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Functional Neurology, Rehabilitation, and Ergonomics
Volume 3, Number 2/3, 2013
Table of Contents
Editorial - Refinding 143 Gerry Leisman
Editorial Note 147
Metabolic Diseases Driven by Immunoinflammation 149 Aristo Vojdani
Brain-Reactive Antibodies in Traumatic Brain Injury 173 Aristo Vojdani
The Role of Environmental Triggers in Neuroautoimmunity 183 Aristo Vojdani and Jama Lambert
Toxicant Loss of Immune Tolerance, Neurologic Disease, and Nutritional Strategies 203 Datis Kharrazian
The Potential Impact of Various Physiological Mechanisms on Outcomes in TBI, mTBI, Concussion and PPCS 215 Joel Brandon Brock, Samuel Yanuck, Michael Pierce, Michael Powell, Steven Geanopulos, Steven Noseworthy, Datis Kharrazian, Chris Turnpaugh, Albert Comey, and Glen Zielinski
DIME (Diplomatic, Information, Military and Economic Power) Effects Modeling System: Applications for the Modeling of the Brain 257 Newton Howard and Gerry Leisman ii Contents
Anatomically Accurate Head Models and Their Derivatives for Dense Array EEG Source Localization 275 Jasmine Song, Kyle Morgan, Sergei Turovets, Kai Li, Colin Davey, Pavel Govyadinov, Phan Luu, Kirk Smith, Fred Prior, Linda Larson-Prior, and Don M. Tucker
A Novel ERP Pattern Analysis Method for Revealing Invariant Reference Brain Network Models 295 Amit Reches, Dan Kerem, Noga Gal, Ilan Laufer, Revital Shani-Hershkovitch, Dalia Dickman, and Amir B. Geva
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States 319 Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria, Calixto Machado, Gerry Leisman, Robert Melillo, Mauricio Chinchilla, Philip DeFina, Maylen Carballo, and Juan M. Morales
If It Is Localization then There Is No Development, Education, and Rehabilitation: Neuroeducation Needs to Be about Building Networks 329 Gerry Leisman
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational Stimulation on Balance Stability and Limits of Stability 341 Frederick R. Carrick,Guido Pagnacco, Elena Oggero, Susan E. Esposito, James L. Duffy, Derek Barton, Matthew Antonucci, Jacob Shores, and Diana M. Stephens
Poster Abstracts - 4th Annual Conference of the International Association of Functional Neurology and Rehabilitation 361
IAFNR News and Events 389
Literature Calling 399
New York
Journal of Functional Neurology, Rehabilitation, and Ergonomics
The Official Journal of the International Association of Functional Neurology and Rehabilitation
The aim of this interdisciplinary journal is to provide a forum for the fields of Biomedical and Rehabilitation Engineering, Neuropsychology, Clinical Neurology, Human Factors and Ergonomics, and vocational assessment and training to present critical ideas, theories, proof-of-concept for technology solutions, and data-based evaluative research to facilitate return to work or more effective functional development in children and adults.
Functional Neurology, Rehabilitation, and Ergonomics is published quarterly by
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ISSN: 2156-941X
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Copyright © 2013 by Nova Science Publishers, Inc. All rights reserved. Printed in the United States of America. No part of this Journal may be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical, photocopying, recording, or otherwise without permission from the Publisher. The Publisher assumes no responsibility for any statements of fact or opinion expressed in the published papers.
Editor-In-Chief
Gerry Leisman Garden City, NY USA Nazareth, Israel
Co-Editor-In-Chief
Robert Melillo Garden City, NY USA
Assistant Editor Assistant Editor Assistant Editor Production Production News and Events
Janet Groschel Alicia M. Zelsdorf Tricia Merlin Gilbert, AZ USA Charlotte, NC USA Cape Canaveral, FL USA
Editorial Board Members
Sergio Azzolino Barbara Hicks Jackie Oldham San Francisco, CA USA Kingsford, MI USA Manchester, UK
Randy Beck Newton Howard Chandler Phillips Perth, Australia Cambridge, MA USA Dayton, OH USA
Paul Berger-Gross Megan L. Hudson Anthony L. Rosner Bayside, NY USA West Springfield, MA USA Boston, MA USA
Eti Ben-Simon Efraim Jaul Peter Scire Tel-Aviv, Israel Jerusalem, Israel Peachtree City, GA USA
John A. Brabyn Datis Kharrazian Fredric Schiffer San Francisco, CA USA Carlspoor, CA USA Boston, MA USA
Orit Braun-Benjamin Samuel Landsberger Suryakumar Shah Karmiel, Israel Los Angeles, CA USA Pomona, NJ USA
Lynn M. Carlson Calixto Machado Maria E. Stalias West Springfield, MA USA Havana, Cuba Manhasset, NY USA Athens, Greece Ted Carrick Joy MacDermid Cape Canaveral, FL USA Hamilton, Ontario Canada Joseph Weisberg Great Neck, NY USA Emmanuel Donchin Joav Merrick Tampa, FL USA Jerusalem, Israel Leslie Weiser Boston, MA USA Andrew L. Egel Raed Mualem College Park, MD USA Nazareth, Israel Seung Won Lee Seoul, S. Korea Khosrow Eghtesadi Paul Noone West Palm Beach, FL USA Hampton E. Victoria, Australia
EDITORIAL
Funct Neurol Rehabil Ergon 2013;3(2-3):143-146 ISSN: 2156-941X © Nova Science Publishers, Inc.
REFINDING
Gerry Leisman Editor-in-Chief FNRE Scientific Director F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neuroscience-USA The National Institute for Brain and Rehabilitation Sciences Biomedical Engineering ORT-Braude College of Engineering Karmiel, Israel University of the Medical Sciences, Havana, Cuba
Re-mind (from 17th c. rememorate or think again), re-view (from Fr., revue to see again), re-place (to find a substitute), re-work (to make changes to something), re-play (to repeat), re-turn (from Latin re, back + tornare, turn). We can go on finding a myriad of examples of how “re” can be part of a compound word with many meanings all relating to the same concept. Something exists and one returns to it. When one contemplates numerous discoveries ranging from the atom, DNA, the earth and other planets in our solar system revolving around the sun and not the other way around, gravity, Higgs- Bosson, and so many other findings one usually does not wonder whether these were actually innovations. The so-called discoveries, certainly existed before they were “discovered.” Similarly, inventions such as the transistor, television, the motor car, airplanes, telephones, record players, CDs, computers, are inventions based on what was already known but never assembled in a fashion that could create a novel function. Discovery then allows us to obtain sight or knowledge for the first time such as finding out that your car was out of gas, a trivial but practical example of the concept. Alternatively the atom existed before Rutherford and the Physics Department at the University of Manchester, but science has allowed us to put what exists together for novel uses, such as positron emission tomography. Columbus, it is claimed, discovered the Americas. In this instance, "discovered" is probably not the correct word. Certainly Columbus put America on the proverbial map. It was his journey that spurred many to follow him and eventually led to the settling of this "new world" in the early 17th century by Europeans. However, when Columbus landed, there were already natives inhabiting the land, named Indians (later Native Americans) as Columbus initially thought he had reached India. These people would certainly take exception to their land being "discovered" as they were obviously aware of it prior to Columbus' arrival. While it is clear Columbus was not the first to inhabit the Americas, he certainly opened the door for the mass settlements that were to come. For small schoolchildren it is easy to explain that "Christopher Columbus discovered America" as this is the type of simplistic idea they can grasp, but for those capable of understanding the bigger picture, the actual truth is much more gray than black and white. The issue of discovery then is, therefore, rendered less important than the doors that it can open to the generation of ideas and understanding of fundamental principles and processes. In 1861, the 144 Gerry Leisman
French surgeon, Pierre Paul Broca, described two patients who had lost the ability to speak after injury to the posterior inferior frontal gyrus of the brain [1]. Numerous studies since Broca have examined the nature of the localization of speech and language based on Broca’s findings in his two patients. Clinical studies of Broca's aphasia often assume that the deficits in these patients are due entirely to dysfunction in Broca's area, thereby attributing all aspects of the disorder to this one brain region. In addition, functional imaging studies often rely on activation in Broca's area as verification that tasks have successfully involved language and speech centers. Despite these strong assumptions, the range of locations ascribed to Broca's area varies broadly across studies [2,3]. We can say the same about Wernicke and his localized region that contains motor neurons involved in the comprehension of language which he “discovered” in 1874, approximately ten years after Broca’s “discovery.” The region is located in the posterior third of the upper temporal convolution of the left hemisphere of the brain. It is reportedly uniquely important for the comprehension of speech sounds and is considered to be the receptive language center. Recent findings with language-impaired patients, however, have suggested that other regions also play a role in speech and language production, some of which are medial to the area originally described by Broca on the lateral surface of the brain. Given the historical significance of Broca's original patients and the increasing reliance on Broca's area as a major speech center, we thought it important to re-inspect these brains to determine the precise location of their lesions as well as other possible areas of damage. Here we describe the results of high-resolution magnetic resonance imaging of the preserved brains of Broca's two historic patients. It had been noted that both patients’ had lesions that extended significantly into medial regions of the brain, in addition to the surface lesions observed by Broca. Results also indicate inconsistencies between the area originally identified by Broca and what is now called Broca's area, a finding with significant ramifications for both lesion and functional neuroimaging studies of this well-known brain area [1,4]. Figure 1 indicates the conception of brain language organization held by most since the time of Broca and Wernicke.
Figure 1. Brain Organization for Language.
We have begun to “re-think” the nature of brain organization due to fMRI, PET, connectography and other new technologies. Broca was so important because like the easily grasped simplistic idea of Columbus “discovering America," and having swept 150 years of thinking from his proposition, re- thinking and re-discovery amongst those capable of understanding the bigger picture, may actually also have the actual truth being more gray than black and white as represented in Fig. 2 where multiple stream models may be more likely [4]. Editorial 145
(A)
(B)
Figure 2. (A) Multiple stream language model in which receptive language functions are organized into multiple self-organizing simultaneously active networks. (B) Grounded meaning indicates that the meaning of words and sentences are both "embodied" and neurologically distributed rather than localized.
Discoveries are not discoveries but “re-findings.” Consensus is developed through painstaking testing, re-testing, dissemination, teaching, learning, communication, and practice, which allows us to re-examine long held “truths” with results that may be quite different from those to which we hold fast. There is no orthodoxy. There are no teachings only findings and open minds continually “re- find.”
REFERENCES
[1] Dronk NF, Plasisant O, Iba-Zissen, MT, Cabanis EA. Paul Broca's historic cases: high resolution MR imaging of the brains of Leborgne and Lelong. Brain. 2007;130(5):1432-1441. 146 Gerry Leisman
[2] Dronkers NF, Wilkins DP, Van Valin Jr. RD, Redfern BB, Jaegerc JJ. Lesion analysis of the brain areas involved in language comprehension. Cognition. 2004;92(1-2):145-177. [3] Grodzinsky Y, Santi A. The battle for Broca’s region. Trends Cogn Sci. 2008;12(12):474-480. [4] Leisman G. Children’s Language Production: How Cognitive Neuroscience & Industrial Engineering Can Inform Public Education Policy and Practice Forum on Public Policy. A Journal of the Oxford Roundtable. 2012;2012;(1):1-14. (http://forumonpublicpolicy.com/ vol2012.no1/archive/leisman.pdf)(http://forumonpublicpolicy.com/vol2012.no1/earlychild2012. html)
Funct Neurol Rehabil Ergon 2013;3(2-3):147 ISSN: 2156-941X © 2013 Nova Science Publishers, Inc.
EDITORIAL NOTE
The following papers did not reach the editorial office for review prior to the publication deadline and resultantly are not included in the IAFNR Conference Issue. They will be included in FNRE Volume 3 Issue 4.
Calixto Machado. Functional and Anatomic Connectivity in Disorders of Consciousness.
Robert Melillo. qEEG Spectral and Coherence Assessment of Autistic Children in Three Different Experimental Conditions
Madeline Cunningham. Unlocking Neuropsychiatric and Movement Disorders in Children
Lilian Calderón-Garcidueñas. Brain-reactive autoantibodies and air pollution
Funct Neurol Rehabil Ergon 2013;3(2-3):149-171 ISSN: 2156-941X © Nova Science Publishers, Inc.
METABOLIC DISEASES DRIVEN BY IMMUNOINFLAMMATION
Aristo Vojdani Immunosciences Laboratories, Los Angeles, CA, USA
ABSTRACT
Inflammation is normally a protective response that is part of the immune system’s reaction to infection. Chronic inflammation, on the other hand, is a sign that there is a breakdown in the immune response system, and leads to chronic inflammatory diseases. More and more researchers are finding evidence that associates low-grade chronic inflammation with metabolic dysfunction. Many metabolic disorders such as diabetes, atherosclerosis, ischemic heart disease, a variety of autoimmune diseases and other metabolic dysfunctions are linked to obesity, which is fast becoming a world-wide epidemic. These findings have been engendered by the increasing recognition and understanding of what has come to be called immunometabolism, the interplay between the two distinct disciplines of immunology and metabolism. Type 1 and type 2 diabetes are examples of disorders in which immunometabolism plays a role. The concept that autoreactive lymphocytes are involved in the destruction of beta-islet cells in chronic autoimmune type 1 diabetes has been known for many years. More recently, the release of proinflammatory cytokines and the promotion of infiltrating macrophages into islet cells has emerged as a mechanism for the loss of beta-islet cells in type 2 diabetes. Therefore, the detection of low-grade chronic inflammation and abnormal immunometabolism may assist in the identification of obese individuals who will be at risk for developing diabetes, cardiovascular disease, autoimmunity and other associated disorders.
In this review we will discuss: 1. The role of M1 and M2 macrophages, and their switch in the inflammatory environment induced by inflammatory cytokines and adipokines. This includes TH1 cytokines such as interferon-alpha, proinflammatory cytokines such as TNF-alpha, and IL-6, IL-18, IL-22, NF- kappaB, which are induced by factors such as bacterial endotoxins and leads to the generation of M1 pathogenic macrophages. 2. The contribution of T-cell subsets, in particular the involvement and upregulation of CD8 cytotoxic lymphocytes plus TH17 cells, and downregulation of TH3 regulatory T cells in adipose tissue. 3. Altered gut microbiota, the change of good to bad bacteria, and the induction of low-grade chronic inflammation, which could be responsible for the induction of obesity. 4. The effect of diet on the composition of gut microbiota and its regulation of immune and inflammatory diseases. Recommended protocols for regulation of gut microbiota and inflammatory responses by repairing the breach in the intestinal barriers.
