Neurosciences Commons^™

Super-Fast, Super-Early: High-Frequency Oscillations May Be A Prelude To Alzheimer's Dementia In Down Syndrome, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease (AD) dementia has near full penetrance in adults with Down syndrome (DS) and is strongly linked to late-onset myoclonic epilepsy in Down syndrome (LOMEDS). However, promising biomarkers of epileptogenicity, such as high-frequency oscillations (HFOs >250 Hz), have not been studied. This study is the first to use wideband polysomnography in DS to investigate if HFOs occurred and preceded AD dementia and LOMEDS. Methods: Wideband (0.1 to 500 Hz, 2048 Hz) polysomnography was performed using the international 10–20 system. HFOs were automatically detected during slow-wave sleep, followed by manual review. Results: Fourteen individuals with DS and five age-matched euploid …

Restoration Of Sfrp3 Preserves The Neural Stem Cell Pool And Spatial Discrimination Ability In A Mouse Model Of Alzheimer's Disease, Chia-Hsuan Fu, Jin Park, Umberto Tosi, Francisco A Blanco, Manuel Silva-Pérez, Kavitha Muralidharan, Jason C You, Minjung Lee, Gabriel S Stephens, Xiaohong Zhang, Yi Zheng, Helen Scharfman, Kimberley F Tolias, Jeannie Chin

Faculty, Staff and Students Publications

Individuals with Alzheimer's disease (AD) have an increased incidence of seizures, which worsen cognitive decline. Using a transgenic mouse model of AD neuropathology that exhibits spontaneous seizures, we previously found that seizure activity stimulates and accelerates depletion of the hippocampal neural stem cell (NSC) pool, which was associated with deficits in neurogenesis-dependent spatial discrimination. However, the precise molecular mechanisms that drive seizure-induced activation and depletion of NSCs are unclear. Here, using mice of both sexes, we performed RNA-sequencing on the hippocampal dentate gyrus and identified differentially expressed regulators of neurogenesis in the Wnt signaling pathway that regulates many aspects of …

The Perspectives And Experiences Of Prospective Parents Declining Diagnostic Prenatal Genome Sequencing In Continuing Pregnancies With Fetal Structural Anomalies, Lisa S Weingarten, Allison Rosenbaum, Jessica De Voest, Stephanie Galloway, Jessica L Giordano, Samantha Stover, Lauren E Westerfield, Grant Bonesteele, Kelly L Gilmore, Leandra Tolusso, Beatrix Wong, A Theresa Wittman, Daniel T Swarr, Nancy Leslie, Anthony Johnson, Ignatia B Van Den Veyver, Neeta L Vora, Rebecca G Clifton, Aaron B Caughey, Ronald J Wapner, Wendy K Chung

Duncan NRI Faculty and Staff Publications

Objective: This study evaluates an understudied perspective: the experiences of prospective parents who decline prenatal genome sequencing (pGS) for continuing pregnancies with fetal structural anomalies.

Method: We recruited a total cohort of 300 parents of 150 pregnancies who declined pGS, including 33 individuals who underwent an invasive procedure. These parents were invited to participate in a semi-structured interview between 1 and 15 months post-partum. We used Thematic Analysis to code and analyze interviews.

Results: We interviewed 22 parents of 16 pregnancies. Reasons for declining testing included risks of invasive procedures (n = 19, 86%), lack of prenatally actionable findings (n …

A Distinct Pp2a Subunit Regulates Local Protein Phosphorylation At The Axon Initial Segment, Andrew P Anderson, Sanghyun Kim, Allison J Melton, Xiaoyun Ding, Wei Zhang, Alexander B Saltzman, Anna Malovannaya, Matthew N Rasband, Yudong Gao

Faculty, Staff and Students Publications

Protein phosphorylation plays a crucial role in regulating the cytoskeletal and membrane proteins at the axon initial segment (AIS). However, our knowledge of AIS-specific kinases and phosphatases is very limited. Here, we report the identification of a protein phosphatase 2A (PP2A) B55 regulatory subunit enriched at the AIS in mice: Ppp2r2c. Our results demonstrate that PP2A-B55 subunits exhibit substantial heterogeneity in their subcellular localization and function. Notably, the Ppp2r2c subunit is selectively concentrated at the AIS, and this enrichment is driven by its unique structure. Utilizing a microelectrode array system (MEA), we show that Ppp2r2c modulates neuronal activity during in …

