Medicine and Health Sciences Commons^™

Topmed Imputed Genomics Enhances Genomic Atlas Of The Human Proteome In Brain, Cerebrospinal Fluid, And Plasma, Heng Yi, Qijun Yang, Charlie Repaci, Cheolmin Matthew Lee, Gyujin Heo, Jigyasha Timsina, Priyanka Gorijala, Chengran Yang, John Budde, Lihua Wang, Carlos Cruchaga, Yun Ju Sung

2020-Current year OA Pubs

Comprehensive expression quantitative trait loci studies have been instrumental for understanding tissue-specific gene regulation and pinpointing functional genes for disease-associated loci in a tissue-specific manner. Compared to gene expressions, proteins more directly affect various biological processes, often dysregulated in disease, and are important drug targets. We previously performed and identified tissue-specific protein quantitative trait loci in brain, cerebrospinal fluid, and plasma. We now enhance this work by analyzing more proteins (1,300 versus 1,079) and an almost twofold increase in high quality imputed genetic variants (8.4 million versus 4.4 million) by using TOPMed reference panel. We identified 38 genomic regions associated …

Multisensory Flicker Modulates Widespread Brain Networks And Reduces Interictal Epileptiform Discharges, Lou T Blanpain, Eric R Cole, Emily Chen, James K Park, Michael Y Walelign, Robert E Gross, Brian T Cabaniss, Jon T Willie, Annabelle C Singer

2020-Current year OA Pubs

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect …

Unsupervised Deep Representation Learning Enables Phenotype Discovery For Genetic Association Studies Of Brain Imaging, Khush Patel, Ziqian Xie, Hao Yuan, Sheikh Muhammad Saiful Islam, Yaochen Xie, Wei He, Wanheng Zhang, Assaf Gottlieb, Han Chen, Luca Giancardo, Alexander Knaack, Evan Fletcher, Myriam Fornage, Shuiwang Ji, Degui Zhi

Journal Articles

Understanding the genetic architecture of brain structure is challenging, partly due to difficulties in designing robust, non-biased descriptors of brain morphology. Until recently, brain measures for genome-wide association studies (GWAS) consisted of traditionally expert-defined or software-derived image-derived phenotypes (IDPs) that are often based on theoretical preconceptions or computed from limited amounts of data. Here, we present an approach to derive brain imaging phenotypes using unsupervised deep representation learning. We train a 3-D convolutional autoencoder model with reconstruction loss on 6130 UK Biobank (UKBB) participants' T1 or T2-FLAIR (T2) brain MRIs to create a 128-dimensional representation known as Unsupervised Deep learning …

Environmental And Sociocultural Factors Are Associated With Pain-Related Brain Structure Among Diverse Individuals With Chronic Musculoskeletal Pain: Intersectional Considerations, Lisa H Domenico, Jared J Tanner, Angela M Mickle, Ellen L Terry, Cynthia Garvan, Song Lai, Hrishikesh Deshpande, Roland Staud, David Redden, Catherine C Price, Burel R Goodin, Roger B Fillingim, Kimberly T Sibille

2020-Current year OA Pubs

Chronic musculoskeletal pain including knee osteoarthritis (OA) is a leading cause of disability worldwide. Previous research indicates ethnic-race groups differ in the pain and functional limitations experienced with knee OA. However, when socioenvironmental factors are included in analyses, group differences in pain and function wane. Pain-related brain structures are another area where ethnic-race group differences have been observed. Environmental and sociocultural factors e.g., income, education, experiences of discrimination, and social support influence brain structures. We investigate if environmental and sociocultural factors reduce previously observed ethnic-race group differences in pain-related brain structures. Data were analyzed from 147 self-identified non-Hispanic black (NHB) …