Keywords: Inflammation, obesity, autoreactive lymphocytes, diabetes, diet, gut microbiota
Correspondence: Dr. Aristo Vojdani Immunosciences Lab., Inc. 822 S. Robertson Blvd., Ste. 312 Los Angeles, CA 90035 e-mail: [email protected]
150 Aristo Vojdani
INTRODUCTION
In recent years special attention has been given to the interplay between the distinct disciplines of immunology and metabolism, and the formation of a new field of investigation called immunometabolism [1]. In the field of immunology it is recognized that effector cells of the immune system, such as natural killer cells, and cytotoxic cells are required to guard the body against tumors and infectious agents [2]. Likewise, it is well known that TH3 or FoxP3+ regulatory T cells guard the body against TH1/TH2 immune dysregulation, which occurs in autoimmunity and allergy. Furthermore, understanding this powerful homeostatic system has resulted in the realization that immune cells also affect non-immune functions such as metabolism, cardiovascular function and even neuroinflammation and neuodegeneration [3-5]. This cross-talk between the immune system and metabolism is based on the fact that behaviors of lymphocytes and other white blood cells are controlled by internal metabolic properties, and metabolic abnormalities, including obesity, results in the mobilization of the innate and adaptive immune systems, followed by low-grade, chronic inflammation, culminating in increased susceptibility to type 1 and type 2 diabetes [6,7]. This concept is not new as a chronic autoimmune disease, type 1 diabetes, involves the destruction of beta-islet cells by pathogenic CD8+ and CD4+ T cells, and at the same time, regulatory T (Treg) cells are reduced [8]. However, more recently, the immune system has emerged as playing a role in the pathogenesis of type 2 diabetes. This pathway includes the release of interleukin (IL) -1, a pro-inflammatory cytokine, thus promoting the infiltration of macrophages into islets [7,8]. Cyclic inflammation results in beta-islet cell loss. This chronic, low-grade inflammation also leads to another type 2 diabetes characteristic, that of obesity-induced insulin resistance [9]. Inflammation of obesity is seen in white adipose tissue (fat), while in lean individuals, adipose tissue contains normal-sized adipocytes (fat cells). Lean state adipocytes are activated by M2 macrophages and Treg cells, thus creating an anti-inflammatory milieu by releasing IL-10. Conversely, pro-inflammatory M1 macrophages and hypertrophic adipocytes are predominant in adipose tissue of the obese. Endoplasmic reticulum stress activates intra-cellular pro-inflammatory pathways, resulting in the secretion of IL-6 [10]. These inflammatory cascades dysregulate the insulin signaling process, which is the molecular feature of insulin resistance. The effect of metabolic stress on the immune system contributes to both the onset of diabetes and the development of late-stage diabetic complications, with the activation of not only the adaptive, but also the innate immune responses, promoting the proapoptotic or profibrotic processes of diabetic nephropathy [11,12]. Destructive pathways may also lead to additional diseases. Cardiovascular disease, also associated with low-grade, chronic inflammation, can be a co- morbidity for diabetes. Therefore, understanding the role of immune system responses in obesity may assist in the identification of obese individuals who are at risk for developing type 2 diabetes and/or cardiovascular disease. To elucidate the epigenetic and environmental mechanisms playing a role in the pathogenesis of metabolic diseases, cross-discipline research is necessary. The complexity of the immune system and metabolism interface has brought multiple scientific worlds together. Research immunologists are now going beyond the classical autoimmune mediated diseases in order to study the emerging biological themes involving the cross-communications between body systems. The following is one such researcher’s personal story.
Metabolic Diseases Driven by Immunoinflammation 151
YOU ARE WHAT YOU FEED YOUR MICROBIOTA
In the classic boy-meets-girl fashion, the hero of this story [13], while in graduate school, met and married the girl of his dreams. Within two years he added a beautiful, healthy daughter to his family, “PhD” to his name and excess weight to his body. He had grown from 132.28 – 176.37 pounds (60 – 80 kilograms). During our hero’s post-doctoral fellowship conducted at Cornell University, he added 10 more kilograms; tipping the scale at just below 200 pounds. By the time he returned to his homeland, China, our hero’s waist measured 43.31 inches (110 centimeters). Of greater concern, his health, like that of his father (who had endured two strokes and whose cholesterol levels had spiked) and obese brothers, was poor. Prompted by the work of Jeffrey I. Gordon and colleagues at Washington University School of Medicine, St. Louis, Missouri, which showed a link between obesity and gut microbiota in mice, our hero adopted a diet regimen containing traditional Chinese food. Bitter melon and Chinese yam are fermented, pre-biotic foods that are believed to alter digestive bacterial growth. As a microbiologist, our hero not only monitored his weight loss during this simple therapy, he assessed his microbiome. Within two years, our hero lost 44.09 pounds (20 kilograms). Additionally, his health condition improved as his blood pressure, heart rate and cholesterol level came down. Changes were also happening in his gastrointestinal tract. An anti-inflammatory bacterium, Faecalibacterium prausnitzii, increased from undetectable to 14.5% of his total gut bacteria. What began as a personal experiment quickly developed into serious study. Our hero, Zhao Liping, Associate Director of Shanghai Jiao Tong University’s Shanghai Center for Systems Biomedicine, started with mice and now conducts clinical research on humans. He hopes to uncover the roles played by the microbiome in obesity, diabetes and liver function.
THE ROLE OF ADIPOCYTES AND ADIPOKINES IN INFLAMMATION AND METABOLIC DISEASES
Once seen predominantly in industrialized, consumer-driven countries, today obesity is a worldwide epidemic and has spawned global research to better understand the biology of adipocytes in obese states [6]. Obesity is linked to a number of economically and societal burdensome diseases such as diabetes, atherosclerosis and ischemic heart disease. Researchers are finding evidence that links chronic, low-grade inflammation to obesity [14, 15], which plays a role in the development of obesity-linked disorders, most notably metabolic dysfunction.
Pro- and Anti-Inflammatory Adipokines in Obesity
Adipose tissue is widely known to store energy. Lesser known is its capacity for secreting bioactive substances [16, 17] like an endocrine organ. These substances are collectively referred to as adipokines. The dysregulated expression of these factors, which may be caused by excess adiposity and adipocyte dysfunction, has been associated with the pathogenesis of different diseases processes via altered immune responses. Thus, researchers are investigating the immunoregulatory functions of adipose tissue. Identification of factors secreted by adipose tissue that promote inflammatory pathways and metabolic dysfunction or play a role in the suppression of inflammation and thus have positive effects on obesity-linked metabolic disorders are elucidating immunometabolism. Such findings support a concept that adipokines secreted by adipose tissue can contribute to metabolic dysfunction.
152 Aristo Vojdani
Once an individual becomes obese, the secretory status of an adipose tissue depot can be altered by changes in the cellular composition of the tissue; these modifications may include alterations in the number, phenotype and localization of immune, vascular and structural cells, as well as the expression of adipokines, depending on the site of the depot [18, 19]. Adipocyte depots are found throughout the body including bone and major blood vessels, and organs such as the heart, kidneys and lungs [20]. A high-calorie diet can promote the development of a pro-inflammatory state in these adipocyte depots [20]. Although the functional importance of many of these individual adipose depots has yet been elucidated, recent findings suggest that diet-induced changes in their adipokine secretion can influence the function of the associated tissue [21]. Noted discoveries of adipose tissue components and their roles in inflammation include the following: complement factor D, or adipsin, was identified in 1987 as an adipokine [22]; tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine, was discovered in 1993 as a product of adipose tissue that is induced in animal models of diabetes and obesity and thus provides a functional link between inflammation and obesity [23]; then in 1994, leptin was identified as an adipose tissue-specific secreted protein that regulates food intake and energy expenditure in an endocrine manner [24]. The 1994 report identified the gene encoding leptin and shows the role of leptin in the regulation of feeding behavior. Similar to this, the identification of plasminogen activator inhibitor 1 (PAI1), a fibrinolysis inhibitor, as an adipokine that is strongly upregulated in visceral adipose depots in obesity [25] suggested a mechanistic link between obesity and thrombotic disorders. Around the same time, adiponectin, which is now known to act as an insulin sensitizer and anti- inflammatory, was identified as an adipocyte-specific adipokine [26-28]. Interestingly, adiponectin expression was found to be decreased in the obese stage, while experimental animal studies have shown that adiponectin protects against several metabolic and cardiovascular disorders that are associated with obesity. Similar to pro- and anti-inflammatory cytokines, these component findings have led to the notion that metabolic dysfunction, due to excess adipose tissue mass, may partly be the result of an imbalance in the expression of pro- and anti- inflammatory adipokines. This contributes to the development of obesity-linked complications.
Infiltration and Interaction of Immune Cells into Adipose Tissue
Although adipocytes make up the bulk of adipose tissue, it is not alone. Also contributing to the growth and function of adipose tissue are pre-adipocytes, lymphocytes, macrophages, fibroblasts and vascular cells. The cellular composition of, and cell phenotypes in adipose tissue are changed in the obese state, as shown in human and experimental animal models of obesity [29,30], in which a large number of macrophages is seen. The recruitment of macrophages, more abundantly in visceral than subcutaneous adipose tissue [31], is linked to systemic inflammation and insulin resistance. However, as shown in both human and mice [29,30], a sustained weight loss results in the reduction of macrophages in adipose tissue, which is accompanied by a decrease in the pro-inflammatory profiles of these individuals. It has been recently reported that macrophages accumulate in adipose tissues in the early stage of weight loss, presumably as a result of adipose tissue lipolysis [32]. Fibroblasts, which produce extracellular matrix components, are also found in adipose tissue. Researchers have been able to show that metabolically dysfunctional adipose tissue produces excess matrix components [33]. This production may interfere with adipose mass expansion and also contribute to metabolic dysregulation. There seems to be mounting evidence that intercellular communication within adipose tissue is required for normal metabolic function (Figures 1, 2).
Metabolic Diseases Driven by Immunoinflammation 153
Figure 1. Lean with normal metabolic function.
Figure 2. Obese with full metabolic dysfunction.
154 Aristo Vojdani
Production of Pro-inflammatory Adipokines
In this paper, adipose tissue is described by two structural and functional classifications: lean, with normal metabolic function, and obese, with full metabolic dysfunction. Lean tissue’s major immune cells are M2 macrophages, CD4+ cells and the adipocyte-produced anti-inflammatory adipokines. In obese individuals, with full metabolic dysfunction, not only is the volume of adipocytes increased significantly; instead of M2 macrophages, the ‘alternatively activated’ macrophage phenotype, obesity leads to the recruitment and accumulation of M1 macrophages, the ‘classically activated’ macrophage phenotype [34]. These M1 macrophages become activated upon contact with toll-like receptor ligands, such as lipopolysaccharides (LPS) and produce a significant amount of pro- inflammatory cytokines. Furthermore, cytotoxic lymphocytes are also accumulated in adipose tissue of obese individuals. Together with M1 macrophages, these cytotoxic lymphocytes form a crown-link structure around the adipocytes, causing adipose tissue dysfunction and chronic inflammation [35-37]. A key immune function of macrophages is to remove apoptotic cells from circulation, thereby preventing the release of noxious substances. Researchers speculate that the crown-like structures in adipose tissue signifies a pro-inflammatory state that may be due to the impairment of macrophage- mediated processes [38].
An inflammatory cascade begins with the stimulation of TH1 cytokines, such as interferon-γ (IFN- γ), or with bacterial products like LPS, which leads to the generation of M1 macrophages, which in turn produces pro-inflammatory cytokines such as TNF-alpha and IL-6, expresses inducible nitric oxide synthase (iNOS) and produces reactive oxygen species (ROS) and nitrogen intermediates [39]. On the other hand, macrophages are polarized to the M2 phenotype by TH2 cytokines, including IL-4 and IL-13. It is important to note that M2 macrophages upregulate the production of IL-10, an anti- inflammatory cytokine, and downregulate pro-inflammatory cytokine secretion, thus giving M2 macrophages an important role in the repair of injured tissues and the resolution of inflammatory states. The transcription of several genes, such as those encoding IL-1 receptor antagonist, macrophage mannose receptor 1, and arginase 1 is also upregulated in M2 macrophages [40]. With their distinct roles, M1 macrophages have been suggested as promoting insulin resistance while M2 macrophages protect against obesity-induced insulin resistance [41]. T cell subsets reside in adipose tissue and play a role in the regulation of macrophage phenotype. Lean mice have more CD4+ regulatory T cells in their adipose tissues and thus have a protection against pro-inflammatory macrophages, thereby a suppression of insulin resistance [42]. Insulin resistance can be linked to CD8+ effector T cells and Th1 cell-associated factors that initiate the recruitment and activation of macrophages in adipose tissues and promote a pro-inflammatory effect
[43,44]. Obesity-induced imbalance between TH1 and TH2 type signals may thus influence the recruitment and activation of macrophages in adipose tissues. Macrophage activation can promote either a pathogenic and inflammatory state, or a non-inflammatory and protective environment. The full function of and communications between adipose tissue components is not fully understood; however, it is important to keep in mind that cellular composition has an influence on inflammation. The macroenvironment in obese adipose tissue can dysregulate T cell responses. Adipose tissue of obese mice, compared to lean mice, had more activated CD8+ effector T cells but fewer CD4+ T cells; furthermore, CD8+ T cell infiltration preceded the accumulation of macrophages [43]. The authors, Nishimura et al., of this study propose, “that obese adipose tissue activates CD8+ T cells, which drive recruitment of macrophages and their differentiation into an inflammatory rather than anti-inflammatory phenotype” [43]. Working on characterizing the populations of Treg cells in obese and lean adipose tissue, Feuerer and colleagues found that fat-associated Treg cells were shown to have a different gene expression profile from Treg cells found at any other site, a unique TCR
Metabolic Diseases Driven by Immunoinflammation 155
repertoire and evidence of antigen-driven selection [42]. Another study found that TH1 cells in adipose tissue of obese mice is antigen driven [44].
