rasband, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused …

Loss Of Irf2bpl Impairs Neuronal Maintenance Through Excess Wnt Signaling, Paul C Marcogliese, Debdeep Dutta, Shrestha Sinha Ray, Nghi D P Dang, Zhongyuan Zuo, Yuchun Wang, Di Lu, Fatima Fazal, Thomas A Ravenscroft, Hyunglok Chung, Oguz Kanca, Jijun Wan, Emilie D Douine, Undiagnosed Diseases Network, Loren D M Pena, Shinya Yamamoto, Stanley F Nelson, Matthew Might, Kathrin C Meyer, Nan Cher Yeo, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction …

Sensory Processing Phenotypes In Phelan-Mcdermid Syndrome And Syngap1-Related Intellectual Disability, Ariel M Lyons-Warren, Maria C Mccormack, Jimmy L Holder

Duncan NRI Faculty and Staff Publications

Sensory processing differences are an established feature of both syndromic and non-syndromic Autism Spectrum Disorders (ASDs). Significant work has been carried out to characterize and classify specific sensory profiles in non-syndromic autism. However, it is not known if syndromic autism disorders, such as Phelan-McDermid Syndrome (PMD) or SYNGAP1-related Intellectual Disability (SYNGAP1-ID), have unique sensory phenotypes. Understanding the sensory features of these disorders is important for providing appropriate care and for understanding their underlying mechanisms. Our objective in this work was to determine the sensory processing abnormalities present in two syndromic ASDs: Phelan-McDermid Syndrome and SYNGAP1-related Intellectual …

Short Chain Fatty Acids Taken At Time Of Thrombectomy In Acute Ischemic Stroke Patients Are Independent Of Stroke Severity But Associated With Inflammatory Markers And Worse Symptoms At Discharge, Nicholas Henry, Jacqueline A. Frank, Christopher J. Mclouth, Amanda L. Trout, Andrew J. Morris, Jianzhong Chen, Ann M. Stowe, Justin F. Fraser, Keith R. Pennypacker

Behavioral Science Faculty Publications

Introduction: Short chain fatty acids (SCFA) are gut microbiota-derived metabolites that contribute to the gut-brain axis and may impact stroke outcomes following gut dysbiosis. We evaluated plasma SCFA concentrations against stroke severity parameters and identified SCFA-associated protein networks.

Methods: The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC), a continuously enrolling tissue bank, was used to obtain stroke samples. Arterial blood distal and proximal to the thrombus was obtained from Acute Ischemic Stroke (AIS) Patients (n=53) during thrombectomy. Patient demographics, stroke presentation and outcome parameters were reported. The SCFAs were isolated from proximal plasma via chemical derivatization UHPLC coupled tandem …

Transcranial Direct Current Stimulation On Parkinson’S Disease: Systematic Review And Meta-Analysis, Paloma Cristina Alves De Oliveira, Thiago Anderson Brito De Araújo, Daniel Gomes Da Silva Machado, Abner Cardoso Rodrigues, Marom Bikson, Suellen Marinho Andrade, Alexandre Hideki Okano, Hougelle Simplicio, Rodrigo Pegado, Edgard Morya

Publications and Research

Background: Clinical impact of transcranial direct current stimulation (tDCS) alone for Parkinson’s disease (PD) is still a challenge. Thus, there is a need to synthesize available results, analyze methodologically and statistically, and provide evidence to guide tDCS in PD.

Objective: Investigate isolated tDCS effect in different brain areas and number of stimulated targets on PD motor symptoms.

Methods: A systematic review was carried out up to February 2021, in databases: Cochrane Library, EMBASE, PubMed/MEDLINE, Scopus, and Web of science. Full text articles evaluating effect of active tDCS (anodic or cathodic) vs. sham or control on motor symptoms of PD were …

The Allergy Mediator Histamine Confers Resistance To Immunotherapy In Cancer Patients Via Activation Of The Macrophage Histamine Receptor H1, Hongzhong Li, Yi Xiao, Qin Li, Jun Yao, Xiangliang Yuan, Yuan Zhang, Xuedong Yin, Yohei Saito, Huihui Fan, Ping Li, Wen-Ling Kuo, Angela Halpin, Don L Gibbons, Hideo Yagita, Zhongming Zhao, Da Pang, Guosheng Ren, Cassian Yee, J Jack Lee, Dihua Yu

