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Graner J.,Uniformed Services University of the Health Sciences | Oakes T.R.,Uniformed Services University of the Health Sciences | French L.M.,U.S. National Institutes of Health | French L.M.,Center for Neuroscience and Regenerative Medicine | And 2 more authors.
Frontiers in Neurology

This review focuses on the application of functional magnetic resonance imaging (fMRI) to the investigation of blast-related traumatic brain injury (bTBI). Relatively little is known about the exact mechanisms of neurophysiological injury and pathological and functional sequelae of bTBI. Furthermore, in mild bTBI, standard anatomical imaging techniques (MRI and computed tomography) generally fail to show focal lesions and most of the symptoms present as subjective clinical functional deficits. Therefore, an objective test of brain functionality has great potential to aid in patient diagnosis and provide a sensitive measurement to monitor disease progression and treatment. The goal of this review is to highlight the relevant body of blast-related TBI literature and present suggestions and considerations in the development of fMRI studies for the investigation of bTBI. The review begins with a summary of recent bTBI publications followed by discussions of various elements of blast-related injury. Brief reviews of some fMRI techniques that focus on mental processes commonly disrupted by bTBI, including working memory, selective attention, and emotional processing, are presented in addition to a short review of resting state fMRI. Potential strengths and weaknesses of these approaches as regards bTBI are discussed. Finally, this review presents considerations that must be made when designing fMRI studies for bTBI populations, given the heterogeneous nature of bTBI and its high rate of comorbidity with other physical and psychological injuries. © 2013 Graner, Oakes, French and Riedy. Source

Shemesh N.,Tel Aviv University | Ozarslan E.,U.S. National Institutes of Health | Ozarslan E.,Center for Neuroscience and Regenerative Medicine | Basser P.J.,U.S. National Institutes of Health | Cohen Y.,Tel Aviv University
NMR in Biomedicine

The accurate characterization of pore morphology is of great interest in a wide range of scientific disciplines. Conventional single-pulsed field gradient (s-PFG) diffusion MR can yield compartmental size and shape only when compartments are coherently ordered using q-space approaches that necessitate strong gradients. However, double-PFG (d-PFG) methodology can provide novel microstructural information even when specimens are characterized by polydispersity in size and shape, and even when anisotropic compartments are randomly oriented. In this study, for the first time, we show that angular d-PFG experiments can be used to accurately measure cellular size and shape anisotropy of fixed yeast cells employing relatively weak gradients. The cell size, as measured by light microscopy, was found to be 5.32±0.83μm, whereas the results from noninvasive angular d-PFG experiments yielded a cell size of 5.46±0.45μm. Moreover, the low compartment shape anisotropy of the cells could be inferred from experiments conducted at long mixing times. Finally, similar experiments were conducted in a phantom comprising anisotropic compartments that were randomly oriented, showing that angular d-PFG MR provides novel information on compartment eccentricity that could not be accessed using conventional methods. Angular d-PFG methodology seems to be promising for the accurate estimation of compartment size and compartment shape anisotropy in heterogeneous systems in general, and biological cells and tissues in particular. © 2011 John Wiley & Sons, Ltd. Source

Heinzelmann M.,U.S. National Institutes of Health | Reddy S.Y.,U.S. National Institutes of Health | French L.M.,Center for Neuroscience and Regenerative Medicine | French L.M.,Defense and Veterans Brain Injury Center | And 6 more authors.
Frontiers in Neurology