Targeting Tet3 Suppresses Group 3 Medulloblastoma Stemness And Progression Via Impairing Hypomethylation Of Otx2 Super-Enhancer, Xuan Chen, Ziwei Wang, Yan Song, Yu Su, Yahui Zhao, Jiankang Li, Wei Wang, Jiao Zhang, Craig Daniels, Xiaochong Wu, Olivier Saulnier, Yanan Wang, Fei Liu, Kaiwen Deng, Dongming Han, Zijia Liu, Meiyu Li, Liam D Hendrikse, Alexandra Rasnitsyn, Evan Y Wang, Dongyang Wang, Zhaoyang Feng, Yanong Li, Zitong Zhao, Hongyu Yuan, Youliang Sun, Yifei Jiang, Yanfeng Shi, Tao Yang, Xueling Qi, Yong Hou, Chunde Li, Yong-Qiang Liu, Yu Tian, Shuaicheng Li, Xiaoguang Qiu, Michael D Taylor, Guo Liang Li, Tao Jiang, Hailong Liu

Faculty, Staff and Students Publications

Medulloblastoma (MB), particularly Group_3 (G3-MB), remains the most aggressive subgroup due to strong stemness and therapeutic resistance. Through genome-wide DNA methylation and transcriptomic analysis of human MB samples, we identify enhancer hypomethylation as a key feature sustaining G3-MB stemness and tumor progression. Notably, hypomethylation of the Otx2 super-enhancer (SE) is a prognostic marker and potential therapeutic target for G3-MB patients. We demonstrate that disrupting Otx2 SE activity effectively reduces tumor growth in vivo, highlighting its critical role in G3-MB maintenance. TET3, recruited by OTX2, demethylates the Otx2 SE, promoting chromatin opening and sustaining tumor proliferation and stemness. To translate these …

Capsinoids, Non-Pungent Trpv1 Agonists, Induce A Mild Hypothermia That Provides Short- And Long-Term Neuroprotection After Ischemic Stroke, Alexander Andersohn, Alexander Andersohn

Dissertations and Theses (Open Access)

Therapeutic hypothermia (TH) has demonstrated neuroprotection in instances of cardiac arrest and neonatal hypoxia/ischemia but faces different challenges in application to stroke due to the activation of cold defense mechanisms in conscious patients. This dissertation examines the efficacy and specificity of capsinoids (a purified mixture of capsiate and dihydrocapsiate) to induce a sustained mild hypothermia in conscious mice that is neuroprotective after stroke. Capsinoids function as TRPV1 agonists. However, unlike capsaicin, capsinoids are vulnerable to esterase-mediated breakdown, thus significantly restricting their action to the site of delivery. We showed that capsinoids delivered intraperitoneally (IP) to mice induced a TRPV1-dependent drop …

A Transdiagnostic, Multi-Modal Approach To Understanding Apathy: Methodological And Analytical Framework, Yunglin Gazes, Hideo Suzuki, Lee-Anne Morris, Seonjoo Lee, Zekai Jin, Edward D Huey, Bryan B Chen, Campbell Le Heron, Sarah R Heibronner, Nora Vanegas-Arroyave

Faculty, Staff and Students Publications

Apathy is characterized by loss of motivation and manifests as a reduction of goal-directed behavior. Apathy is highly prevalent across neurodegenerative diseases, including Alzheimer's Disease (AD) and Parkinson's Disease (PD), and is an important contributor to the disability and reduce quality of life in these conditions. The treatment of apathy remains challenging due to a lack of specific therapies, largely attributed to an incomplete understanding of its cognitive and neuroanatomical underpinnings, crucial for developing targeted interventions. Apathy can be mechanistically studied through effort-based decision-making (EBDM) paradigms, where individuals choose between low- and high-effort tasks for varying reward magnitudes. Anatomically, apathy …