Brain High-Throughput Multi-Omics Data Reveal Molecular Heterogeneity In Alzheimer's Disease, Abdallah M. Eteleeb, Brenna C. Novotny, Carolina Soriano Tarraga, Christopher Sohn, Eliza Dhungel, Logan Brase, Aasritha Nallapu, Jared Buss, Fabiana Farias, Kristy Bergmann, Joseph Bradley, Joanne Norton, Jen Gentsch, Fengxian Wang, Albert A. Davis, John C. Morris, Celeste M. Karch, Richard J. Perrin, Bruno A. Benitez, Oscar Harari

2020-Current year OA Pubs

Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, …

Precision Of Metabolite-Selective Mrs Measurements Of Glutamate, Gaba And Glutathione: A Review Of Human Brain Studies., Kesavi Kanagasabai, Lena Palaniyappan, Jean Theberge

Department of Medicine Publications

Single-voxel proton magnetic resonance spectroscopy (SV 1 H-MRS) is an in vivo noninvasive imaging technique used to detect neurotransmitters and metabolites. It enables repeated measurements in living participants to build explanatory neurochemical models of psychiatric symptoms and testing of therapeutic approaches. Given the tight link among glutamate, gamma-amino butyric acid (GABA), glutathione and glutamine within the cellular machinery, MRS investigations of neurocognitive and psychiatric disorders must quantify a network of metabolites simultaneously to capture the pathophysiological states of interest. Metabolite-selective sequences typically provide improved metabolite isolation and spectral modelling simplification for a single metabolite at a time. Non-metabolite-selective sequences provide …

Mfsd7c Functions As A Transporter Of Choline At The Blood-Brain Barrier, Xuan Thi Anh Nguyen, Angela Lee, Jorge L Granadillo, Catherine Gooch, Et Al.

2020-Current year OA Pubs

Mutations in the orphan transporter MFSD7c (also known as Flvcr2), are linked to Fowler syndrome. Here, we used Mfsd7c knockout (Mfsd7c

Causal Influence Of Linguistic Learning On Perceptual And Conceptual Processing: A Brain-Constrained Deep Neural Network Study Of Proper Names And Category Terms., Phuc T U Nguyen, Malte R Henningsen-Schomers, Friedemann Pulvermüller

Journal Articles

Language influences cognitive and conceptual processing, but the mechanisms through which such causal effects are realized in the human brain remain unknown. Here, we use a brain-constrained deep neural network model of category formation and symbol learning and analyze the emergent model's internal mechanisms at the neural circuit level. In one set of simulations, the network was presented with similar patterns of neural activity indexing instances of objects and actions belonging to the same categories. Biologically realistic Hebbian learning led to the formation of instance-specific neurons distributed across multiple areas of the network, and, in addition, to cell assembly circuits …

Prenatal Exposure To Maternal Disadvantage-Related Inflammatory Biomarkers: Associations With Neonatal White Matter Microstructure, Ashley F P Sanders, Brian Tirado, Nicole A Seider, Regina L Triplett, Rachel E Lean, Jeffrey J Neil, J Philip Miller, Rebecca Tillman, Tara A Smyser, Deanna M Barch, Joan L Luby, Cynthia E Rogers, Christopher D Smyser, Barbara B Warner, Et Al.

2020-Current year OA Pubs

Prenatal exposure to heightened maternal inflammation has been associated with adverse neurodevelopmental outcomes, including atypical brain maturation and psychiatric illness. In mothers experiencing socioeconomic disadvantage, immune activation can be a product of the chronic stress inherent to such environmental hardship. While growing preclinical and clinical evidence has shown links between altered neonatal brain development and increased inflammatory states in utero, the potential mechanism by which socioeconomic disadvantage differentially impacts neural-immune crosstalk remains unclear. In the current study, we investigated associations between socioeconomic disadvantage, gestational inflammation, and neonatal white matter microstructure in 320 mother-infant dyads over-sampled for poverty. We analyzed maternal …

A Comparative Biochemical And Pathological Evaluation Of Brain Samples From Knock-In Murine Models Of Gaucher Disease, Makaila L Furderer, Bahafta Berhe, Tiffany C Chen, Stephen Wincovitch, Xuntian Jiang, Nahid Tayebi, Ellen Sidransky, Tae-Un Han