Pro-inflammatory Cytokines in Adipose Tissue
Cytokines, the immune system’s messengers, can be classified as anti-inflammatory or pro- inflammatory based on their individual effect on other cells. The pro-inflammatory cytokines that have been shown to play a significant role in adipose tissue include TNF, IL-6, and IL-18. Each is described below. TUMOR NECROSIS FACTOR (TNF) – TNF is well known to autoimmunity. This pro- inflammatory cytokine is mainly produced by monocytes and macrophages and plays a leading role in inflammatory cascades and multiple autoimmune diseases. In experimental animals, TNF expression has been shown to be increased in models of obesity and type 2 diabetes [23]. Conversely, insulin sensitivity improves in obese animals in which TNF-induced signaling is lacking [45]. Where it is present, a fully active TNF function attenuates insulin-stimulated tyrosine phosphorylation of the insulin receptor and IRS1 in muscle and adipose tissues, promoting insulin resistance [46]. As with other pro-inflammatory cytokines described here, TNF levels are increased in obesity and decline with reduction in weight. Likewise, TNF levels in blood have been found to positively correlate with markers of insulin resistance [47-49]. More work, however, needs to be conducted for a better understanding of TNF’s role in insulin resistance. To give a few examples, short-term administration of TNF-blocking reagents led to a reduction in systemic inflammation, but did not ameliorate insulin resistance in type 2 diabetic obese patients [50]; while blocking TNF secretion in patients with metabolic syndrome led to an increase in muscle adiposity [51]; and prolonged TNF neutralization improved fasting glucose levels in patients with metabolic syndrome [52]. INTERLEUKIN-6 (IL-6): IL-6 is suspected of contributing to obesity-related insulin resistance. Elevated plasma levels of IL-6 positively correlate with obesity in humans, while levels are decreased after weight loss [19]. Additionally, elevated levels of IL-6 are seen in patients with type 2 diabetes and thus, can be used as a predictive biomarker for the development of type 2 diabetes [19]. An estimated one third of circulating IL-6 is believed to be produced in adipose tissue; therefore, in an obese state, the secretion of IL-6 is thought to play a role in metabolic dysfunction. The mechanistic role played by IL-6 in insulin resistance is not yet agreed upon. IL-6 is known to suppress insulin- stimulated metabolic actions in hepatocytes, a result of the induction of SOCS3 expression, and it has been shown that infusion of IL-6 into mice prevents insulin from suppressing glucose production in the liver [53]. Additionally, IL-6 deficiency may exacerbate hepatic insulin resistance and inflammatory conditions, while on the other hand, a reduction of IL-6 in adipose tissue can protect against the development of insulin resistance. Thus, IL-6 actions may be dependent upon the tissue (liver or fat) and the source (muscle or fat) [52-54]. INTERLEUKIN-18 (IL-18): IL-18 is also known to be produced by adipose tissues. Like IL-6, serum levels of IL-18 are increased during the obese state, and decline after weight loss. In mice, elevated secretion of IL-18 resulted in an increase of endothelial cell adhesion molecules, macrophage infiltration of the blood vessel wall and vascular abnormalities; in humans, increased levels of IL-18 were detected in atherosclerotic lesions, which are thought to be an indication of plaque instability [55,56]. Mice deficient in IL-18 have shown hyperphagia and have insulin resistance, hyperglycemia and/or obesity, all characteristics of metabolic syndrome [57]. IL-18 appears to have a complex role in coordinating inflammation and metabolism, which needs further research to elucidate.
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Macrophage Interactions Influence Metabolic Homeostasis in Adipose Tissue
In a healthy state or metabolic homeostasis, adipose tissue macrophages (ATMs) and adipocytes interact in a way that favors the inhibition of inflammatory pathways in the adipocytes and the classical activation of the ATMs; this healthy interaction also maintains insulin sensitivity in the former and alternative macrophage (M2) activation in the latter [40-42]. Unsaturated free fatty acids (FAs), such as omega3 FAs, signal, via G-protein coupled receptor 120 (GPR120), to dampen NF- kappaB activation in ATMs. NF-kappaB inhibition is also mediated by factors secreted by adipocytes. The decrease in NF-kappaB activity decreases transcription of IL-1beta, whereas decreased production of ceramides, an inflammasome activator, prevents activation of caspase-1. Lipolysis in adipocytes via CD5-like antigen (CD5l) and ingestion of saturated fatty acids is restrained in the lean state; this attenuates signaling via Toll-like receptors 2/4 (TLR2/4) in macrophages and adipocytes. These changes in the ATMs combine to maintain insulin sensitivity in adipocytes, decrease the production of chemotactic factors (leptin, S100A8/9, serum amyloid A [SAA]), reduce chemotaxis and recruitment of Ly-6C+CCR2+ inflammatory monocytes into adipose tissue, and decrease the production of complement protein C3, thus preventing activation of NF-kappaB in ATMs. Since activation of NF-kappaB is essential to the production of inflammatory cytokines, inhibition of NF- kappaB signaling in adipocytes and ATMs by statins, glucocorticoids and resveratrol, as well as induction of alternatively activated ATMs by thiazolidinediones, holds some therapeutic promise in combating obesity-induced insulin resistance and metabolic dysfunction [58-59]. In an obese state brought about by excessive food consumption, macrophages are recruited into adipose tissue, promoting local inflammation and insulin resistance. Dietary saturated fatty acids activate TLR2/4 on ATMs. Activation of TLR2/4 on ATMs leads to activation of NF-kappaB inflammatory signaling cascades. This activation of NF-kappaB results in the production of inflammatory cytokines such as IL-1beta and TNF-alpha, which inhibits insulin action in neighboring adipocytes. In obesity, ceramides induce activation of NLRP3, which contributes to the formation of inflammasomes, further augmenting IL-1beta production [60]. The increased IL-1beta and TNF-alpha plus various chemokines and chemotactic factors (such as MCP-1 and leptin) further contribute to the inflammatory cascade and perpetuate crosstalk between the inflamed adipocytes and adipose tissue, macrophages T cells and beta-islet cells. The MCP-1 and other chemokines secreted by adipocytes and macrophages lead to recruitment of inflammatory monocytes which differentiate into classically activated macrophages to promote adipose tissue inflammation. The classically activated macrophages and adipocytes secrete abundant amounts of several chemo-attractants such as S100A8/9, MCP-1 and serum amyloid A (SAA) during obesity, which further recruits monocytes to the inflammatory environment [34,61]. ATMs release CD5l, which promotes lipolysis after being incorporated into adipocytes via CD36-mediated endocytosis. In a feed-forward loop, the released fatty acids resulting from the increased lipolysis induce expression of chemokines in a TLR4-dependent manner, leading to recruitment of Ly-6C+CCR2+ inflammatory monocytes and ATMs. Reciprocally, saturated FAs, C3 complement, and inflammatory cytokines (TNF-alpha, IL-1beta) sustain inflammatory cascades in classically activated ATMs. Reduction in circulating levels of adipokines potentiate leads to inflammatory (M1) activation of ATMs, resulting in inflammation. The wave of inflammation spreads from adipocytes to the other organs, e.g. liver and skeletal muscle, bringing about systemic insulin resistance [62] (Figures 3, 4).
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Figure 3. (1) Dietary saturated fatty acids activate toll like receptors 2/4 (TLR2/4) on adipose tissue macrophages (ATMs). (2) Activation of TLR2/4 on ATMs leads to activation of NF-kappaB inflammatory signaling cascades. (3) This activation of NF-kappaB results in the production of inflammatory cytokines such as IL-1beta and TNF- alpha, which inhibits insulin action in neighboring adipocytes. (4) In obesity, ceramides induce activation of NLRP3, which contributes to the formation of inflammasomes, further augmenting IL-1beta production. (5) The increased IL-1beta and TNF-alpha plus various chemokines and chemotactic factors (such as MCP-1 and leptin) further contribute to the inflammatory cascade and perpetuate crosstalk between the inflamed adipocytes and adipose tissue, macrophages T cells and beta-islet cells. Modified from Nat Med: August 2011 Vol 17 (8) suppl, Metabolic Syndrome.
Low-Grade Inflammatory Responses and Metabolic Diseases
Inflammation is a beneficial immune response designed by nature to protect the body from infection, and to restore damaged tissues after acute trauma. Chronic inflammation, defined as persisting for weeks, months or years, leads to chronic inflammatory diseases. Chronic inflammation is a sign that there is a breakdown in the resolution of the immune response. Following is a summary of a recent Nature Conference, held at Keble College, Oxford, UK, and themed “Resolving Inflammation: Mechanisms and Drug Discovery” [63]. Increasingly evidence is accumulating to show that obesity causes chronic low-grade inflammation, and that this continuous low-grade inflammatory condition contributes to systemic metabolic dysfunction, which is associated with obesity-linked disorders [6]. Clinical and epidemiological studies have been published that link the development of low-grade inflammatory immune response to metabolic diseases such as obesity and type 2 diabetes. C-reactive protein (CRP), a pro-inflammatory marker in the blood, is found in individuals with excess adipose mass or obesity. Increased levels of CRP and IL-6, its inducer, are predictive for the development of type 2 diabetes [14,15]. Lifestyle changes aimed at weight loss for these individuals have resulted in reductions in the levels of pro-inflammatory markers including CRP and IL-6 [64].
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Since microbiome disharmony, in general, and microbiota imbalance or gut dysbiosis is responsible for the induction of low-grade inflammation, and hence, obesity, the following section will describe the role of infection, in particular altered gut microbiota, in obesity.
Figure 4. (6) The MCP-1 and other chemokines secreted by adipocytes and macrophages lead to recruitment of inflammatory monocytes which differentiate into classically activated macrophages to promote adipose tissue inflammation. (7) The classically activated macrophages and adipocytes secrete abundant amounts of several chemo-attractants such as S100A8/9, MCP-1 and serum amyloid A (SAA) during obesity, which further recruits monocytes to the inflammatory environment. (8) ATMs release CD5-like antigen (CD5l), which promotes lipolysis after being incorporated into adipocytes via CD36-mediated endocytosis. (9) In a feed-forward loop, the released fatty acids resulting from the increased lipolysis induce expression of chemokines in a TLR4-dependent manner, leading to recruitment of Ly6C+CCR2+ inflammatory monocytes and ATMs. (10) Reciprocally, saturated FAs, C3 complement, and inflammatory cytokines (TNF-alpha, IL-1beta) sustain inflammatory cascades in classically activated ATMs. Modified from Nat Med: August 2011 Vol 17 (8) suppl, Metabolic Syndrome.
Altered Gut Microbiota and Metabolic Syndrome
Two landmark programs were launched for the study of gut microbiota and its effect on the host. In the US, the Human Microbiome Project (HMP), linked to the US National Institutes of Health, spent five years creating a reference database that will allow scientists to more rapidly sequence and assemble microbial genomes taken from humans and other animal subjects. Across the pond, Metagenomics of the Human Intestinal Tract (MetaHIT), a European program, worked for four years on a sequencing study of 124 subjects from Denmark and Spain. MetaHIT counted 3.3 million genes in the gut alone. Using 300 volunteers, HMP decoded microbial genomes found in the gut, mouth, nose, skin and reproductive tract. Sadly, both programs are ending this year. However, publications from these two groups are filling the pages of many scientific journals and providing scientists,
Metabolic Diseases Driven by Immunoinflammation 159 researchers and clinicians with important information that may help in the prevention or management of many inflammatory autoimmune conditions. The increasing incidence of metabolic diseases is thought to be the result of excessive food consumption, leptin deficiency and reduced levels of physical activities. The hallmarks of this disorder include high cholesterol, high triglycerides, hyperglycemia, insulin resistance and increased fat mass throughout the body [65]. Recent work suggests a possible role for gut microbiota and its induction of low-grade chronic inflammation in obesity [66]. In both lean and obese human volunteers, as well as genetically obese mice and their lean counterparts, comparisons of gut microbiota were made using shotgun sequencing of microbiomes [66]. Shifts in the relative abundance of two bacterial phyla, Bacteroidetes and the Firmicutes, in both humans and mice, correlated with the development of obesity. Bacteroidetes and the Firmicutes are two major members of the more than 50 known divisions of bacteria making up more than 90% of all phylogenetic types in mice and in humans [67], and the Bacteroidetes to Firmicutes ratio in humans and in mice is about 3:1. Interestingly, this ratio changes significantly in the obese state. The relative abundance of Bacteroidetes in obese mice is reduced by 50%, while the Firmicutes are increased by a similar percentage [68]. In other words, the ratio of Bateroidetes to Firmicutes in obese individuals is more in favor of Firmicutes. These differences cannot be attributed to differences in relative food consumption since the obese mice had reduced chow consumption, but still exhibited marked increases in percent body fat. Furthermore, the percent body fat correlated with an increase in the ratio of Firmicutes to Bacteroidetes [68] (Figure 5).
Figure 5. Correlation of body weight to ratio of Firmicutes to Bacteroidetes.
When an obese human is put on either a low-fat, or carbohydrate-restricted, diet, they lose weight and the weight loss correlates with relative abundance of Bacteroidetes [66] (Figure 5). Moreover, the increase in Bacteroidetes was correlated with weight loss but not total caloric intake [69]. It appears the obese microbiome has an increased capacity to harvest energy from the diet; this trait of increased energy harvest from the diet is transmissible. It has been shown that transfer of gut microbiota from obese to wild-type germ-free mice caused an increase in fat mass in the recipient mice. This data leads to speculation that gut microbiota promote obesityp Using mice that are prone to develop type 1 diabetes mellitus, scientists found that if altered gut microbiota is transplanted into germ-free recipients, the functional characteristics of the donor microbiota are transferred as well [70]. The obesity trait was transmissible by transplanting microbiota of leptin-deficient, ‘obese’ mice into germ-free mice [66], or by transplanting a Western-diet- associated microbiome to germ-free mice, even if the donor recipient mice consumed a standard, low- fat, high-carbohydrate diet after transplantation [71].
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We are Never Alone: Our Co-developing Microbiota
The number of microorganisms living on the outer surfaces of the human body, mouth, nose, lungs, skin, gastrointestinal tract, eyes, and reproductive tract outnumber the total cells of the human body. These friends of ours protect us, and thus are vital to our health. When the delicate balance within the microbiota environment is dysregulated, the host experiences inflammation. An inflammatory cascade can result in autoimmunity. Beginning at birth, the composition and activity of gut microbiota co-develop. The impact of the host genome, nutrition and lifestyle on gut microbiota is body-wide. Gut microbiota are involved through metabolic signaling and immune inflammatory pathways in not only the gut, but also the liver, muscle and brain. By understanding the roles that gut microbiota play in mechanisms of inflammation, one can better optimize therapeutic protocols by manipulation of gut microbiota and thus prevent disease onset and improve the overall health of the host. Just as a person’s fingerprint is unique, so is his microbiome. Unlike the fingerprint, which remains constant throughout one’s life (with the exception of the addition of scar tissue or ridges worn down from a lifetime of manual labor), the microbiota composition changes based on host nutrition, lifestyle stressors and antibiotic use. This composition is subject to the host’s phase of life and environment. Within the host microbiota compositions can change from one niche of the body to another, such as skin versus reproductive tract or upper gastrointestinal tract versus colon. The microbiota of an infant (Figure 6) are sown at birth. Delivery method and whether or not the infant is breastfed have influence on infant microbiota. Vaginally-delivered babies have microbiota compositions dominated by Lactobacillus, Prevotella and Atopobium, while Cesarean section babies have microbiota that resemble maternal skin composition, with staphylococci dominance [72]. If the baby is born with a lower number of Bifidobacteria, he has a greater chance of being overweight in later childhood [73]. Furthermore, a neonate is prone to ‘obesogenic microbiota’ if his mother is obese, suggesting a decreased number of Bifidobacteria at birth is a heritable trait [74]. During peri- and postnatal development, the predominance of aerobic bacteria is altered over the first few weeks of life to form a complex anaerobic-dominated microbial community [75]. It is during this stage of development that the activation of the hypothalamic-pituitary-adrenal (HPA) axis occurs. The HPA axis has an important impact on the enteric nervous system and thus the gastrointestinal tract. Aside from adolescent years, when there is a higher abundance of bifidobacteria and clostridia [76], core gut microbiota remains constant. At the age when immune function declines (60 + years), microbiota composition shifts, resulting in a significant decrease in Bifidobacteria [77]. A symbiotic relationship exists between gut microbiota and host immune system. At birth the microbiota shapes the immune system, which in turn, shapes the composition of the microbiota. An array of signaling pathways keeps these two constantly connected. Their complex interactions comprise a series of host-microbe metabolic axes. Nicholson et al. define such an axis as “a multi- directional interactive chemical communication highway between specific host cellular pathways and a series of microbial species, sub-ecologies and activities” [78]. Small molecules, low-molecular weight metabolites, peptides and proteins are co-produced by the host and its gut microbiota in order to transmit information between cells and microbial symbionts. As part of this signaling, humans excrete between 50 and 100 mg of volatile phenals per day, predominantly in the form of 4-cresol and phenol [79].