Objective: Approximately one-quarter of military personnel who deployed to combat stations sustained one or more blast-related, closed-head injuries. Blast injuries result from the detonation of an explosive device. The mechanisms associated with blast exposure that give rise to traumatic brain injury (TBI), and place military personnel at high risk for chronic symptoms of post-concussive disorder (PCD), post-traumatic stress disorder (PTSD), and depression are not elucidated. Methods: To investigate the mechanisms of persistent blast-related symptoms, we examined expression profiles of transcripts across the genome to determine the role of gene activity in chronic symptoms following blast-TBI. Active duty military personnel with (1) a medical record of a blast-TBI that occurred during deployment (n = 19) were compared to control participants without TBI (n = 17). Controls were matched to cases on demographic factors including age, gender, and race, and also in diagnoses of sleep disturbance, and symptoms of PTSD and depression. Due to the high number of PCD symptoms in the TBI+ group, we did not match on this variable. Using expression profiles of transcripts in microarray platform in peripheral samples of whole blood, significantly differentially expressed gene lists were generated. Statistical threshold is based on criteria of 1.5 magnitude fold-change (up or down) and p-values with multiple test correction (false discovery rate <0.05). Results: There were 34 transcripts in 29 genes that were differentially regulated in blast-TBI participants compared to controls. Up-regulated genes included epithelial cell transforming sequence and zinc finger proteins, which are necessary for astrocyte differentiation following injury. Tensin-1, which has been implicated in neuronal recovery in pre-clinical TBI models, was down-regulated in blast-TBI participants. Protein ubiquitination genes, such as epidermal growth factor receptor, were also down-regulated and identified as the central regulators in the gene network determined by interaction pathway analysis. Conclusion: In this study, we identified a gene-expression pathway of delayed neuronal recovery in military personnel a blast-TBI and chronic symptoms. Future work is needed to determine if therapeutic agents that regulate these pathways may provide novel treatments for chronic blast-TBI-related symptoms. © 2014 Heinzelmann, Reddy, French, Wang, Lee, Barr, Baxter, Mysliwiec and Gill. Source

Shively S.B.,Uniformed Services University of the Health Sciences | Shively S.B.,Center for Neuroscience and Regenerative Medicine | Shively S.B.,Foundation Medicine | Perl D.P.,Uniformed Services University of the Health Sciences | Perl D.P.,Center for Neuroscience and Regenerative Medicine
Journal of Head Trauma Rehabilitation

With preferential use of high explosives in modern warfare, traumatic brain injury (TBI) has become a common injury for troops. Most TBIs are classified as "mild," although military personnel with these injuries can have persistent symptoms such as headache, memory impairment, and behavioral changes. During World War I, soldiers in the trenches, undergoing unrelenting artillery bombardment, suffered from similar symptoms, designated at the time as "shell shock." Dr Frederick Mott proposed studying the brains of deceased soldiers to elucidate the neuropathology of this clinical entity. Subsequent to a British government enquiry after World War I, the term "shell shock" was banned and further investigation into a possible organic cause for these symptoms was discontinued. Nevertheless, similar clinical entities, such as combat or battle fatigue and posttraumatic stress disorder, continue to be encountered by combatants in subsequent military conflicts. To this day, there exists a paucity of neuropathology studies investigating the effects of high explosives on the human brain. By analogy, studies have recently revealed that athletes with repeated head trauma can develop a neurodegenerative disease, chronic traumatic encephalopathy, who present with similar clinical features. Given current circumstance, we propose completing the work envisioned by Dr Mott almost 100 years ago. Copyright © 2012 Lippincott Williams &Wilkins. Source

Bergstrom H.C.,Bethesda University | Bergstrom H.C.,Center for Neuroscience and Regenerative Medicine | Bergstrom H.C.,Center for the Study of Traumatic Stress | McDonald C.G.,George Mason University | And 3 more authors.

Understanding the physical encoding of a memory (the engram) is a fundamental question in neuroscience. Although it has been established that the lateral amygdala is a key site for encoding associative fear memory, it is currently unclear whether the spatial distribution of neurons encoding a given memory is random or stable. Here we used spatial principal components analysis to quantify the topography of activated neurons, in a select region of the lateral amygdala, from rat brains encoding a Pavlovian conditioned fear memory. Our results demonstrate a stable, spatially patterned organization of amygdala neurons are activated during the formation of a Pavlovian conditioned fear memory. We suggest that this stable neuronal assembly constitutes a spatial dimension of the engram. © 2011 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Source

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