2020-Current year OA Pubs

Gaucher disease (GD) is a lysosomal storage disorder stemming from biallelic mutations in

Stem Cell Modeling Of Nervous System Tumors, Frank B Furnari, Corina Anastasaki, Shan Bian, Howard A Fine, Tomoyuki Koga, Lu Q Le, Fausto J Rodriguez, David H Gutmann

2020-Current year OA Pubs

Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations …

Associations Between Early Trajectories Of Amygdala Development And Later School-Age Anxiety In Two Longitudinal Samples, Catherine A Burrows, Kelly N Botteron, John R Pruett Jr, Et Al.

2020-Current year OA Pubs

Amygdala function is implicated in the pathogenesis of autism spectrum disorder (ASD) and anxiety. We investigated associations between early trajectories of amygdala growth and anxiety and ASD outcomes at school age in two longitudinal studies: high- and low-familial likelihood for ASD, Infant Brain Imaging Study (IBIS, n = 257) and typically developing (TD) community sample, Early Brain Development Study (EBDS, n = 158). Infants underwent MRI scanning at up to 3 timepoints from neonate to 24 months. Anxiety was assessed at 6-12 years. Linear multilevel modeling tested whether amygdala volume growth was associated with anxiety symptoms at school age. In …

Optimal Approaches To Analyzing Functional Mri Data In Glioma Patients, Ki Yun Park, Joshua S Shimony, Satrajit Chakrabarty, Aaron B Tanenbaum, Carl D Hacker, Kara M Donovan, Patrick H Luckett, Mikhail Milchenko, Aristeidis Sotiras, Daniel S Marcus, Eric C Leuthardt, Abraham Z Snyder

2020-Current year OA Pubs

BACKGROUND: Resting-state fMRI is increasingly used to study the effects of gliomas on the functional organization of the brain. A variety of preprocessing techniques and functional connectivity analyses are represented in the literature. However, there so far has been no systematic comparison of how alternative methods impact observed results.

NEW METHOD: We first surveyed current literature and identified alternative analytical approaches commonly used in the field. Following, we systematically compared alternative approaches to atlas registration, parcellation scheme, and choice of graph-theoretical measure as regards differentiating glioma patients (N = 59) from age-matched reference subjects (N = 163).

RESULTS: Our results …

Functional Network Disorganization And Cognitive Decline Following Fractionated Whole-Brain Radiation In Mice, Benjamin A. Seitzman, Francisco J. Reynoso, Timothy J. Mitchell, Annie R. Bice, Anmol Jarang, Xiaodan Wang, Cedric Mpoy, Lori Strong, Buck E. Rogers, Carla M. Yuede, Joshua B. Rubin, Stephanie M. Perkins, Adam Q. Bauer

2020-Current year OA Pubs

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain's functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of …

Spatial And Amplitude Dynamics Of Neurostimulation: Insights From The Acute Intrahippocampal Kainate Seizure Mouse Model, Thomas J Foutz, Nicholas Rensing, Lirong Han, Dominique M Durand, Michael Wong

2020-Current year OA Pubs

OBJECTIVE: Neurostimulation is an emerging treatment for patients with drug-resistant epilepsy, which is used to suppress, prevent, and terminate seizure activity. Unfortunately, after implantation and despite best clinical practice, most patients continue to have persistent seizures even after years of empirical optimization. The objective of this study is to determine optimal spatial and amplitude properties of neurostimulation in inhibiting epileptiform activity in an acute hippocampal seizure model.

METHODS: We performed high-throughput testing of high-frequency focal brain stimulation in the acute intrahippocampal kainic acid mouse model of status epilepticus. We evaluated combinations of six anatomic targets and three stimulus amplitudes.