Exploration Of Zileuton Protective Mechanisms Against Vancomycin-Associated Nephrotoxicity, Cole S Hudson, James E Smith, Rongjin Sun, Linh T Vuong, Luan D Truong, David Sheikh-Hamad, Masayuki Nigo, Ming Hu, Vincent H Tam

Faculty, Staff and Students Publications

Vancomycin is one of the most commonly used parenteral antibiotics for treating drug-resistant bacterial infections, however, it is hindered by nephrotoxicity. We previously demonstrated that zileuton could delay the onset of vancomycin-associated nephrotoxicity in rats. Here, we sought to understand the mechanism(s) of zileuton renal protection. Sprague-Dawley rats were administered vancomycin (200 mg/kg) and zileuton (1 and 4 mg/kg) daily for 10 days. After 3 days, kidneys were collected from select animals for histopathological analysis of renal injury. Single-dose vancomycin serum pharmacokinetics and renal tissue spatial distribution with adjuvant zileuton were evaluated. In vitro, proximal tubular cells were exposed …

From Bladder To Brain: How You Know When It’S Time To Go, Anne M J Verstegen, Kara L Marshall

Duncan NRI Faculty and Staff Publications

The decision to urinate relies on assessing bladder fullness and context to determine an appropriate time and place to go. Any disruption in this interoceptive process results in frequent and sometimes debilitating consequences in daily life. Recent work has uncovered key pathways and brain regions that contribute to the sense of bladder stretch and the control of urinary reflexes, but many open questions remain. Here, we review the known mechanisms that convey sensory information from the bladder to the brain and back down again, and we highlight the knowledge gaps and opportunities for better understanding this system, which will be …

Loss Of The Lysosomal Protein Cln3 Triggers C-Abl-Dependent Yap1 Pro-Apoptotic Signaling, Neuza Domingues, Alessia Calcagni', Sofia Freire, Joana Pires, Ricardo Casqueiro, Ivan L Salazar, Niculin Joachim Herz, Tuong Huynh, Katarzyna Wieciorek, Tiago Fleming Outeiro, Henrique Girão, Ira Milosevic, Andrea Ballabio, Nuno Raimundo

Duncan NRI Faculty and Staff Publications

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment …

Cross-Species Standardised Cortico-Subcortical Tractography, Stephania Assimopoulos, Shaun Warrington, Davide Folloni, Katherine Bryant, Ali-Reza Mohammadi-Nejad, Wei Tang, Saad Jbabdi, Sarah R Heilbronner, Rogier B Mars, Stamatios N Sotiropoulos

Faculty, Staff and Students Publications

Despite their importance for brain function, cortico-subcortical white matter tracts are under-represented in diffusion magnetic resonance imaging tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus, and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed …

Diaphragm Resuspension To Titanium Neo-Ribs: A Technique For Chest-Wall Reconstruction Involving The Costal Margin, Patrick Mcgeoghegan, Vuong-Lam Pham, Cristian Medina, Sebastian Winocour, Robert Taylor Ripley, Ramiro Fernandez

Faculty, Staff and Students Publications

No abstract provided.

Profiling Tumour-Infiltrating Immune Cells In A Large Paediatric Medulloblastoma Cohort: A Retrospective Analysis, Mingze Chen, Xiangjun Shi, Yi Wang, Jiao Zhang, Jirong Guo, Xiuchen Guan, Yu Sun, Wenhao Wu, Chunde Li, Yongji Tian, Yunwei Ou, Tian Li, Kai Jiang, Michael D Taylor, Xuebin Liao, Liwei Zhang, Tao Sun

Faculty, Staff and Students Publications

Background: Tumour-infiltrating immune cells exert both pro-tumour and anti-tumour effects on intracranial tumours. In this study, we investigated the prognostic value of various infiltrating immune cells in medulloblastoma (MB) within a large cohort.