Duncan NRI Faculty and Staff Publications

Reinvigoration of antitumor immunity remains an unmet challenge. Our retrospective analyses revealed that cancer patients who took antihistamines during immunotherapy treatment had significantly improved survival. We uncovered that histamine and histamine receptor H1 (HRH1) are frequently increased in the tumor microenvironment and induce T cell dysfunction. Mechanistically, HRH1-activated macrophages polarize toward an M2-like immunosuppressive phenotype with increased expression of the immune checkpoint VISTA, rendering T cells dysfunctional. HRH1 knockout or antihistamine treatment reverted macrophage immunosuppression, revitalized T cell cytotoxic function, and restored immunotherapy response. Allergy, via the histamine-HRH1 axis, facilitated tumor growth and induced immunotherapy resistance in mice and humans. …

Repeated Exposure To Chlorpyrifos Is Associated With A Dose-Dependent Chronic Neurobehavioral Deficit In Adult Rats, Ana C. R. Ribeiro, Elisa Hawkins, Fay M. Jahr, Joseph L. Mcclay, Laxmikant Deshpande

Neurology Publications

Organophosphate (OP) chemicals include commonly used pesticides and chemical warfare agents, and mechanistically they are potent inhibitors of the cholinesterase (ChE) enzyme. Epidemiological studies report long-term neuropsychiatric issues, including depression and cognitive impairments in OP-exposed individuals. Chlorpyrifos (CPF) is one of the most widely used pesticides worldwide. Multiple laboratory studies have reported on either the long-term behavioral effect of an acute high-dose CPF (30-250 mg/kg) or studied sub-chronic behavioral effects, particularly the motor and cognitive effects of repeated low-dose CPF. However, studies are lacking on chronic mood and depression-related morbidities following repeated CPF doses that would mimic occupationally relevant OP …

Aneurysmal Subarachnoid Hemorrhage And Acute Subdural Hematoma, Neurosurgical And Endovascular Rescue. Case Report., José Omar Santellan Resident, José Ramón Aguilar Dr., Abraham Ibarra Dr., Ulises García Dr.

Archives of Neurosurgery

Introduction: Acute subdural hemorrhage (aSDH) in association with aneurismal subarachnoid hemorrhage (SAH) is a severe disease with an incidence of 0.5% to 7.9% of all SAH. Due to the rarity of aneurysmal aSDH, it remains difficult to define a comprehensive management protocol. In this case review, following the CARE guidelines, we show the hybrid management of this pathology to know the importance of using different types of neurosurgical treatments in case of two severe diseases in critical patients.

We present two patients who developed sudden onset cephalea and neurological impairment secondary to aneurysmal subarachnoid hemorrhage associated with acute subdural hematoma. …

Brain Antigens Stimulate Proliferation Of T Lymphocytes With A Pathogenic Phenotype In Multiple Sclerosis Patients, Assaf Gottlieb, Hoai Phuong T Pham, John William Lindsey

Faculty, Staff and Student Publications

A method to stimulate T lymphocytes with a broad range of brain antigens would facilitate identification of the autoantigens for multiple sclerosis and enable definition of the pathogenic mechanisms important for multiple sclerosis. In a previous work, we found that the obvious approach of culturing leukocytes with homogenized brain tissue does not work because the brain homogenate suppresses antigen-specific lymphocyte proliferation. We now report a method that substantially reduces the suppressive activity. We used this non-suppressive brain homogenate to stimulate leukocytes from multiple sclerosis patients and controls. We also stimulated with common viruses for comparison. We measured proliferation, selected the …

Recurrent Liponeurocytoma: A Case Report And Systematic Review Of The Literature, Darsh S Shah, Himanshu Sharma, Prem Patel, Arya Shetty, Collin William English, J Clay Goodman, Ashwin Viswanathan, Akash J Patel

Duncan NRI Faculty and Staff Publications

Background: Liponeurocytomas are rare neurocytic neoplasms that most often arise in the posterior fossa and affect individuals in the third and fifth decades of life. Most reported cases of this unique tumor in the literature have described a favorable clinical prognosis without recurrence. However, increasing reports of recurrent cases prompted the World Health Organization, in 2016, to recategorize the tumor from Grade I to the less favorable Grade II classification. We conducted a systematic review to identify recurrent cases of this unique tumor and to summarize differences between the primary and recurrent cases of liponeurocytoma.