RESULTS: …

Children's Neural Reactivity To Maternal Praise And Criticism: Associations With Early Depressive Symptoms And Maternal Depression, Matthew R J Vandermeer, Pan Liu, Ola Mohamed Ali, Andrew R Daoust, Marc F Joanisse, Deanna M Barch, Elizabeth P Hayden

2020-Current year OA Pubs

Caregiving experiences are implicated in children's depression risk; however, children's neural reactivity to positive and negative feedback from mothers, a potential mediator of depression risk, is poorly understood. In a sample of 81 children (

Current Understanding Of The Alzheimer's Disease-Associated Microbiome And Therapeutic Strategies, Dong-Oh Seo, David M Holtzman

2020-Current year OA Pubs

Alzheimer's disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms …

Tempo And Mode Of Gene Expression Evolution In The Brain Across Primates, Katherine Rickelton, Trisha M Zintel, Jason Pizzollo, Emily Miller, John J Ely, Mary Ann Raghanti, William D Hopkins, Patrick R Hof, Chet C Sherwood, Amy L Bauernfeind, Courtney C Babbitt

2020-Current year OA Pubs

Primate evolution has led to a remarkable diversity of behavioral specializations and pronounced brain size variation among species (Barton, 2012; DeCasien and Higham, 2019; Powell et al., 2017). Gene expression provides a promising opportunity for studying the molecular basis of brain evolution, but it has been explored in very few primate species to date (e.g. Khaitovich et al., 2005; Khrameeva et al., 2020; Ma et al., 2022; Somel et al., 2009). To understand the landscape of gene expression evolution across the primate lineage, we generated and analyzed RNA-seq data from four brain regions in an unprecedented eighteen species. Here, we …

Stable, Neuron-Specific Gene Expression In The Mouse Brain, Osama Ahmed, Kingsley M. Ekumi, Francesco V. Nardi, Gulimiheranmu Maisumu, Khaled Moussawi, Eric D. Lazartigues, Bo Liang, Abraam M. Yakoub

School of Medicine Faculty Publications

Gene delivery to, and expression in, the mouse brain is important for understanding gene functions in brain development and disease, or testing gene therapies. Here, we describe an approach to express a transgene in the mouse brain in a cell-type-specific manner. We use stereotaxic injection of a transgene-expressing adeno-associated virus into the mouse brain via the intracerebroventricular route. We demonstrate stable and sustained expression of the transgene in neurons of adult mouse brain, using a reporter gene driven by a neuron-specific promoter. This approach represents a rapid, simple, and cost-effective method for global gene expression in the mouse brain, in …

Gene-Sgan: Discovering Disease Subtypes With Imaging And Genetic Signatures Via Multi-View Weakly-Supervised Deep Clustering, Zhijian Yang, John C Morris, Pamela Lamontagne, Daniel S Marcus, Tammie L S Benzinger, Et Al.

2020-Current year OA Pubs

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN - a multi-view, weakly-supervised deep clustering method - which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first …

Inhibiting Metabotropic Glutamate Receptor 5 After Stroke Restores Brain Function And Connectivity, Jakob Hakon, Miriana J Quattromani, Carin Sjölund, Daniela Talhada, Byungchan Kim, Slavianka Moyanova, Federica Mastroiacovo, Luisa Di Menna, Roger Olsson, Elisabet Englund, Ferdinando Nicoletti, Karsten Ruscher, Adam Q Bauer, Tadeusz Wieloch

2020-Current year OA Pubs

Stroke results in local neural disconnection and brain-wide neuronal network dysfunction leading to neurological deficits. Beyond the hyper-acute phase of ischaemic stroke, there is no clinically-approved pharmacological treatment that alleviates sensorimotor impairments. Functional recovery after stroke involves the formation of new or alternative neuronal circuits including existing neural connections. The type-5 metabotropic glutamate receptor (mGluR5) has been shown to modulate brain plasticity and function and is a therapeutic target in neurological diseases outside of stroke. We investigated whether mGluR5 influences functional recovery and network reorganization rodent models of focal ischaemia. Using multiple behavioural tests, we observed that treatment with negative …