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Figure 6. Influences on microbiota through life.
Altered levels of 4-cresol metabolites in urine have been associated with a variety of physiological and pathological conditions including weight loss (differences in ratio of Firmicutes to Bacteroidetes [69]) and inflammatory bowel disease (loss of Lactobacillus and Bacteroides species [80]). A notable change in gut microbiota species ratio occurs in bariatric surgery, particularly gastric bypass. Such gastrointestinal trauma induces a marked shift in gut microbitoa composition from predominant Firmicutes and Bacteroidetes toward a predominance of gamma proteobacteria [81,82]. Post-surgery, Faecalibacterium prauznitzii has been shown to correlate inversely with inflammatory markers such as C-reactive protein and IL-6 [83].
Nutrition and Gut Microbiota
A high-fat diet increases the proportion of gram-negative to gram-positive microbes in the gut [84]. A dominance of gram-negative microbes produces an increase in the release of LPS, endotoxins on the membrane of gram-negative bacteria. LPS induces gut inflammation, which may contribute to increased intestinal permeability. Leaky intestinal barriers allow the transference of LPS through the barrier. Increased toxin exposures triggers inflammatory cascades, which result in a decrease in the host’s metabolism. When LPS enters the blood stream, it has been shown to play detrimental roles in major depression [85], chronic fatigue syndrome [86], seizure disorders [87], atherosclerosis [88] and type 2 diabetes [89]. Furthermore, oral cavity Veillonella and Streptococcus combined with atherosclerotic plaques that contain more Proteobacteria species and fewer Firmicutes, correlates with atherosclerotic plaque formation [90]. An interesting target for restoring host immune function is n-butyrate. A short-chain fatty acid (SCFA), n-butyrate has many beneficial effects. It regulates neutrophil function and migration, inhibits inflammatory cytokine-induced expression of vascular cell adhesion molecule-1, increases expression of tight junction proteins, and reduces cytokine and chemokine release from human immune cells, which shows its anti-inflammatory effect [78].
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If diet affects the composition of gut microbiota, and it has been shown that microbiota regulates the immune and inflammatory responses [91] throughout the body, then quantifiable results on immune responses based on diet should easily follow. Indeed, small independent studies have been performed, but larger numbers in research have thus far been indirect [92]. Some study results are summarized in Table 1.
Table 1. Effects of Diet on Inflammatory Diseases
DIET OUTCOME Dietary Fiber in adequate or large Decrease in incidence of colitis amounts [92] Decrease in incidence of type 2 diabetes Decrease in incidence of cancer Vegan diet [93] Diminishes severity of rheumatoid arthritis Short Chain Fatty Acids [94] Improve inflammatory bowel conditions Omega-3 Fish Oil [95] Decrease in inflammatory disease activity Reduced need for use of anti-inflammatory drugs Berberine Protected against obesity, even with high-fat diet [(rat study) 96] Protected against the development of insulin resistance Decrease in pathogenic populations of gut bacteria Increase in beneficial gut bacteria Dietary Fructans [97,98] Energy source for Bifidobacteria Increased satiety Decreased caloric intake Decreased post-prandial glycaemia
Lipopolysaccharide Released by Gut Microbiota is Associated with Diet-Induced Obesity
In the microbiology lab, students learn that each type of bacteria requires a specific medium for growth. Although the base of these media is agar-agar, it is not enough for many bacteria. In addition to agar-agar, bacteria desire specific carbohydrates, sugars, fatty acid proteins, such as rice, corn, soy, egg, whole blood, heart or brain, in order to grow. Similar to the growth of bacteria in test tubes and laboratory flasks, the human gastrointestinal tract and the composition of the gut microbiota is influenced by the diet and its components [99]. For example, it has been shown that low-intake of fiber, or complex plant polysaccharides, adversely affects the makeup of intestinal bacteria. This can lead to decreased production of immunomodulatory products, such as SCFAs, which are important for the overall regulation of immune function [100]. Accordingly, certain types of diets induce selective bacterial growth and release of endotoxins, or LPS. Immune responses against these bacterial toxins are likely the explanation for greater inflammatory diseases in developed countries [101]. Increased incidence of gut dysbiosis for the past six decades is associated with gastric ulcers caused by Helicobacter pylori infection, and life-style- related disorders such as obesity and diabetes. This proposed change in diet and microbiota, and their association with increasing incidence of inflammatory diseases such as asthma, obesity or type 1 and type 2 diabetes, is shown in Figure 7.
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Figure 7. Changes in diet and microbial composition may result in symbiosis or dysbiosis in the gut.
Diet and other environmental factors have a major effect on gut microbial composition. This suggests that balanced microbial composition results in symbiosis. If harmonious, there is regulation of immune and inflammatory responses through anti-inflammatory and/or immunomodulatory products, all of which help maintain homeostasis. Dysbiosis, therefore, would lead to dysregulation of the immune system via a lack of beneficial microbial products and an increase in bacterial endotoxic factors. This scenario leads to inflammation. Clearly, certain gut microbiota are required for the regulation of immune responses and any modification of this milieu may result in immune dysregulation, the overgrowth of pathogenic bacteria, the release of endotoxins, LPS, and the promotion of inflammation. People who are genetically susceptible to metabolic diseases are particularly prone to this inflammatory cascade [102]. It was recently reported that moderate increase of plasma concentration of LPS increased during a fat-enriched diet and defined metabolic endotoxemia [84]. It was demonstrated that LPS was responsible for the onset of metabolic disease due to a chronic low-rate infusion of LPS into circulation induced many of metabolic disease characteristics. Moreover, when LPS receptors were knocked out in animal models, the animals did not develop the disease. Change in the intestinal microbiota, due to antibiotic treatment to reduce the elevated concentration of plasma LPS, also reduced metabolic endotoxemia and the cecal LPS contents in high fat-fed and obese mice [103]. Therefore, it is clear that gut bacteria are involved in high-fat diet-induced metabolic endotoxemia.
Microbiota and the Immune System: Crossing Barriers
Gut bacteria are usually confined to the luminal side of the gastrointestinal barrier. However, the sheer number of intestinal bacteria makes an occasional breach inevitable. Microorganisms that
164 Aristo Vojdani breach the intestinal barrier are typically phagocytosed and eliminated by lamina propria macrophages [104]. A sampling of the invader is taken by the immune system which induces the production of antibodies specific to that bacterial antigen. The next penetration of that antigen is met by a barrage of dendritic cells. Microbiota should not be seen only as inflammatory to the intestinal barrier, as described earlier. Indeed, microbiota can induce repair of damaged epithelial cells through an MyD88-dependent process; the innate signals, conveyed largely through myeloid cells, are required for the enhancement of epithelial cell proliferation [104]. Gastrointestinal tract tissue is rich in myeloid and lymphoid cells and it has long been established that the gut microbiota have a critical role in the development of organized lymphoid structures and the function of immune system cells. Bacteria have been shown to enhance the anti-inflammatory branches of the adaptive immune system by influencing the differentiation of Tregs or by inducing IL-10 expression. Within the intestinal tract, the balance of effector lymphoid cells and Treg cells can have a marked influence on how the mucosa responds to stresses that trigger inflammatory damage [104]. The influencing reach of gut bacteria on the balance of T cell subsets is now known to extend beyond the intestinal barrier.
Adipose Tissue Inflammation and Metabolic Disorders
The effect of gut bacteria may be mediated by a mechanism that could increase, not only the release of LPS, but also gut permeability, and enhance LPS absorption and subsequent antibody production against it. Finally, it has been concluded that gut microbiota could control intestinal permeability, which determines the threshold at which metabolic disorders occur through endotoxemia [103]. A high-fat diet initiates the cascade that leads ultimately to metabolic disorders. With each stage (high-fat feeding, change in glut flora, increased gut permeability, increased LPS absorption, increased endotoxemia, low-grade inflammation, metabolic disorders) the fat cell grows and the inflammation increases. These findings are summarized in Figure 8. Poor diet, lack of exercise, daily stress and microbiome composition all play a role in metabolic disorders. Addressing all of these triggers in combination may help in a therapeutic approach to inflammatory, autoimmune, or metabolic conditions. Still, more work needs to be conducted to fully understand the role microbiota play in human immune responses. Nicholson and colleagues [78], pose challenges for future research into understanding the microbial impact on health. They state that we need:
1. Better understanding of maternal to fetus transfer of microbiota and influence of nutrition on infant development of microbiota. 2. To map the impact of early anti-biotic use in the developmental ecology, function and resilience of microbiota in childhood. 3. More knowledge on how gut microbiota influence drug metabolism, bioavailability, and toxicity. 4. To develop strategies for the in vitro culturing of complete microbiota in order to study bacterial species and their interactions within ecological constructs and ecosystems. 5. Comprehensive, cross-discipline studies to elucidate the changing interactions between the immune system and gut microbiota that affect gut, liver and brain function.
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Figure 8. Cascade leading to metabolic disorders.
Despite the ending of two great programs, HMP and MetaHIT, scientists will continue the work that was catalyzed by US and European researchers. Responses to the above may still be forthcoming. Until then, the recommended protocol is to regulate inflammatory responses, support the mucosal immune system and repair the breached intestinal tight junctions (Table 2).
Table 2. How to Regulate Inflammatory and Immune Responses, and Repair Breach of Intestinal Barriers
Include a regimen of pre- and probiotics whenever using antibiotics Include probiotics in daily supplement routine Consume complex plant polysaccharides Include mercury-free omega-3 fish oil in daily supplement routine Use vitamin A to support the mucosal immune system Get a daily dose of sun for the production of vitamin D, which helps to regulate the immune system and supports the mucosal immune system
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Received: November 9, 2012 Revised: January 12, 2013 Accepted: January 15 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):173-181 ISSN: 2156-941X © 2013 Nova Science Publishers, Inc.
BRAIN-REACTIVE ANTIBODIES IN TRAUMATIC BRAIN INJURY
Aristo Vojdani Immunosciences Lab., Inc., Los Angeles, CA USA
ABSTRACT
Neuroautoimmune diseases are disorders that involve the body’s immune system attacking its own brain or neural tissues. Normally the brain is protected from the outside world by the blood- brain barrier (BBB), which is composed of highly specialized brain endothelial cells. However, repetitive traumatic brain injury (TBI), such as occurs in football and other sports, can lead to repeated disruptions to the BBB. This opening of the door to the brain can lead to a dysfunctional exchange of molecules between the blood and the brain. A dysfunctional immune system can mistakenly identify neural antigens as invasive agents and produce autoreactive antibodies against BBB proteins such as S100-B and various neural tissue antigens. S100-B has been used in conjunction with CT scanning to successfully confirm concussions or brain injuries. The detection of S100-B antibodies actually goes further to indicate that the BBB has been damaged and autoimmunity has been activated against the brain cells, and can even be used to indicate degree of recovery and when to return to normal activity. These findings support the importance of measuring antibodies against S100-B and other neural autoantigens in the diagnosis and therapy of patients with TBI.
Keywords: Autoimmune, traumatic brain injury, autoantigens, S100-B antibodies
INTRODUCTION
Autoimmune diseases affect about 7% of the world’s population. In these disorders, pathogenic
TH1 cells, autoreactive TH17 cells, antibodies and associated molecules attack antigens of various tissues, including brain tissue. Brain-reactive antibodies are detected in about 3% of the general population but do not contribute to brain pathology unless they cross the blood-brain barrier (BBB) [1]. The BBB is composed of highly specialized brain endothelial cells which are fully differentiated to the neurovascular system. It is estimated that the human brain contains more than ten billion capillaries, which translates into one vessel for each neuron. The total length of the capillaries in the human brain is about 400 miles. In conjunction with microglia, astrocytic foot processes and pericytes, the BBB separates the neurons from various components of the circulating blood [2]. The endothelial tight junctions, together with astrocytic foot processes, prevent the passage of all soluble
Correspondence: Dr. Aristo Vojdani, Immunosciences Lab., Inc. Los Angeles, CA USA, 822 S. Robertson Blvd., Ste. 312, Los Angeles, CA 90035 E-mail: [email protected]
174 Aristo Vojdani molecules greater than 400 Da into the nervous system; consequently, during immune maturation B cells are not exposed to a variety of unique brain antigens expressed on neurons, oligodendrocytes, microglia and astrocytes. As a result, the immune system has no mechanism for regulatory T-cell development to establish tolerance for brain antigens [3]. However, various conditions such as stress, infection (in particular, bacterial endotoxins), toxic chemicals, drugs, some medication, and, more importantly, traumatic brain injury (TBI), directly or indirectly, through the activation of inflammatory signals, can disrupt the integrity of the BBB [4-12]. The breakdown of the BBB due to the disruption of tight junctions by various triggers results in the altered transport of molecules as well as pathogenic TH1 and TH17 cells between the blood and the brain, and to some degree from brain to blood. This molecular and cellular exchange between blood and brain can result in aberrant angiogenesis, vessel regression, brain hyperfusion, neuroinflammatory responses, neural cell damage, and the release of neural antigens into the blood [2]. Due to defects in immune tolerance or response against various neural antigens, these antigens will be transmitted by antigen-presenting cells, first to
T cells and then to B cells, resulting in brain-specific antibodies, and autoreactive TH1 and TH17 cells. The entry of these pathogenic cells and antibodies into the brain tissue may result in progressive synaptic and neuronal dysfunction and loss in neuroautimmune and neurodegenerative disorders such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer’s and Parkinson’s disease [1,13]. In some cases, it might be expected that brain antibodies that arise in diseases with clear antigenic triggers such as bacterial endotoxins or lipopolysaccharides (LPS), dietary antigens (gluten, milk proteins, excessive salt), and environmental toxins (heavy metals, polychlorinated biphenyls), disappear once the inciting triggers are no longer present [4-12,14,15]. Thus, eradication of the exogenous triggers may result in BBB repair, followed by termination of autoantibody production. However, in the case of brain concussion or repeated TBI, this may not be the case.
