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      The Dynamics of Concussion: Mapping Pathophysiology, Persistence, and Recovery With Causal-Loop Diagramming

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          Abstract

          Despite increasing public awareness and a growing body of literature on the subject of concussion, or mild traumatic brain injury, an urgent need still exists for reliable diagnostic measures, clinical care guidelines, and effective treatments for the condition. Complexity and heterogeneity complicate research efforts and indicate the need for innovative approaches to synthesize current knowledge in order to improve clinical outcomes. Methods from the interdisciplinary field of systems science, including models of complex systems, have been increasingly applied to biomedical applications and show promise for generating insight for traumatic brain injury. The current study uses causal-loop diagramming to visualize relationships between factors influencing the pathophysiology and recovery trajectories of concussive injury, including persistence of symptoms and deficits. The primary output is a series of preliminary systems maps detailing feedback loops, intrinsic dynamics, exogenous drivers, and hubs across several scales, from micro-level cellular processes to social influences. Key system features, such as the role of specific restorative feedback processes and cross-scale connections, are examined and discussed in the context of recovery trajectories. This systems approach integrates research findings across disciplines and allows components to be considered in relation to larger system influences, which enables the identification of research gaps, supports classification efforts, and provides a framework for interdisciplinary collaboration and communication—all strides that would benefit diagnosis, prognosis, and treatment in the clinic.

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          A default mode of brain function.

          A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
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            Sleep drives metabolite clearance from the adult brain.

            The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
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              Rich-club organization of the human connectome.

              The human brain is a complex network of interlinked regions. Recent studies have demonstrated the existence of a number of highly connected and highly central neocortical hub regions, regions that play a key role in global information integration between different parts of the network. The potential functional importance of these "brain hubs" is underscored by recent studies showing that disturbances of their structural and functional connectivity profile are linked to neuropathology. This study aims to map out both the subcortical and neocortical hubs of the brain and examine their mutual relationship, particularly their structural linkages. Here, we demonstrate that brain hubs form a so-called "rich club," characterized by a tendency for high-degree nodes to be more densely connected among themselves than nodes of a lower degree, providing important information on the higher-level topology of the brain network. Whole-brain structural networks of 21 subjects were reconstructed using diffusion tensor imaging data. Examining the connectivity profile of these networks revealed a group of 12 strongly interconnected bihemispheric hub regions, comprising the precuneus, superior frontal and superior parietal cortex, as well as the subcortical hippocampus, putamen, and thalamus. Importantly, these hub regions were found to be more densely interconnected than would be expected based solely on their degree, together forming a rich club. We discuss the potential functional implications of the rich-club organization of the human connectome, particularly in light of its role in information integration and in conferring robustness to its structural core.
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                Author and article information

                Contributors
                Journal
                Front Neurol
                Front Neurol
                Front. Neurol.
                Frontiers in Neurology
                Frontiers Media S.A.
                1664-2295
                04 April 2018
                2018
                : 9
                : 203
                Affiliations
                [1] 1Systems Science Program, Portland State University , Portland, OR, United States
                [2] 2Department of Psychology and Neuroscience Center, Brigham Young University , Provo, UT, United States
                [3] 3Department of Emergency Medicine, Emory University School of Medicine , Atlanta, GA, United States
                [4] 4Sleep Disorders Clinic, Division of Hospital and Specialty Medicine, Research Service, VA Portland Health Care System , Portland, OR, United States
                [5] 5Departments of Neurology, Medicine, and Behavioral Neuroscience, Oregon Institute of Occupational Health Sciences, Oregon Health & Science University , Portland, OR, United States
                [6] 6TBI/Concussion Program, Orthopedics & Rehabilitation, Neurology and Family Medicine, Oregon Health & Science University , Portland, OR, United States
                [7] 7Department of Neurosurgery, University of Utah , Salt Lake City, UT, United States
                [8] 8Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, United States
                Author notes

                Edited by: Kenneth Curley, Iatrikos Research and Development Solutions, LLC, United States

                Reviewed by: Tom M. McMillan, University of Glasgow, United Kingdom; Edwin Arthur Shores, Macquarie University, Australia

                *Correspondence: Erin S. Kenzie, erin.kenzie@ 123456pdx.edu

                Specialty section: This article was submitted to Neurotrauma, a section of the journal Frontiers in Neurology

                Article
                10.3389/fneur.2018.00203
                5893805
                29670568
                84bdb02c-2812-4366-8614-b4a2a3f47ab4
                Copyright © 2018 Kenzie, Parks, Bigler, Wright, Lim, Chesnutt, Hawryluk, Gordon and Wakeland.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 November 2017
                : 14 March 2018
                Page count
                Figures: 9, Tables: 0, Equations: 0, References: 114, Pages: 16, Words: 11621
                Funding
                Funded by: U.S. Army 10.13039/100006751
                Award ID: W911QY-14-C-0086, W81XWH-13-2-0095
                Funded by: U.S. Department of Veterans Affairs 10.13039/100000738
                Award ID: IK2 BX002712
                Categories
                Neuroscience
                Original Research

                Neurology
                concussion,traumatic brain injury,systems science,complexity,recovery,causal-loop diagram,models of injury,systems medicine

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