Accuracy Of True-Net In Comparison To Established White Matter Hyperintensity Segmentation Methods: An Independent Validation Study, Jeremy F Strain, Maryam Rahmani, Donna Dierker, Christopher Owen, Hussain Jafri, Andrei G Vlassenko, Kyle Womack, Jurgen Fripp, Duygu Tosun, Tammie L S Benzinger, Michael Weiner, Colin Masters, Jin-Moo Lee, John C Morris, Manu S Goyal, Adopic And Adni Investigators

2020-Current year OA Pubs

White matter hyperintensities (WMH) are nearly ubiquitous in the aging brain, and their topography and overall burden are associated with cognitive decline. Given their numerosity, accurate methods to automatically segment WMH are needed. Recent developments, including the availability of challenge data sets and improved deep learning algorithms, have led to a new promising deep-learning based automated segmentation model called TrUE-Net, which has yet to undergo rigorous independent validation. Here, we compare TrUE-Net to six established automated WMH segmentation tools, including a semi-manual method. We evaluated the techniques at both global and regional level to compare their ability to detect the …

Neurosteroids: Mechanistic Considerations And Clinical Prospects, Jamie L Maguire, Steven Mennerick

2020-Current year OA Pubs

Like other classes of treatments described in this issue's section, neuroactive steroids have been studied for decades but have risen as a new class of rapid-acting, durable antidepressants with a distinct mechanism of action from previous antidepressant treatments and from other compounds covered in this issue. Neuroactive steroids are natural derivatives of progesterone but are proving effective as exogenous treatments. The best understood mechanism is that of positive allosteric modulation of GABA

Automatic Hemorrhage Segmentation In Brain Ct Scans Using Curriculum-Based Semi-Supervised Learning, Solayman H. Emon, Tzu-Liang (Bill) Tseng, Michael Pokojovy, Peter Mccaffrey, Scott Moen, Md Fashiar Rahman

Mathematics & Statistics Faculty Publications

One of the major neuropathological consequences of traumatic brain injury (TBI) is intracranial hemorrhage (ICH), which requires swift diagnosis to avert perilous outcomes. We present a new automatic hemorrhage segmentation technique via curriculum-based semi-supervised learning. It employs a pre-trained lightweight encoder-decoder framework (MobileNetV2) on labeled and unlabeled data. The model integrates consistency regularization for improved generalization, offering steady predictions from original and augmented versions of unlabeled data. The training procedure employs curriculum learning to progressively train the model at diverse complexity levels. We utilize the PhysioNet dataset to train and evaluate the proposed approach. The performance results surpass those of …

Colonial Drivers And Cultural Protectors Of Brain Health Among Indigenous Peoples Internationally, Rita Henderson, Joyla A Furlano, Shayla Scott Claringbold, Ashley Cornect-Benoit, Anh Ly, Jennifer Walker, Lisa Zaretsky, Pamela Roach

Journal Articles

Despite relatively higher rates of dementia among Indigenous populations internationally, research into drivers of disparities in brain health and cognitive function has tended to focus on modifiable risk factors over cultural understandings and contextual determinants. By seeking to characterize social and cultural factors that shape brain health and cognition in Indigenous populations, this mini scoping review expands prevailing schools of thought to include Indigenous knowledge systems. This reveals important gaps in culturally aligned care. It also reclaims horizons for research important to Indigenous Peoples that have garnered diminished attention in biomedical approaches. Twenty-three sources were included for data extraction. This …

A Global Multicohort Study To Map Subcortical Brain Development And Cognition In Infancy And Early Childhood, Ann M Alex, Kelly Botteron, Et Al.

2020-Current year OA Pubs

The human brain grows quickly during infancy and early childhood, but factors influencing brain maturation in this period remain poorly understood. To address this gap, we harmonized data from eight diverse cohorts, creating one of the largest pediatric neuroimaging datasets to date focused on birth to 6 years of age. We mapped the developmental trajectory of intracranial and subcortical volumes in ∼2,000 children and studied how sociodemographic factors and adverse birth outcomes influence brain structure and cognition. The amygdala was the first subcortical volume to mature, whereas the thalamus exhibited protracted development. Males had larger brain volumes than females, and …