Methods: We employed multiplex immunofluorescent (mIF) staining of tissue microarrays to assess the densities of T cells, B cells, NK cells, macrophages, and immune checkpoints in tumour samples from 249 primary paediatric patients with primary MB. Overall survival (OS) analysis, progression-free survival (PFS), and Cox regression analyses were utilised to explore potential relationships between immune cell densities and survival outcomes. Subsequently, multivariate Cox regression was validated using …

Alteration Of Gut Microbial Ecology By The Direct Activation Of The Brain: Inverse Gut-Microbiome-Brain Dynamics, I-Ching Wang, Jessica L Swanson, Jillian L Waters, Mikhail Y Kochukov, Shelly A Buffington, Sean W Dooling, Benjamin R Arenkiel, Mauro Costa-Mattioli

Faculty, Staff and Students Publications

The gut-microbiome-brain axis is a bidirectional communication system influencing host physiology and overall fitness. While "bottom-up" effects-where gut microbes influence brain function and behavior-are well established, direct evidence for "top-down" modulation-where the brain shapes the gut microbial ecology-remains elusive. Here, we show that the selective expression of the bacterial ion channel mNaChBac in glutamatergic lateral habenula (LHb) neurons increases their bursting activity and leads to endophentypes associated with depression. Importantly, this chronic activation leads to changes in the gut microbiome composition over time, as reflected by shifts in alpha-diversity and alterations in specific microbial taxa. These findings provide direct evidence …

The Effect Of Uterine Entry Technique On Chorioamniotic Membrane Separation In Fetoscopic Laser Photocoagulation For Twin-To-Twin Transfusion Syndrome: Protocol For A Randomized Controlled Trial, Brian A Burnett, Jessian L Munoz, Rebecca M Johnson, Christian M Parobek, Luis E Delgadillo Chabolla, Cara Buskmiller, Roopali V Donepudi, Magdalena Sanz Cortes, Michael A Belfort, Ahmed A Nassr

Faculty, Staff and Students Publications

Background: Chorioamniotic membrane separation (CAS) is a recognized complication of fetoscopic laser photocoagulation (FLP) for twin-to-twin transfusion syndrome (TTTS), associated with increased risks of preterm prelabor rupture of membranes (PPROM) and preterm birth (PTB). Although CAS is well described, its incidence and relationship to specific surgical techniques, particularly the method of uterine entry, are not well defined in the published literature. No randomized trials have evaluated whether entry technique influences the risk of CAS.

Methods: We present the protocol for a randomized controlled trial comparing sharp-trocar and Seldinger uterine entry techniques for FLP in TTTS diagnosed between 16 + 0 …

Apathy Self-Awareness And Its Neural Correlates In Parkinson’S Disease, Hannah Conn, Hideo Suzuki, Zekai Jin, Ana Marin, Xi Zhu, Seonjoo Lee, Edward Huey, Ratko Radakovic, Sarah R Heilbronner, Nora Vanegas-Arroyave

Faculty, Staff and Students Publications

Apathy is a prevalent non-motor symptom in Parkinson's disease (PD) that negatively impacts quality of life. Impaired self-awareness of apathy (ISA-a) further impacts patient care by limiting engagement. While apathy has been associated with reduced fronto-striatal functional connectivity (FC), the neural basis of ISA-a remains unclear. We examined ISA-a in 52 individuals and the neural basis of ISA-a in 35 individuals with PD using a dimensional approach (i.e., initiation, executive, and emotional apathy) and resting-state fMRI (3T scanner). Apathetic PD patients (42%) showed poorer self-awareness than non-apathetic peers. Apathetic PD patients showed a trend towards reduced FC between the left …

Disinhibited Behavior Associated With Rapid Clinical Response To Deep Brain Stimulation For Obsessive-Compulsive Disorder: Illustrative Cases, Sarah S Soubra, Tommy B Liu, Zain U Naqvi, Thomas Hamre, Danika L Paulo, Kalman A Katlowitz, Nisha Giridharan, Katie Van Arsdel, Jonathan H Bentley, Kasra A Mansourian, Davin Devara, Eric A Storch, Sarah R Heilbronner, Sameer A Sheth, Wayne Goodman, Nicole R Provenza

Faculty, Staff and Students Publications

Background: Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) can alleviate symptoms of obsessive-compulsive disorder (OCD) refractory to conventional therapies. Overstimulation, however, can elicit pathological behaviors marked by disinhibition and recklessness.