TRAUMATIC BRAIN INJURY, BLOOD-BRAIN BARRIER DISRUPTION, AND BRAIN ANTIBODIES
TBI is a multifaceted pathology involving excitotoxicity, free radical formation, brain swelling, and the entry of locally produced molecules such as cytokines, chemokines, and other molecules that can disrupt the metabolism and contribute to neuroinflammation [16-18]. Understanding the diverse mechanisms involved in TBI is becoming increasingly important; it is estimated that 4 million people experience sports and recreation-related concussion annually in the United States [12,19,20]. Following TBI, in addition to a leaky BBB, a cascade of biochemical, immunological and excitotoxic events which are mediated by the innate and adaptive immune systems occurs in the central nervous system (CNS). These excitotoxic events begin with acute microglial activation followed by the release of massive amounts of glutamate and aspartate which over-stimulate the glutamate receptors. This results in the opening of calcium channels, the influx of calcium, neuronal toxicity and cell death [13,21]. Depending on the degree of injury, this excitotoxic reaction may improve within hours or days. But with repeated injuries and multiple concussions, the excitotoxic reaction could be followed by immunoexcitotoxicity and neuro-destructive process (Figure 1). Microglial cells or resident macrophages constitute about 15% of the total glial cell population within the brain. These cells are the major components of active immune defense in the CNS. Normally microglia are in a resting state, but upon exposure to environmental triggers, trauma or injury, disruption of the BBB, or disruption of brain homeostasis, the microglia can be activated and switch to a state of active immune defense.
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Figure 1. Proposed mechanism for excitotoxicity from leaky BBB. Repeated head trauma and multiple disruptions of the BBB leads to the release of free radicals and immunoinflammatory factors, causing acute microglia activation, which contributes to immunoexcitotoxicity.
To facilitate the healing process after an injury, the host body tries to remove the inciting agents and clear dead or dying cells by releasing immune factors, in particular chemokines and cytokines, reactive oxygen and nitrogen species, inflammatory prostaglandins, proteases, nitric oxide and trophic factors [21]. During this healing process, microglia secrete a number of neurotrophic factors and immunoregulatory or anti-inflammatory cytokines, such as nerve growth factors, brain-derived neurotrophic factors which contribute to the reduction of neurotoxic processes in the brain and the repair of the disrupted BBB. One of the major concerns after a first injury is the prevention of recurrent injuries before the brain is completely healed. This is because repetitive brain injury that occurs before the complete healing and repair of the neuroinflammatory response can accelerate and exacerbate chronic activation of the microglia, with serious consequences. Indeed, it has been shown that the primed microglia get fully activated and release significantly higher levels of pro-inflammatory cytokines/chemokines and excitotoxins than the initial injury. In most cases the activated microglia will switch to a reparative mode, but in some cases this normal protective microglial response to the injury does not have the time to “turn off’ the switching mechanism. When the switching mechanism becomes locked in the “on” position, it can lead to prolonged and severe brain immunoexcitotoxicity, neurodegeneration, and possibly neuroautoimmunities [12, 22]. The process of neuroautoimmunity depends largely on the integrity of the BBB. A disrupted BBB leads to exposure to many environmental triggers. Due to the antigenic similarity of these triggers with neuronal cell antigens, brain-reactive antibodies are detected in healthy subjects who do not exhibit neurological symptomatologies. These autoantibodies contribute to a host of neuroimmunological disorders. For example, neuron-binding autoantibodies have been detected in the
176 Aristo Vojdani sera of patients with obsessive-compulsive disorders, Sydenham’s chorea, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection, autism, multiple sclerosis, Guillain-Barré syndrome, Hashimoto’s encephalopathy, lupus, schizophrenia, chronic peripheral neuropathy, optic neuritis, vascular dementia, stiff person syndrome, celiac disease and Alzheimer’s disease [1].
Figure 2. Autoreactive antibodies and intact BBB. In an intact BBB, autoantibodies are restricted to the lumen of the blood vessels, so that the antibodies are prevented from causing damage to brain tissue, regardless of how high the antibody level is.
Figure 3. Autoreactive antibodies and disrupted BBB. With a disrupted BBB, autoantibodies gain access to the brain tissues. With only a few autoreactive antibodies, damage is minimal and the neurons and brain may recover. However, a high level of autoreactive antibodies can lead to extensive neuronal damage, neuronal cell death, and possibly neuroautoimmune disorders.
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It seems that in these conditions a defective BBB allows these autoantibodies access to various targets on the surfaces of brain cells. These antibodies may therefore contribute to the initiation and/or progression of many neuroinflammatory and neurodegenerative diseases that involve BBB compromise. A proposed model for the role of brain-reactive autoantibodies and BBB integrity disruption in the pathogenesis of neurological disease is shown in Figures 2 and 3.
CONSEQUENCES OF REPEATED BBB DISRUPTION IN TRAUMATIC BRAIN INJURY
The annual incidence of traumatic brain injuries is about one in 250 persons or 5% of total ER patients [23]. In the National Football League, the number of sub-concussive head hits has been estimated to be in the range of hundreds per season. Clinically, concussions can produce symptoms that are of short or long duration lasting from several minutes to several months. Severe post- concussive symptoms have been reported to last several years in some athletes and have caused numerous athletes to retire from their sport. Although football-related concussions are becoming increasingly recognized, the mechanisms involved remain poorly understood. BBB disruption (BBBD) or increased permeability of the brain vasculature has been linked to a variety of neurological disorders including seizures, Alzheimer’s disease, stroke and TBI [11]. Circulating autoantibodies against CNS antigens become pathogenic to the brain when the BBB allows their access to the brain [24]. The consequences of BBBD could be deleterious when accompanied by autoimmune reactivity as in neuroautoimmune disorders. In these cases the loss of BBB integrity initiates humoral and cellular immune response in the CNS and unmasking of the CNS antigens, including BBB proteins and astrocytic antigens called S100-B, which triggers peripheral immune responses against these antigens. S100-B is a 21 kDa calcium-binding glial-specific protein mainly expressed by astrocytes on their endfeet. These endfeet, together with the tight junction proteins zonula occludens and ZO-1, form the BBB. The prevailing method of choice for detecting intracranial injury in patients with minor injury is computed tomography (CT) scan. Although the CT scan has high sensitivity in detecting intracranial injury in patients with brain injury, it is expensive, exposes patients to high doses of radiation, and reveals clinically relevant lesions in less than 10% of cases [23]. For this reason, the measurement of S100-B in blood was introduced as an indicator of minor as well as severe head injury [25,26]. This S100-B protein level in the blood was used as a screening tool for the early assessment of minor head injuries in more than 2,000 patients in Bordeaux, France, comparing CT scans with plasma S100-B levels [23]. With a cutoff of 0.12 microgram/L of S100-B, TBIs on CT scan were identified with a sensitivity of 99% and specificity of 20% [23]. It was concluded that plasma S100-B in patients with minor head injury is a promising screening tool that may be of help in the clinician’s decision not to perform CT imaging [23]. It is important to mention that the half-life of S100-B 21 kDa protein is about 4 hours, and therefore, in many players where S100-B was detected, antigen levels returned to pre-game values within 24 hours after the game [23]. This speedy elimination of 21 kDa from the blood may be related to immune response and the production of specific antibodies against S100-B. As opposed to the antigens, S100-B antibodies are much more stable in blood, with IgG having a half-life of 21 days. Therefore, the measurement of antibodies against S100-B is more useful than just measuring the levels of S100-B itself in TBI.
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CLINICAL SIGNIFICANCE OF AUTOANTIBODIES AGAINST S100-B AND OTHER NEURONAL ANTIGENS
It is possible that repeated “opening” of the BBB can result in a delayed pathological response consisting of immune cell activation against a brain antigen. Activated immune cells mistakenly “recognize” self antigens as foreign invaders and mount an immune response against them. A very recent study examined both the levels of S100-B and specific antibodies against S100-B in football players with TBI [11], but other brain antigens, such as myelin basic protein (MBP), tau, and beta- trace protein could also be attacked by the activated immune cells, resulting in neuroautoimmunity. Although antibodies are produced as a result of BBBD, the presence of neural autoantibodies in blood alone does not necessarily translate into an autoimmune or neurological disease. In fact, autoantibodies can be detected in individuals who do not present autoimmune symptoms [27]. However, autoantibodies may become pathogenic upon penetration into the CNS through either a BBBD or extravasation into cerebrospinal fluid from the sub-arachnoid space [24]. As has been stated earlier, the presence or detection of autoantibodies is associated with many neurological and/or autoimmune diseases. Elevated antibody titers for S100-B and other brain proteins have been described in a variety of human diseases including Alzheimer’s disease [28-30]. Immunoglobulins in the brain have also been detected in epilepsy [31]. Recent reports have shown that in patients with senile dementia, one of the early markers of cognitive decline is the presence of antibodies directed against S100-B [28,29]. The presence of an autoimmune response that persists for an extended period following repetitive BBBDs in adulthood may cause neuronal cell death and an early cognitive decline [32]. To borrow the parlance of sports, it has been proposed that a number of molecular “players” “switch teams” in the event of a BBBD [33]. These molecular players in serum (albumin, magnesium ions, potassium ions, immunoglobulins) may enter the brain after a BBBD and disrupt the homeostasis of the CNS. On the other hand, brain proteins may activate an autoimmune response by antigen unmasking. This decline in cognitive function and the risk of developing neurodegenerative diseases have been found in football players with head injuries [30]. If repeated head trauma is causing BBBDs and leading to the presence of autoantibodies in the CNS, it should be no surprise that autoantibodies to S100-B can be found in football players after playing even a single season, during which a typical player may experience 1,000 head hits or more [34]. In the latest study involving 67 football players, the number of head hits and brain injuries were assessed by conducting CT scans and tests that measured balance, motor control and memory [11]. They collected blood from 57 players before and after football games and measured the level of S100-B protein in their blood. Serum S100-B was detected in players who experienced the greatest number of sub-concussive hits. Since S100-B is a large molecule (21 kDa), even trace amounts handled by cells involved in the immune system resulted in specific antibodies against S100-B. The fact that this protein found its way into the blood means that the blood-brain barrier or the biological door to the brain had been damaged, and the antibodies produced against S100-B had made their way into the brain, producing autoimmune response against the brain tissue. Indeed, this autoimmune response was even found in a subgroup of players that did not suffer from brain concussion [11]. Considering the fact that it is sometimes difficult to diagnose concussion, which occurs in about 40% of football players, the detection of antibodies against S100-B indicates that not only is there an abnormal opening or a door to the brain, but that autoimmunity has been activated against the brain cells. Furthermore, elevated levels of autoantibodies against S100-B and other brain tissue antigens such as myelin basic protein, myelin oligodendrocyte glycoprotein, tubulin, cerebellar and synapsin indicate repeated sub-concussive events characterized by BBBD. The presence or absence of these antibodies against S100-B and other brain tissue antigens can determine whether or not TBI or
Brain-Reactive Antibodies in Traumatic Brain Injury 179 concussion has occurred, and it can also indicate when it will be safe to return to normal activities. This process of neuroautoimmunity and neurodegeneration in repeated concussions or sub- concussions is shown in Figure 4.
Figure 4. Repetitive sports brain injuries and neurologic disorders. Repeated trauma caused to the brain in a short period of time, such as often occurs in many sports, can overwhelm the brain’s healing capacity, potentially leading to neuroautoimmunity and neurodegeneration.
Serum levels of S100-B autoantibodies also predicted the persistence of white matter abnormalities detected by MRI, which in turn correlated with cognitive changes. The correlation of serum S100-B autoantibodies with white matter abnormalities support a link between repeated BBB disruption and future risk for cognitive changes. Even in the absence of concussion, the athletes may experience repeated BBB disruption and the surge of potential autoantigens in the blood. Additional autoantigens that were detected in the blood were microtubule-associated protein isoforms 5 and 7, neuromodulin 2, synapsin 1, beta-tubulin 3 and MBP. Finally, it should be noted that much attention is being paid to the big hits and concussions suffered by athletes, but there should be concern as well for sub-concussive hits that also appear to cause damage. These findings support the proposition that measurement of antibodies against S100-B and these other neural autoantigens is important for the diagnosis and therapy management of patients with TBI. The detection of these brain-reactive antibodies is part of the Neurological Autoimmune Reactivity Screen that is being offered by Cyrex Labs in Phoenix, AZ as its Array 7.
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REFERENCES
[1] Diamond B, Honig G, Mader S, Brimberg L, Volpe BT. Brain-reactive antibodies and diseases. Annu. Rev Immunol. 2013;31:345-385. [2] Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57:178-201. [3] Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT. Losing your nerves? Maybe it’s the antibodies. Nat. Rev. Immunol 2009;9:449-456. [4] Hanin I. The Gulf war, stress, and a leaky blood-brain barrier. Nat. Med. 1996;2(12):1307-1308. [5] Friedman A, Kaufer D, Shemer J, Hendler I, Soreq H, Tur-Kaspa I. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat. Med. 1996;2:1382-1385. [6] Xaio H, Banks WA, Niehoff ML, Morley JE. Effect of LPS on the permeability of the blood- brain barrier to insulin. Brain Res. 2001;896:36-42. [7] Hazleton JE, Berman JW, Eugenin EA. Novel mechanism of central nervous system damage in HIV infection. HIV/AIDS Res Palliat Care. 2010;2:39-49. [8] Zheng W, Aschner M, Ghersi-Egea JF. Brain barrier systems: a new frontier in metal neurotoxicological research. Tox. App. Pharmacol. 2003;192:1-11. [9] Seelbach M. Polychlorinated bishpenyls disrupt blood-brain barrier integrity and promote brain metastases formation. Env. Health Persp. 2010;118:479-484. [10] Dietrich JB. Alteration of blood-brain barrier function by methamphetamine and cocaine. Cell Tissue Res. 2009;336:385-392. [11] Marchi N, Bazarian JJ, Puvenna V, Janigro M, Ghosh C, Zhong J, Zhu t, Blackam E, Stewart D, Ellis J, Butler R, Janigro D. Consequences of repeated blood-brain barrier disruption in football players. PLoS One. 2013;8(3):e56805. [12] Maroon JC, Lepere DB, Blaylock RL, Bost JW. Postconcussion syndrome: a review of pathophysiology and potential nonpharmacological approaches to treatment. Phys. Sportsmed. 2012;40:73-87. [13] Calderon-Garciduenas L, Franco0Lira M, Mora-Tiscareño A, Medina-Cortina H, Torres-Jardon R, Kavanaugh M. Early Alzheimer’s and Parkinson’s disease pathology in urban children: friends vs foes responses – it is time to face the evidence. BioMed Res Int. 2013;Article ID 161687. [14] Vojdani A, O’Bryan T, Kellermann GH. The immunology of gluten sensitivity beyond the intestinal tract. Eur. J. Inflamm. 2008;6(2):49-57. [15] Vojdani A, Campbell A, Anyanwu E, Kashanian A, Bock K, Vojdani E. Antibodies to neuron- specific antigens in children with autism: possible cross-reaction with encephalitogenic proteins from milk, Chlamydia pneumoniae and Streptococcus Group A. J. Neuroimmunol. 2002;129:168- 177. [16] Pellman EJ, Lovell MR, Viano DC, Casson IR, Tucker AM. Concussion in professional football: neuropsychological testing – part 6. Neurosurgery. 2004;55:290–1303. [17] Pellman EJ, Viano DC, Casson IR, Tucker AM, Waeckerle JF, Powell JW, Feuer H. Concussion in professional football: neuropsychological testing – part 4. Neurosurgery. 200455:290–1303. [18] Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnár Z, O'Donnell ME, Povlishock JT, Saunders NR, Sharp F, Stanimirovic D, Watts RJ, Drewes LR. Engaging neuroscience to advance translational research in brain barrier biology. Nat. Rev. Neurosci. 2011;12:169–182.