Methods: A systematic review exploring …

Theta Burst Brain Stimulation In Painful Diabetic Neuropathy Patients: Investigating Neural Mechanisms, Bhushan Thakkar

Theses and Dissertations

Chronic pain (CP) is a significant contributor to disability and disease burden globally. In 2019, approximately 50.2 million adults (20.4% of the US population) experienced chronic pain, contributing to $560-635 billion in direct medical costs. In addition, the worldwide prevalence of diabetes mellitus has reached epidemic proportions and is set to increase to 629 million by 2045. Almost 50% of patients with diabetes present with diabetic neuropathy (DN), and one in five patients with diabetes presents with painful DN (pDN) which is the most common cause of neuropathic pain (NP) in the US. Symptomatic treatment is the mainstay of management …

Multi-Center, Single-Blind Randomized Controlled Trial Comparing Functional Electrical Stimulation Therapy To Conventional Therapy In Incomplete Tetraplegia, Kim D Anderson, Radha Korupolu, Kristin E Musselman, Jacqueline Pierce, James R Wilson, Nuray Yozbatiran, Naaz Desai, Milos R Popovic, Lehana Thabane

Faculty, Staff and Student Publications

BACKGROUND: Loss of upper extremity function after tetraplegia results in significant disability. Emerging evidence from pilot studies suggests that functional electrical stimulation (FES) therapy may enhance recovery of upper extremity function after tetraplegia. The aim of this trial was to determine the effectiveness of FES therapy delivered by the Myndmove stimulator in people with tetraplegia.

METHODS: A multi-center

RESULTS: Between June 2019 to August 2021, 51 participants were randomized to FES (

CONCLUSION: Forty sessions of FES therapy delivered by the MyndMove stimulator are as effective as conventional therapy in producing meaningful functional improvements that persist after therapy is completed. …

Anatomy And Function Of Ventral Tegmental Area Glutamate Neurons, Jing Cai, Qingchun Tong

Faculty, Staff and Student Publications

The ventral tegmental area (VTA) is well known for regulating reward consumption, learning, memory, and addiction behaviors through mediating dopamine (DA) release in downstream regions. Other than DA neurons, the VTA is known to be heterogeneous and contains other types of neurons, including glutamate neurons. In contrast to the well-studied and established functions of DA neurons, the role of VTA glutamate neurons is understudied, presumably due to their relatively small quantity and a lack of effective means to study them. Yet, emerging studies have begun to reveal the importance of glutamate release from VTA neurons in regulating diverse behavioral repertoire …

Mri Free Water As A Biomarker For Cognitive Performance: Validation In The Markvcid Consortium, Pauline Maillard, Laura J Hillmer, Hanzhang Lu, Konstantinos Arfanakis, Brian T Gold, Christopher E Bauer, Joel H Kramer, Adam M Staffaroni, Lara Stables, Danny J J Wang, Sudha Seshadri, Claudia L Satizabal, Alexa Beiser, Mohamad Habes, Myriam Fornage, Thomas H Mosley, Gary A Rosenberg, Baljeet Singh, Herpreet Singh, Kristin Schwab, Karl G Helmer, Steven M Greenberg, Charles Decarli, Arvind Caprihan

Faculty, Staff and Student Publications

Introduction: To evaluate the clinical validity of free water (FW), a diffusion tensor imaging-based biomarker kit proposed by the MarkVCID consortium, by investigating the association between mean FW (mFW) and executive function.

Methods: Baseline mFW was related to a baseline composite measure of executive function (EFC), adjusting for relevant covariates, in three MarkVCID sub-cohorts, and replicated in five, large, independent legacy cohorts. In addition, we tested whether baseline mFW predicted accelerated EFC score decline (mean follow-up time: 1.29 years).

Results: Higher mFW was found to be associated with lower EFC scores in MarkVCID legacy and sub-cohorts (p-values < 0.05). In addition, higher baseline mFW was associated significantly with accelerated decline in EFC scores (p …