Observations: Two patients with OCD underwent DBS of the VC/VS region and met responder status within 1 month of stimulation onset, as evidenced by a ≥ 35% reduction in their Yale-Brown Obsessive Compulsive Scale score. Notably, both patients exhibited signs of disinhibited behavior soon after DBS activation, including gambling, sleep disruption, and interpersonal relationship volatility. Through careful management, responder status persisted stably beyond the transient period of …

Multisite Assembly Of Gateway Induced Clones (Magic): A Flexible Cloning Toolbox For Use In Vertebrate Model Systems, William B Gillespie, Yuwen Zhang, Oscar E Ruiz, Juan Cerda, Joshua Ortiz-Guzman, Michelle Sherman, Williamson D Turner, Gabrielle Largoza, Lili E Mosser, Esther Fujimoto, Chi-Bin Chien, Kristen M Kwan, Benjamin R Arenkiel, W Patrick Devine, Joshua D Wythe

Duncan NRI Faculty and Staff Publications

Here, we present MultiSite Assembly of Gateway Induced Clones (MAGIC), which leverages Gateway-based recombinatorial cloning technology for rapid, modular assembly of plasmids to facilitate transgenesis in cells and vertebrate animal models. The MAGIC collection of plasmids spans a range of in vitro and in vivo uses, from tools for optically and chemically tunable gene expression, to simultaneous expression of microRNAs and fluorescent reporters, to a suite of distinct subcellular compartmental fluorescent reporters, to Cre and Dre recombinase-dependent gene expression. MAGIC system components are compatible with existing MultiSite Gateway Tol2 systems currently used in zebrafish and mammalian lentiviral and adenoviral Destination …

Weight Loss And A Shunt On “Off”: An Odd Case Of Overshunting In An Idiopathic Intracranial Hypertension Patient Illustrative Case, Thomas Hamre, Ashley Ricciardelli, Alex Flores, Ashwin Viswanathan

Faculty, Staff and Students Publications

Background: CSF diversion with ventriculoperitoneal (VP) shunts is a common treatment for idiopathic intracranial hypertension (IIH). Rarely, overshunting can occur. Diagnosing and managing overshunting in an IIH patient with a shunt can be challenging. The authors present a unique etiology of overshunting successfully treated with shunt ligation.

Observations: A 48-year-old female with IIH who had undergone VP shunt placement with a programmable Certas valve presented with symptoms concerning for low-pressure headaches following a 25-kg weight loss. Intracranial pressure (ICP) monitoring along with an inpatient headache diary facilitated the diagnosis of intracranial hypotension secondary to CSF overdrainage through the shunt. Following …

Ezhip Boosts Neuronal-Like Synaptic Gene Programs And Depresses Polyamine Metabolism, Elham Hasheminasabgorji, Huey-Miin Chen, Taylor A Gatesman, Subhi Talal Younes, Gabrielle A Nobles, Farhang Jaryani, Heather Mao, Kwanha Yu, Benjamin Deneen, Wee Yong, Michael D Taylor, Sameer Agnihotri, Marco Gallo

Faculty, Staff and Students Publications

It is currently understood that the characteristic loss of the repressive histone mark H3K27me3 in PFA ependymoma and diffuse midline glioma (DMG) are caused by complementary mechanisms mediated by EZHIP and the oncohistone H3K27M, respectively. To support the complementarity of these mechanisms, rare H3K27M-negative DMGs express EZHIP. Interestingly, EZHIP is one of the few genes recurrently mutated in PFA. The significance of EZHIP mutations in PFA, and whether EZHIP has wider functions in addition to repression of H3K27me3 deposition, are not known. Here, we investigated the mutational landscape of EZHIP in pediatric brain tumors. We found that EZHIP mutations occur …

Cognitive Reserve Predicts Baseline Tau Burden In The Us Pointer Trial Imaging Cohort, Valory N Pavlik, Chris J Weber, Joseph C Masdeu, Laura D Baker, Melissa M Yu, Michele York, Rachel A Whitmer, Susan M Landau, Theresa M Harrison, Tomas M Holland, Laura Lovato

Faculty, Staff and Students Publications

Introduction: Higher cognitive reserve (CR) is associated with reduced dementia risk. We hypothesized that higher CR is associated with less baseline Alzheimer's disease (AD) pathology in the U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort.