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[19] Maroon JC, Field M, Lovell M, Colins M, Bost J. The evaluation of athletes with cerebral concussion. Clin. Neurosurg. 2002;49:319-332. [20] Hoge CW, Goldberg HM, Castro CA. Care of war veterans with mild traumatic brain injury. N. Engl. J. Med. 2009;360(16):1588-1591. [21] Arundine M, Tymianski M. Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury. Cell Mol Life Sci. 2004;61:657-668. [22] Blaylock RL, Maroon JC. Immunoexcitotoxicity as a central mechanism in chronic traumatic encephalopathy – a unifying hypothesis. Surg. Neurol. Int. 2011:2:107. doi: 10.4103/2152- 7806.83391. [23] Zongo D, Ribéreau-Gayon R, Masson F, Laborey M, Contrand B, Salmi LR, Montaudon D, Beaudeux JL, Meurin A, Dousset V, Loiseau H, Lagarde E. S100-B as a screening tool for the early assessment of minor head injury. Ann. Emerg Med. 2012;59:209-218. [24] Vincent A, Bien CG, Irani SR, Waters P. Autoantibodies associated with diseases of the CNS: new developments and future challenges. Lancet Neurol. 2011;10:759–772. [25] Raabe A, Grohms C, Sorge O, Zimmerman M, Seifert V. S-100B protein in severe head in jury. Neurosurgery. 1999;45(3):477-483. [26] Poletaev AB, Morozov SG, Gnedenko BB, Zlunikin VM, Korzhenevskey DA. Serum anti- S100b, anti-GFAP and anti-NGF autoantibodies of IgG class in healthy persons and patients with mental and neurological disorders. Autoimmun. 2000;32:33–38. [27] Biberthaler P, Linsenmeier U, Pfeiffer KJ, Kroetz M, Mussack T, Kanz KG, Hoecherl EF, Jonas F, Marzi I, Leucht P, Jochum M, Mutschler W. Serum S-100B concentration provides additional information for the indication of computed tomography in patients after minor head injury: a prospective multicenter study. Lancet. 1995;346: 221-223. [28] Maetzler W, Berg D, Synofzik M, Brockmann K, Godau J, Melms A, Gasser T, Hörnig S, Langkamp M. Autoantibodies against amyloid and glial-derived antigens are increased in serum and cerebrospinal fluid of Lewy body-associated dementias. J. Alzheimers Dis. 2011;26:171– 179. [29] Gruden MA, Davidova TB, Malisauskas M, Sewell RD, Voskresenskaya NI, Wilhelm K, Elistratova EI, Sherstnev VV, Morozova-Roche LA. Differential neuroimmune markers to the onset of Alzheimer’s disease neurodegeneration and dementia: autoantibodies to Abeta((25– 35)) oligomers, S100b and neurotransmitters. J. Neuroimmunol. 2007;186:181-192. [30] Storace D, Cammarata S, Borghi R, Sanguineti R, Giliberto L, Piccini A, Pollero V, Novello C, Caltagirone C, Smith MA, Bossù P, Perry G, Odetti P, Tabaton M. Elevation of {beta}-amyloid 1-42 autoantibodies in the blood of amnestic patients with mild cognitive impairment. Arch. Neurol. 2010;67:867–872. [31] Lehman EJ, Hein MJ, Baron SL, Gersic CM. Neurodegenerative causes of death among retired National Football League players. Neurol. 2010;79:1970-1974. [32] Vincent A, Lang B, Kleopa KA. Autoimmune channelopathies and related neurological disorders. Neuron. 2006;52:123-138. [33] Janigro D. Are you in or out? Leukocyte, ion, and neurotransmitter permeability across the epileptic blood-brain barrier. Epilepsia. 2012;53(Suppl 1):26-34, 2012. [34] Ocwieja KE, Mihalik JP, Marshall SW, Schmidt JD, Trulock SC, Guskiewicz KM. The effect of play type and collision closing distance on head impact biomechanics. Ann. Biomed. Eng. 2012;40:90-96.
Received: June 12 2013 Revised: June 18 2013 Accepted: June 28 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):183-202 ISSN: 2156-941X © 2013 Nova Science Publishers, Inc.
THE ROLE OF ENVIRONMENTAL TRIGGERS IN NEUROAUTOIMMUNITY
Aristo Vojdani1 and Jama Lambert2 1Immunosciences Lab, Inc., Los Angeles, CA USA 2Cyrex Laboratories, LLC., Phoenix, AZ USA
ABSTRACT
Lipophilic chemicals have been identified as playing a role in neurological dysfunctions. Researchers are working to define the mechanisms by which environmental chemicals disrupt normal body immune and neuronal functions. Chemical exposures can occur in both the occupational and home environments, and can be acute (high-level) or chronic (low-level). Any of these scenarios can result in neuroautoimmunity. In this article we review seven incidents of environmental chemical exposure and discuss their effects on the human immune and nervous systems.
Keywords: Lipophillic, immunity, neuroimmune, environmental toxin
INTRODUCTION
Researchers, public health officials and the medical community are continuously defining environmental risk factors that can lead to neuroautoimmunity. The list grows each year. Currently, we know that infectious agents, chemicals, hormones and genetics each play a role in the pathogenesis of some neuroautoimmunities. Our focus is on specific environmental chemicals and their effect on the human immune and nervous systems. Contemporary industrialized environments are becoming overly toxic to many of Earth’s habitants. Paradoxically, the human immune system has not had time enough to evolve into a mechanism of absolute protection against this multitude of human-made and organic chemicals seeping into all parts of the world. Under normal working conditions, the human immune system is able to identify friend from foe, or self from invader, and respond appropriately to the exposure. However, the taxing of our immune systems by a daily multitude of environmental toxins has, for many individuals, affected the immune system’s ability to recognize the good versus the bad. Toxic chemicals, both acute and chronic, low-level and high-level, can affect the human body. The interaction of the immune system with a single chemical or combination of toxins may result in three principal, undesirable effects:
Correspondence: Dr. Aristo Vojdani, Immunosciences Lab., Inc., 822 S. Robertson Blvd., Ste. 312, Los Angeles, CA 90035, E-mail: [email protected].
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1. immediate or delayed hypersensitivity responses, 2. immune suppression, and/or 3. immune activation leading to neuroautoimmunity.
Rising rates of autoimmunity and possible outcomes of toxic exposure lead to the problem of finding reliable health risk assessments. Discovery of reliable biomarkers could assist affected individuals in the prevention of cancer or autoimmunity by identifying which carcinogens or chemicals to avoid. Exposures to chemicals may also elicit immune cascades that can lead to neuroinflammation and neuroautoimmune reactivity (see Figure 1).
Figure 1. Potential molecular mechanisms in chemical-induced autoimmune reactivity.
Some xenobiotics are labeled “neurotoxic” due to the pathogenic role they play in the neuroautoimmune process. Chemical infiltration of the body can occur by contact through the skin, inhalation via the lungs, and ingestion breaching the gastrointestinal tract. Once through the barrier, the chemical will elicit a systemic reaction leading to the production of antibodies. Circulating antibodies can ignite the autoimmune process. For a detailed mapping of xenobiotic-induced autoimmunity, see “Allergic and autoimmune reactions to xenobiotics: how do they arise?” by Peter Griem1 and colleagues. Below is an abbreviated version of how the body produces autoantibodies following xenobiotic exposure.
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During humoral immune responses of the adaptive immune system (see Figure 2), an invading antigen is recognized by an antigen presenting cell (APC). The APC picks up and transports the antigen to a T cell, which introduces the antigen to a B cell in the lymph node. Clonal expansion of the B cell follows and triggers antibody production. Immunoglobulin M (IgM) is produced as a primary response in the first days of defense. If previous exposures have occurred, a secondary immune response results in immunoglobulin G (IgG) production. High levels of these antibodies indicate an immune reaction to an antigen that threatens the homeostasis of the body and may result in autoimmune reactivity. The adaptive immune system consists of lymphocytes that recognize a wide range of foreign antigens from dietary peptides to xenobiotics without reacting to self- antigens. However, in cases of autoimmunity, some autoreactive lymphocytes, those that react to self-antigens, escape clonal deletion in the thymus (T lymphocytes) or bone marrow (B lymphocytes), lie dormant, and later become activated. Once activated, these autoreactive lymphocytes may initiate autoimmune diseases such as multiple sclerosis (MS), systemic lupus erythematosus (SLE), or Parkinson’s disease. In most cases, scientists can only speculate about the triggering mechanism by which autoreactive lymphocytes become activated; in some scenarios viruses, chemicals or physical/emotional trauma is thought to be the cause. In the case of mercury exposure, the chemical will bind to nucleoproteins such as fibrillarin and chromatin resulting in aberrant migration of the autoantigen [1-3]. Under stressful stimuli, auto- antigens yield intracellular relocalization [2]. For example, the auto-antigen fibrillarin is a substrate of granzyme B, a protease, and undergoes alteration by mercury via oxidative fragmentation [2]. Thus modified during apoptosis, chromatin and fibrillarin may circulate, either in native form, or packaged in apoptotic bodies in the serum of patients with systemic autoimmune disorders [2, 4, 5]. Apoptosis is programmed cell death. It plays a significant role in the deletion of autoreactive lymphocytes, the removal of virally infected cells and the elimination of cancerous cells [6]
Figure 2. Putative mechanisms for mercury-induced autoimmunity. Modified from Schiraldi M, Monestier M. Trends in immunology. 2009;30:502-509.
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In most tissues, apoptosis, including clearance of cell corpses by neighboring parenchymal cells, transpires quickly, usually in less than one hour. However, in the absence of the first component of complement, the clearance of apoptotic corpses is delayed. Delayed clearance increases immunogenicity, which may result in antibody production. Based on this mechanism of induction of cell death by mercury, researchers have shown that the release of auto-antigens bound to mercury may be important in the genesis of autoimmune disorders, most notably, scleroderma [6]. Antibody test results of environmental chemicals can be useful tools in assessing a person’s health risk whether the exposure was short-lived but in high doses, or was presented in low doses over a long period of time.
Detection of antibodies against metals in blood indicates metal bound to human tissue, formation of neo-antigens and immunological intolerance of self after exposure to metals [2, 3, 6, 7]. Detection of anti-nucleolar autoantibodies and/or heavy metal binding proteins fibrillarin and chromatin, along with antibodies to metals, indicates autoimmune reaction induced by heavy metals [4, 5]. Detection of antibodies against metals, as well as different brain antigens (neurofilament, tubulin) and receptors, will measure the neurotoxic effect and neuroautoimmune reactivity of metals [1-3, 6, 8].
Specific antibody testing thus provides reliable health risk evaluations that can be used in conjunction with additional laboratory analysis and other pertinent clinical data to identify potential autoimmune or neuroimmune disorders. In an ever-growing chemically-laden world, it is vital for the medical community to provide the most useful, cost-effective analysis of health risk involved in such exposures. Although the presence of circulating autoantibodies does not always indicate immediate or future pathological consequences, they are often associated with disease processes [9]. The measurement of specific autoantibodies in serum assists health care professionals in determining an individual’s immune function, neuronal function and potentiality for progressive dysfunction resulting in a neuroautoimmune disorder. In the following pages we will review seven scenarios of chemical exposures that have been shown to affect the human nervous system. These include Silicone Implants, the Cantara Metam Sodium Spill, Gasoline Chemicals Exposure, the Effect of Industrial Solvents, Mold and Mycotoxin Exposure, Gulf War Syndrome and heavy air pollution. These examples illustrate the various types of exposures from purposefully-injected to accidental, from acute to chronic low-dose and the combination of xenobiotics that can elicit neurologic complaints from mild to severe.
SILICONE IMPLANTS
Silicone implants are not just for female breast augmentation; they are also common in calf enhancements and other muscle cosmetic treatments for body builders [10, 11], as well as in rhinoplasty [12]. Silicone implants have been shown to contribute to the autoimmune process [13, 14] and to suppress the immune system [15]. In a study on 40 women with silicone breast implants and 40 age-matched controls without implants [13], it was demonstrated that the silicone implant patients had much higher levels of rheumatoid factor, immune complexes, anti-nuclear antibodies, thyroid antibodies and myelin basic protein (MBP) antibodies. Furthermore, there was correlation between silicone implant patients with significantly elevated anti-MBP IgM antibodies and degree of symptomatology (see Table 1). The marked increase in anti-MBP antibodies in patients with implants indicates that body burden due to
Environmental Triggers of Neuroautoimmunity 187 silicone exposure contributes to autoimmunity that may involve the central and peripheral nervous systems. As described by Vojdani et al. [14], silicone exposure can occur as the implant oozes or bleeds silicone particles into circulation; these particles are absorbed or bound to macromolecules surrounding the silicone bag; combined tissue antigen with silicone spheres is presented to macrophages via T helper cells to B cells interaction; antibodies are produced against silicone and human tissues.
Table 1. Clinical complaints: 40 silicone breast implant patients versus 40 controls
CLINICAL COMPLAINTS REPORTED PATIENTS CONTROLS Fatigue 90% 4% Fibromyalgia 81.8% 5% Attention Deficit 75% 3%
Three years after results of the above study were published a larger group of women with silicone breast implants were tested for 20 autoantibodies against age-matched controls. Bar-Meir and colleagues assessed 116 female patients, whose chief complaints included polyarthralgias, fatigue, myalgias, morning stiffness, and decreased memory, and 134 controls [15]. The results showed a statistically significant greater frequency of autoantibodies in women with implants for 15 of the 20 autoantigens; the most striking were anti-histones, ribosomal phosphate, SS-A, SS-B, Scl-70, cardiolipin, phosphatidylserine, gangliosides, and glomerular basement membrane [15]. Many patients produced multiple autoantibodies; 20% had four autoantibodies, 8% had six autoantibodies [15]. The presence of these autoantibodies in patients with silicone implants may possibly indicate future development of an autoimmune disease [15]. At the time of publication 10 out of 116 silicone implant patients had a diagnosed autoimmune disease [15]; given more time, the number may have been higher. The propensity toward autoimmunity in silicone breast implant patients is not the only medical concern. Immune suppression has also been shown. Specifically, natural killer cell activity is lowered in patients with implants [16]. When silicone breast implants were removed, 50% of the study patients had significant improvement in natural killer cell activity [16]. Researchers have not identified the mechanisms involved in natural killer cell activity suppression due to silicone implants and are speculating whether the effect is direct or indirect. The end result of immune suppression leaves the patient vulnerable to infectious agents. Epstein-Barr virus (EBV) has been implicated in MS [17,18]; Chlamydia pneumoniae infection of the central nervous system is suspected in encephalitis [19,20], and group A streptococcus is seen in PANDAS, ANDAS, neuropsychiatric disorders and Sydenham’s chorea [21,22]. In either case, whether autoimmunity targeting myelin sheaths or immune suppression, the clinical manifestation of toxic body burden to silicone implants may result in neurological disorder.