Methods: A subsample of participants underwent amyloid beta and tau positron emission tomography imaging. Regression analysis was used to model the association between educational attainment (EA) as a CR proxy measure, amyloid positivity, and entorhinal cortex (ERC) and meta-temporal region of interest (meta-ROI) tau standardized uptake value ratio (SUVR).

Results: In 911 participants with complete imaging data, higher …

Neural Signatures And Personalized Neuromodulation In A Subject Experiencing Context-Dependent Inhibitory Control Deficits, Layth S Mattar, Shraddha Shah, Lily S Chamakura, Denise Oswalt, Yue Zhang, Davin Devara, Jung Uk Kang, Zahra Jourahmad, Ryan Jafri, Geoffrey Liu, Joshua Adkinson, Isabel A Danstrom, Xiaoxu Fan, Yvonne Y Reed, Kelly R Bijanki, Alica Goldman, Lu Lin, Vaishnav Krishnan, Nicole R Provenza, Andrew J Watrous, Sameer A Sheth, Sarah R Heilbronner, Garrett P Banks, Eleonora Bartoli

Faculty, Staff and Students Publications

The ability to override prepotent actions is critical to control impulses and adjust behavior depending on goals and contextual needs. In this study, we investigate the inhibitory control abilities of a patient diagnosed with Klüver-Bucy Syndrome following a left temporal resection. The patient presented with disruptive hypersexuality symptoms akin to compulsions, leading to the inability to control and suppress inappropriate actions. The patient was recruited for the current research study while undergoing intracranial monitoring for epilepsy, to investigate the cognitive and neural processes underlying the patient's inhibitory control symptoms. We formulated the hypothesis that a reactive inhibitory control deficit emerges …

Pkr-Driven Isr Signaling Controls Synaptic Translation And Structural Plasticity In An Age-Dependent Manner, Nicolás W Martínez, Felipe Gómez, Ariel Tapia-Godoy, Juan Francisco Roa, Fernanda Moreso-Contreras, Yuwei Liu, Claudia Jara, Cheril Tapia-Rojas, Iván Alfaro, Mauro Costa-Mattioli, Soledad Matus

Faculty, Staff and Students Publications

The integrated stress response (ISR) modulates protein homeostasis in response to both intracellular and extracellular signals. The four kinases involved in the ISR all phosphorylate the same target, the alpha subunit of eukaryotic initiation factor 2 (eIF2α), to integrate various stress signals, thereby regulating cell fate. The activation of the ISR reprograms the proteome by inhibiting general protein synthesis while increasing the translation of specific mRNAs. In the brain, the ISR regulates the type of synaptic plasticity necessary for forming long-term memory. More importantly, the activation of the ISR has emerged as a causal mechanism underlying cognitive decline associated with …

Sensory-Selective Peripheral And Neuraxial Nerve Blockade With 2',6'-Pipecoloxylidide, Claire A Ostertag-Hill, Shuanglong Chen, Tianrui Xue, Rachelle Shao, Matthew Torre, Bin Feng, Zahra Vahedi, Longtu Chen, Steven J Staffa, Yueqin Zheng, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Background: Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. This articles describes the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics, 2',6'-pipecoloxylidide (PPX).

Methods: PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. …

Microglia Sensing Of Peripheral Signals That Bridge The Brain And Body, Claire E Young, Melanie A Samuel

Faculty, Staff and Students Publications

Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could …

Injectable Microparticle-Nanoliposome Hydrogel For Extended Release Of Small Hydrophilic Molecules, Gil Aizik, Wonmin Choi, Claire A Ostertag-Hill, Matthew Torre, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Achieving sustained local release of small hydrophilic drugs is challenging and is particularly important when the drugs are toxic. To address these challenges, we developed a hybrid system comprising drug-containing microparticles embedded within a nanoliposomal hydrogel matrix. This system forms through salt-induced gelation using physiologically relevant sodium chloride concentrations (0.9%), allowing for microparticle encapsulation without harsh chemical processes. In vitro, the hybrid system exhibited a slower release of encapsulated cargo compared to microparticles or hydrogel alone. In vivo proof of principle was provided with tetrodotoxin (TTX), a small hydrophilic and ultrapotent local anesthetic, which can cause systemic toxicity if the …

The Fast And The Very Fast: High-Frequency Oscillations In Alzheimer's Disease, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Alzheimer's disease increases the risk of developing epilepsy together with cognitive decline. Early diagnosis or prediction of parameters associated with epileptic activity can greatly help in managing disease outcomes. Network hyperexcitability is a candidate of interest as a neurophysiological biomarker of Alzheimer's disease. High-frequency oscillations are increasingly recognized as potential biomarkers of hyperexcitability and epileptic activity. However, they have not yet been identified in Alzheimer's disease. In this study, we measured high-frequency oscillations via magnetoencephalography recordings in Alzheimer's disease patients with and without epileptic activity, as part of a Phase 2a randomized, double blind clinical trial of the efficacy of …

Generative Modeling For Interpretable Anomaly Detection In Medical Imaging: Applications In Failure Detection And Data Curation, Mckell E Woodland, Mais Altaie, Caleb S O'Connor, Austin H Castelo, Olubunmi C Lebimoyo, Aashish C Gupta, Joshua P Yung, Paul E Kinahan, Clifton D Fuller, Eugene J Koay, Bruno C Odisio, Ankit B Patel, Kristy K Brock

Faculty, Staff and Students Publications

This work aims to leverage generative modeling-based anomaly detection to enhance interpretability in AI failure detection systems and to aid data curation for large repositories. For failure detection interpretability, this retrospective study utilized 3339 CT scans (525 patients), divided patient-wise into training, baseline test, and anomaly (having failure-causing attributes—e.g., needles, ascites) test datasets. For data curation, 112,120 ChestX-ray14 radiographs were used for training and 2036 radiographs from the Medical Imaging and Data Resource Center for testing, categorized as baseline or anomalous based on attribute alignment with ChestX-ray14. StyleGAN2 networks modeled the training distributions. Test images were reconstructed with backpropagation and …

Intracranial Neural Biomarkers Of Psychiatric Symptoms And Their Utility For Guiding Neuromodulation Therapy: A Systematic Review, Katherine E Kabotyanski, Nicole R Provenza, Sameer A Sheth

Faculty, Staff and Students Publications

The quest to develop and improve neuromodulatory therapies for treatment-resistant psychiatric disorders has been fueled by the discovery of intracranial neural biomarkers of symptom dimensions. These neural correlates shed light on the underlying neurophysiology of the disorder and may even be useful in guiding therapy delivery. This systematic review summarizes recent efforts in this field relating neural activity to behavior and symptomatology. For years, the majority of these neurobehavioral relationships had been studied in the hospital or clinic environment. Recent technological advances in implanted neuromodulation devices that permit not only stimulation, but also intracranial neural recording have enabled this research …

Advancements In Prenatal Genetic Screening And Testing: Emerging Technologies And Evolving Applications, Mona M Makhamreh, Mei Ling Chong, Ignatia B Van Den Veyver

Duncan NRI Faculty and Staff Publications

Advancements in genomic technologies have transformed prenatal genetic testing, offering more accurate, comprehensive, and noninvasive approaches to reproductive care. This review provides an in-depth overview of current methodologies and emerging innovations, including expanded carrier screening (ECS), cell-free DNA (cfDNA) testing, chromosomal microarray analysis (CMA), and sequencing-based diagnostics. We highlight how next-generation sequencing (NGS) technologies have revolutionized carrier screening and fetal genome analysis, enabling detection of a broad spectrum of genetic conditions. The clinical implementation of cfDNA has expanded from common aneuploidies to include copy number variants (CNVs), and single-gene disorders. Diagnostic testing has similarly evolved, with genome sequencing outperforming traditional …