THE CANTARA METAM SODIUM SPILL
Early December 1984 the world watched the horror of the Union Carbide pesticide plant disaster. In the wee hours of a single night 27 tons of methyl isocyanate leaked into the air over the 900,000 sleeping residents of Bhopal, India. This travesty caused thousands of premature deaths in the 20-year aftermath. On the other side of the world, July 14, 1991 at 9:50 pm, a Southern Pacific 97-car train derailed on the Cantara loop above the Upper Sacramento River. An estimated 19,000 gallons of metam sodium spilled into the river. By early morning, while volunteer firefighters went house to house in nearby Dunsmuir, California, and the California Highway Patrol closed a 50 mile stretch of
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Interstate 5, many residents had already become ill with symptoms including headaches, shortness of breath, chest pains, rashes, dizziness and vomiting, and were filling local medical offices and emergency rooms [23]. Metam sodium [C2H4NNaS2] is the active ingredient in many pesticide products. Agriculturally it is used as a soil fumigant to kill weeds, soil diseases and insects. Metam sodium was not designated by the EPA as “hazardous” while the US Coast Guard considered it “extremely hazardous” because it becomes poisonous when mixed with water [23]. The breakdown products of metam sodium include methyl isothiocyanate, hydrogen sulfide, carbon disulfide and methylamine. In the Cantara Spill, the train car fell from the bridge, landed on a rock below the water line and seeped metam sodium into the river. A toxic methyl isothiocyante plume 18 feet thick, 100 yards wide and ¾ of a mile long eventually made its way into Lake Shasta [23-25]. The environmental toll on the 100-mile stretch of river was staggering. Over a million fish perished, hundreds of thousands of willows, alders and cottonwoods along the river died, wildlife either starved or left the area [26], more than 700 people, including emergency responders and Dunsmuir residents, sought medical help (7 were hospitalized) [25], many reported lingering effects even 9 months after the incident [25,27], and in total 1500 personal injury claims were made [24]. Many of these patients exhibited neurological abnormalities and some developed peripheral neuropathy [unpublished data]. Abbott points out that environmental accidents, like the Cantara Spill, not only pose injury to humans from toxic insults, but disaster- associated morbidity includes emotional stress and other psychological effects on the community and emergency responders and thus plays a potential role for increased risk of communicable disease [24]. Although less toxic than the methyl isocyante gas released in Bhopal, metam sodium and its breakdown product, methyl isothiocyanate (MITC) [CH3N=C=S], are known to cause dizziness and headaches [28]. Furthermore, in vitro experiments showed that MITC is inactivated by body fluids (saliva, gastric juice), and the low-concentration-DNA-damaging properties of MITC are attenuated by non-enzymatic protein binding [29]. In laboratory experiments, exposure of human hepatoma cells to MITC led to formation of thiobarbituric acid reactive substances; therefore, it is likely that its DNA-damaging effects involve lipid peroxidation processes [29]. Industrial disasters, accidents or incidents expose humans not only to toxic chemicals but also to great physical and emotional stress. Individually, or in combination, these events can trigger neurological discomforts.
CHEMICALS IN GASOLINE AND SOLVENTS
Classified as a hydrocarbon, benzene [C6H6] is an organic chemical compound composed of six carbon atoms arranged in a hexagonal ring. Benzene is naturally found in crude oil and because it has a high octane number, it is utilized in gasoline. Benzene is also used as a precursor to chemicals (ethylbenzene, cumene). Benzene has been an important solvent especially in the rubber and surface coating industries. Methyl tert-butyl ether (MTBE), is an organic compound [(CH3)3COCH3]. MTBE is a gasoline additive, used as an oxygenate to raise the octane number of gasoline and prevent engine knocking. Benzene ring containing materials such as phenol, toluene and MTBE can bind to human tissue proteins and form neo-antigens. These new antigen proteins are comprised of the haptenic chemical plus the tissue antigen. The formation of neo-antigens initiates immune responses which may result in antibody production against the chemical bound to human tissue. Continued exposure to the chemical and the subsequent continual production of antibodies against various tissue antigens may result in autoimmune reactivity. Acute inhalation exposure to high concentrations of chemicals in gasoline and solvents can cause drowsiness, fatigue, nausea, vertigo, narcosis, and other symptoms of central nervous system depression; however, the most damaging health outcomes associated with benzene exposure are the chronic effects due to repeated exposure of low concentrations over a period of many years [29].
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Due to their ability to dissolve in fats, most organic solvents, like benzene ring compounds, tend to accumulate in lipid-rich organs, such as nerve tissues of both the peripheral and the central nervous systems [30]. Benzene is also known to cross the placenta and has been found in cord blood at levels equal to or higher than maternal blood [31]. Indeed, an association between maternal airborne benzene exposure and birth defects has been noted [32]. With the oil industry centered in the state, it is no surprise that Texas ranks number one in the United States for benzene levels in ambient air and accounts for 48% of all benzene emissions in the nation [33]. In a study conducted in the oil state of Texas [33], it was shown that the risk of delivering a spina bifida-affected infant more than doubled for mothers living in census tracts with estimated benzene levels of ≥ 3 μg/m3. Benzene can lead to genetic toxicity by covalently binding to DNA and forming DNA adducts, which, if not repaired quickly, disrupts the microenvironment of the cell, leading to inhibition of important enzymes, cell death, and alteration of other cells. [31]. When this occurs during the critical window of fetal development, the complex cellular processes involved in neurulation (e.g., folate metabolism, cell proliferation, cellular adhesion, and vascular development) may be disturbed [33]. The final result could be a baby born with neural tube defects. Studies with adult populations exposed to occupational benzene ring compounds [30,34] support the finding that changes in the visual function can serve as an early marker of neurotoxic damage, especially that resulting from chronic low-level industrial exposure. Comparing the MTBE blood levels of gas station workers to car repair shop employees and commuters, there was a significant difference, 8 – 30 microgram/L, 0.1-32 microgram/L and 0.07 – 2.3 microgram/L respectively, between industry workers and commuters [29]. Gas station workers were more apt to complain of ailments than the other two groups [29]. Exposures to MTBE may result in eye irritation, burning of nose and throat, headaches, memory effects or skin rashes [35]. These chemicals may also contaminate drinking water and cause symptomatology described in persons exposed to benzene and MTBE via inhalation [35]. Utilizing the World Health Organization’s Neurobehavioral Core Test Battery (NCTB) researchers concluded that diesel pollutant-exposed workers in the locomotive industry had reduced neurobehavioral performance scores in hand-eye coordination, cognitive function, speed stimulation of motor nerve, visual assessments and memory skills [34]. Locomotive workers are exposed to not only benzene, but also toluene, n-hexane and cyclohexane.
INDUSTRIAL SOLVENTS
A solvent is any liquid that can dissolve a substance. The name organic solvent is used for a large group of these chemicals that come from petroleum-based products. They are often used as degreasing agents and paint thinners. They are also used to manufacture a wide range of other products, such as adhesives, fuels, pharmaceuticals and cosmetics. Organic solvents came into the environment out of the Industrial Revolution in the latter half of the 19th Century from the coal-tar industry [36]. Solvents can be classified as chlorinated, petroleum, benzene or non-benzene aromatic. Studies on solvent exposures have shown solvents can affect central nervous system functioning in attention, processing speed and motor performance [37]. These chemicals are used in a number of common areas (see Table 2). The human effects of these solvents are varied. For example, trichloroethylene exposure can result in lymphoproliferative reaction, anti-nuclear and cardiolipin antibodies, protein modification, formation of adducts, stimulation of active TH17, production of ROS and NO, activation of T cells, cellular infiltration, increase in CD4+ and CD8+ T cells and inhibition of cellular apoptosis of naïve CD4+ and CD8+ T cells [reviewed in 36]. In a study conducted on 289 subjects exposed to chemicals in computer manufacturing plants, immunological abnormalities and markers of neural autoimmunity were found [38].
190 Aristo Vojdani and Jama Lambert
Table 2. Short list of common uses for organic solvents
USE CHEMICAL Dry Cleaning Tetrachloroethylene Paint Thinner Toluene, Turpentine Nail Polish Removers and Glue Solvents Acetone, Methyl Acetate, Ethyl Acetate Spot Removers Hexane, Petrol Ether Detergents Citrus Turpenes Perfumes Ethanol Octane Booster Methyl tert-butyl ether Lighter Fluid Butane Air Conditioning Coolant Chlorofluorocarbon
The patients in the study had been exposed to phthalic anhydride, formaldehyde, isocyanate trimellitic anhydride and aliphatic and aromatic hydrocarbons for ten years or more. Significant levels of IgM followed by IgG and IgA antibodies against MBP were detected in the exposed subjects [38]. Individuals with abnormal T4/T8 ratios exhibited simultaneous elevation of IgM and IgG rheumatoid factor and immune complexes [38]. This cocktail of chemicals contributed to a range of dysfunctions in the exposed subjects including [38]:
Decreased cell-mediated immunity Abnormal lymphokine and cytokine production Natural killer cell function decline Mitogen-induced lymphocyte blastogenesis Impaired suppressor or helper cell generation Changes in helper/cytotoxic cell ratios
Increase in antigen reactive TA1 positive cells Elevation in autoimmune biomarkers o Rheumatoid factor o Anti-nuclear antibodies o Immune complexes o Myelin basic protein antibodies
The authors concluded that the majority of exposed subjects demonstrated elevated MBP antibodies, an indication of demyelination, which should lead neurologists to look for autoimmune reactivity in their patients with a history of toxic exposures [38]. The excellent organic solvent review by Barragán-Martínez and colleagues includes a number of studies conducted on the prevalence of MS in a variety of work environments where organic solvents are used. These publications showed a rise in MS for nurse anesthetists; leather and shoe industry workers; auto repair workers; mechanical, oil textile, wood-working, paint, printing, plastic and rubber industries; and painters [36]. Organic solvents that have been shown to specifically affect the cerebellum are toluene, benzene and carbon disulfide [39]. Cerebellar disorders can manifest as depression, developmental delay, cerebellar cognitive affective syndrome, impaired multitasking ability, limited cognitive flexibility and other psychological distress [39]. Those studying the neurological effects of solvent exposures state:
o Sustained motor or attention difficulties and intellectual impairment have been seen among French gas utility workers [37].
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o The immune system and the immune defense mechanisms may be affected as a result of prolonged occupational chemical exposure, which mediates some of the symptomatology associated with such exposures [38]. o Individuals with family history of autoimmunity, or carrying genetic factors, should avoid exposure to organic solvents in order to deter increasing their risk for autoimmune diseases [36].
Due to the varying immunologic effects of organic solvents that may lead to neuroinflammatory responses and neuroautoimmunity, susceptible individuals should endeavor to avoid exposures to solvents both in the work place and home environments.
MOLDS AND MYCOTOXINS
Molds are multicellular fungi that are ubiquitous in outdoor and indoor environments. Mycotoxins are the metabolites produced by molds (see Table 3). Exposure to molds and mycotoxins can occur through inhalation, ingestion, and touching moldy surfaces. Adverse health effects may occur through allergic, infectious, irritant, or toxic processes.
Table 3. Mycotoxins and their source molds
MYCOTOXIN PRODUCED BY Aflatoxin Aspergillus flavus Alternariol Alternaria Aspergillus Aspergillus fumigatus Chaetoglobosins Chaetomium Cladosporin Cladosporium herbarum Cladosporium HSP-70 Cladosporium herbarum Mycophenolic acid Penicillium Ochratoxin Penicillium Penicillium major antigen Penicillium Stachyhemolysin Stachybotrys Stachytoxins Stachybotrys T-2 Toxin Fusarium Trichothecenes (satratoxin, verrucarin, roridin) Stachybotrys Versitoxins Aspergillus versicolor Vomitoxin Fusarium
Dietary Sources of Mycotoxins
Aflatoxin B1 is the most potent natural carcinogen known and is usually the major aflatoxin produced by toxigenic strains. It is a well-studied mycotoxin found on grains and nuts, thus it is often consumed. However, in other cases it can be inhaled. The Curse of the Mummy stories have entertained us in literature, films and folklore for generations. Although an engaging thought, Egyptian pharaoh Tutankhamen, the Boy King, did not reach from the great beyond to strike down the
192 Aristo Vojdani and Jama Lambert men who audaciously entered his tomb. Instead, the mysterious and painful deaths of the archeologists, including Americans Arthur Mace and George Jay Gould, who died within 24 hours of opening the famous tomb, and British adventurer and financier Lord Carnarvon, who passed weeks later, were more likely caused by aflatoxicosis [40]. Tutankhamen and many other royals on a number of continents were entombed with baskets of rice. Aspergillus flavus grows on rice. This mold and its mycotoxin, aflatoxin, can thrive in a tomb environment [41]. When Carnarvon entered King Tut’s tomb, he crawled on his hands and knees, close to the wall, where he overturned containers. By disturbing the contents of the containers, now suspected of holding rice, Carnarvon inhaled copious amounts of aflatoxins. Carnarvon died after suffering from a high fever, severe pain, pneumonia in both lungs, and eventually heart and respiratory failure; exposure to mycotoxins can cause a form of pneumonia to which immune-compromised individuals, like Carnarvon had been, are susceptible [40]. Aflatoxin exposure can occur via airborne spores entering through the lung barrier, ingested food products entering through the intestinal barrier, or contacted spores entering through the skin barrier. The symptoms of aflatoxicosis depend on the amount and duration of the exposure; the age, health, and sex of the exposed individual; and many poorly understood synergistic effects involving genetics, dietary status, and interactions with other toxic insults [40,41]. Thus, the severity of aflatoxin harmfulness can be compounded by factors such as vitamin deficiency, caloric deprivation, alcohol abuse, and infectious disease status [42]. Aflatoxosis can suppress immune function, including lowering secretory IgA (SIgA) levels [44]. Due to the vital role SIgA plays in host defense, insufficient SIgA levels may cause a heightened vulnerability to microbial diseases, worsen the effects of malnutrition, and interact synergistically with other toxins [42,44]. Animal studies show that aflatoxin interferes with vitamins A and D, iron, selenium, and zinc nutrition [43]. In a review of animal studies [45], authors have mapped the effects aflatoxin exposure cause on:
Respiratory System Gastrointestinal System Immune System Nervous System Renal System Reproductive System
Birth defects have also been reported. Tortillas made with contaminated corn may have caused a rash of newborns with missing or rudimentary brains in the Rio Grande Valley in the 1990s. Tortillas are an inexpensive dietary staple along the Texas-Mexico border. One study [46] found that pregnant women who ate 300 to 400 tortillas per month during the first trimester had twice the risk of giving birth to babies with the defects as women who ate less than 100 tortillas. Blood samples taken from these women indicated that the higher the level of the mycotoxin, fumonisin, the greater the risk of neural tube defects [46]. Clearly, the risks of eating molding grains may have devastating consequences. Authors in Pakistan suggest storing and preparing rice commodities with garlic and/or lemon grass extracts due to their ability to inhibit Aspergillus flavus and its aflatoxin production [43].
Water-Damaged Building Source of Mycotoxins
Mold and mycotoxin growth is rampant in water-damaged buildings. A family left their North American home to rent a house in Hawaii. What sounds like a dream come true turned into a nightmare. The family described by Thrasher and colleagues [47] consisted of mom, dad, daughter, son, in utero daughter and pet dog. Ochratoxin A was the predominant mycotoxin in samples of urine,
Environmental Triggers of Neuroautoimmunity 193 nasal secretions, breast milk, placenta and umbilical cord [47]. Among the family members symptoms ranged from mild wheezing to long-term memory loss, and a series of neurological evaluations including Profile of Mood States, Beck’s depression inventory and Limbic System Check List Score revealed mom and dad each had 17 neurological deficits, the daughter had noticeable tremors and when the son began school, his teacher reported that he lacked concentration while in class [47]. Additional studies have shown neurological effects on humans after exposure to molds and mycotoxins in water-damaged buildings [48-51]. Patients with documented mold exposures along with elevated antibodies to molds and mycotoxins exhibited symptoms of peripheral neuropathy (tingling, numbness, tremors and muscle weakness in extremities) [48]. These 119 patients were evaluated for 9 neuronal autoantibodies (MBP, myelin associated glycoprotein, asialoganglioside GM1, sulfatide, myelin oligodendrocyte glycoprotein, crystalline, glutamate, tubulin, chondroitin sulfate and neurofilament antigen) and all patients had significant elevations in neuronal autoantibodies [48]. Additionally 99 of the patients had abnormalities in latencies, amplitudes, and velocities of selected peripheral nerves, and peripheral neuropathy [48]. A comparison study [49] to evaluate the neurobehavioral and pulmonary impairment of 105 adults exposed to molds (Stacybotrus chartarum, Aspergillus, Penicillium, Chaetomium, Alterenaria, Fusarium, Rhizopus) and 100 patients exposed to other chemicals (hydrogen sulfide, diesel exhaust, formaldehyde, indoor air, organophosphate insecticides, glutaraldehyde, cleaning chemicals, polycholorinated biphenyls, carbon monoxide, chlorine, chrordane) were compared to 202 community referents without mold or chemical exposures. Neurophysiological tests, Simple Reaction Time and Choice Reaction Time were performed on the participants. The mold-exposed group had a total of 6.1 abnormalities and those exposed to chemicals had 7.1 compared to 1.2 abnormalities in referents [49]. The exposed groups showed decreased balance, longer reaction times, lengthened blink reflex latencies, increased color discrimination errors, and reduced visual field performances and grip strengths [49]. Compared to referents, the exposed groups had decreased verbal recall, impaired perceptual motor functions for peg placement and trail making, and reduced problem solving in digit Symbol Substitution and Culture Fair [49]. Due to the irreversible impact water-damaged buildings can have on neurological and respiratory human health, susceptible individuals must avoid these areas completely [49]. After mold exposure susceptible patients will show signs and symptoms of central and peripheral nervous system effects [51]. Measuring antibodies to the molds and mycotoxins alone may not complete the clinical picture. The presentation of clinical manifestations did not always correlate with the levels of mold or mycotoxin antibodies in all patients [50]. The presence of antibodies therefore may be an indication of exposure, when antibody levels do not correlate with disorder severity. Treatment of patients with mold/mycotoxin exposure must not only address the clinical condition of the patient, but also must include in-tandem bio-balancing of the home and work environments for mold [51].
GULF WAR SYNDROME
War ravages every living being on the planet. Although relatively short-lived, as wars go, the Gulf War (August 2, 1990 – February 28, 1991) and its codename Operation Desert Storm (January 17, 1991 – February 28, 1991) had a lasting physical effect on deployed men and women compared to non-deployed military personnel. The name for the effect has been known as “Gulf War Syndrome” (GWS), “Chronic Multi-Symptom Illness” (CMI), “Gulf War Illness” and “Multi-Symptom condition” [52]. Symptoms of GWS include: muscle fatigue, tiredness, malaise, myalgia, impaired cognition, ataxia, diarrhea, bladder dysfunction, sweating disturbances, headaches, fever, arthralgia, skin rashes, gastrointestinal disturbances sleep disturbances, chemical sensitivity and odor intolerance [52]. The
194 Aristo Vojdani and Jama Lambert symptoms are very similar to those of patients chronically ill with immunologic alterations after exposure to chlorinated pesticides, silicone implants and solvents [53]. Officially, the Research Advisory Committee on Gulf War Veterans’ Illnesses ruled out wartime stress or psychiatric illness as the cause of GWS; instead suspected factors for GWS are combinations of the low-level exposure to sarin, pesticides, benzene, other solvents, pyridostigmine bromide [53,54], Arabian sand dust, depleted uranium shells, combustion by-products of oil well fires, diesel exhaust and infectious agents [53]. Research has pointed to subtle damage to the parasympathetic nervous system as an underlying mechanism in the GWS pathogenesis [54]. In Gulf War veterans (GWV) with unexplained symptoms (not attributed to medical diagnosis) 87% had cognitive symptoms, 38% experienced musculoskeletal symptoms and 42% were fatigued [55]. The 1.92 risk of developing amyotrophic lateral sclerosis (ALS) was significantly increased in deployed versus non-deployed veterans with a mortality risk of 1.53 for deployed GWV [55]. An increased rate of ALS, increased incidences of neurological diseases and abnormalities of basal ganglia and brainstem are found in GWVs [53] and have been explained by genetic polymorphism of paraoxonase [56,57], butyrylcholinesterase [58], esterase [59], glutathione
S-transferase and cytochrome P4501A1 [60]. Furthermore the risk of ALS was significantly higher in GWVs in the Air Force or Army [55]. Of the 700,000 deployed US GWVs about 25% developed GWS [61]. Chronic low-level exposure to organophosphates is the major suspect. Organophosphates are the basis for insecticides and nerve gases, both of which were used during the Gulf War. Insecticides were applied to the skin, clothing, tents, sleeping quarters and sprayed in the camps [61]. This can explain the increased risk for ALS in deployed Air Force and Army GWVs. GWS has been reported more in those with the highest exposures to organophosphates [61]. The insecticide chlorpyrifos (CP) was used extensively in camps. The metabolite of CP is chlorpyrifos oxon (CPO), which is several-fold more potent than CP as a neurotoxin due to its irreversible inhibition of acetylcholinesterase activity [61]. Oxidative conversion of CP to CPO occurs when CP comes into contact with oxidizing decontaminating cleaning and laundry products [61]. The human immune defense against organophosphates is the liver enzyme paraoxanase I (PONI). This antioxidant neutralizes nerve agents. GWVs who became chronically ill had lower levels of PONI and thus were unable to clear the toxins from the body, which may have negatively impacted the nervous system [61]. Pyridostigmine bromide (PB), another chemical used during the Gulf War, has also been studied. PB exposures contribute to many of the above mentioned GWS conditions. There are noticeable trends toward worse health with greater exposure to PB [52]. Central nervous system injury has been reported in animal studies of exposure to PB [63]. Studying GWVs, researchers have found an increase in autoantibodies to MBP [53] which is thought to have occurred from tissue injury after exposure to toxic chemicals [1,64]. The increase of IgM to MBP appears to indicate that an active process involving the release of neuronal antigens occurs up to 8 years after initial injury of the central nervous system [53]. GWS seems to be the result of a confluence of chemical exposures and both the physical and emotional stress of war. The bombardment of chemical exposures easily penetrates the over-stressed human body. If the soldier is genetically weak in enzyme activity, these chemicals are not cleared out of the body and instead are able to injure the central and peripheral nervous systems.
AIR POLLUTION
Air pollution is a composite mixture of ozone and particulate matter. Composition depends on industrial pollutants, automobile exhaust and wind currents, and thus varies from region to region, city to city, continent to continent. Air pollution may include serious xenobiotics such as carbon
Environmental Triggers of Neuroautoimmunity 195 monoxide, lead, nitrogen dioxide and sulfur dioxide, lipopolysaccharides, mercury, arsenic, benzene, formaldehyde and acid gases. Chronic exposure to air pollution is associated with respiratory and cardiovascular-related sickness and death [65]. Ozone has been shown to cause respiratory tract epithelial injury and inflammation [66], while particulate matter can evoke inflammatory responses [67-69]. Inflammatory processes beginning in the nose can result in brain inflammation (see Figure 3). The residents of two highly-polluted cities in Mexico were studied due to their chronic exposure to a complex mixture of air pollutants, including ozone and particulate matter [70].
Figure 3. The nose-brain connection to brain inflammation.
Studying autopsied brain samples from lifelong residents of Mexico City, Monterrey, and five small cities with low levels of air pollution (Abasolo, Iguala, El Mante, Tlaxcala, and Veracruz), researchers found Alzheimer’s-like pathology in residents exposed to high levels of air pollution [70]. Ozone and particulate matter are the major air pollutants for both Mexico City and Monterrey. The high-exposure group included 10 subjects, while 9 subjects made up the low-exposure group. Interesting to note, all subjects were non-smokers from middle socioeconomic status [70]. Inclusion criteria for the study were as follows :
Researcher access to complete clinical information for at least 3 months prior to death No evidence of neurological disease or cognitive abnormalities by medical history and by complete neuropathological examination Body mass index between 19 and 25 Negative family history of dementia Negative history of drug addictions, occupational exposures to potential neurotoxicants, recent vaccinations, and intake of vitamins, dietary or herbal supplements Negative history of non-steroidal anti-inflammatory drugs (NSAID) and steroidal compounds A negative history of depression, memory complaints, and speech or learning disabilities was required.
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Additionally, the subjects had no clinical history or pathological evidence of short- or long-term inflammatory processes, administration of anti-inflammatory drugs or hormones, or events such as cerebral ischemia, head trauma, or epilepsy. This, and previous studies by the author, have provided evidence of brain inflammation in the form of an upregulation of the expression of prostaglandin-endoperoxide synthase 2, also known as cyclooxygenase-2 (COX2), an extremely potent biologically-active mediator of inflammation, in the brains of both human and dog residents of Mexico City [68,70]. COX-2 is rapidly expressed in several cell types in response to growth factors, cytokines, and pro-inflammatory molecules and is responsible for ‘‘pathological’’ prostaglandin (PG) H synthase. COX2 expression was predominantly observed in capillary endothelium [70]. Blood vessels of the brain exhibit inherent and induced expression of receptors for inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) [71,72]. Chronic respiratory tract inflammation may lead to chronic brain inflammation by altering levels of circulating cytokines [71] and that are known to be transported across the blood–brain barrier [71,72]. The brains of Mexico City dogs exhibit upregulation of COX2 expression, indicative of chronic brain inflammation, and accelerated accumulation of 42-amino acid form of β-amyloid (Aβ42), a neurotoxic fragment of the amyloid precursor protein (APP) that causes neuronal dysfunction [68,73]. The canine data suggested that chronic exposure of humans to severe urban air pollution may also have adverse effects in human brains [70]. Lipopolysaccharide (LPS) is a component of Mexico City particulate matter [69]. Systemic administration of LPS to rodents causes upregulation of COX2 in brain perivascular and endothelial cells [68,74] and alters the expression or processing of APP or both. LPS also accelerates the generation of Aβ42 in transgenic mice [75] and increases the abundance of APP751 [76]. This pairing of LPS and COX2 appears to have lasting neurological effects. An estimated 5.4 million Americans have Alzheimer’s disease (AD) [77]. The environmental role in the pathogenesis of AD is unknown. The identification and alleviation of environmental factors that influence AD pathogenesis is a fundamental approach to limiting the rising numbers of AD cases. About half of all Americans live in areas where levels of smog are unhealthy, while many individuals endure occupational and indoor exposures to air pollutants [70].
CLINICAL MECHANISMS
Depending on the person’s genetic ability to handle toxins, amount and duration of exposure and body burden of accumulated insults, immunotoxicity may lead to:
Neuroinflammation Neuroautoimmune reactivity Neurodegeneration
Autoimmune responses can be induced by environmental chemicals through a variety of effects including cellular, biochemical and molecular [78]. The chemical’s toxic effects can indirectly damage the structural integrity or function of organs or tissues (see Figure 4) [78]. As a chemical enters the body it is metabolized. The parent compound and the metabolite may attach to human tissue. The toxic effect of the chemical and its metabolite can cause tissue damage resulting in the release of tissue antigens into circulation. At this point the APC can pick up the parent compound bound to tissue, the metabolite bound to tissue or the tissue antigen. The APC hands the antigen(s) to the T-cell, which begins the process of antibody production.
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The potential immune responses are:
Antibodies to the chemical bound to human tissue Antibodies to the chemical’s metabolite bound to human tissue Autoantibodies to human tissue.
Figure 4. Possible antibodies produced from chemical exposure.
Chemicals can directly influence cytokine production or inhibition of certain lymphocyte subsets
[78]. Polycyclic aromatic hydrocarbons (PAHs) are known to influence TH17 cells [79] which produce IL-17A, an inflammatory cytokine implicated in autoimmunity. Although this article is focused on neuroautoimmunity, it is important to note the role some chemicals play in cancers. Aflatoxin is a potent carcinogen. The liver is the primary target organ for aflatoxins. Cytochrome P450 enzymes convert aflatoxins to the reactive 8,9-epoxide form, which can bind to both DNA and human proteins [42]. To clear aflatoxins, a reactive glutathione S-transferase system, found in the cytosol and microsomes, catalyzes the conjugation of activated aflatoxins with reduced glutathione, thus inducing the expulsion of aflatoxin [42]. Subjects exposed to aflatoxins were four times more likely to develop liver cancer than unexposed controls, while the subject group infected with hepatitis B virus and exposed to aflatoxins was sixty times more likely to develop liver cancer [78]. Silicone breast implants have been shown to increase the risk of multiple myeloma [81]. Although this study [82] was performed on occupational exposures to specific agricultural pesticides not discussed in this paper, it is important to state that pesticides have been shown to increase the risk of monoclonal gammopathy of undetermined significance (MGUS) in men.
CONCLUSION
Exposures to environmental chemicals occur daily around the world. It is only when these exposures, which can be acute or chronic low-level, reach a threshold of body burden that clinical effects will manifest. If a person’s genetic ability to clear toxic substances from the body functions properly, the person will remain healthy. Unfortunately for many individuals, environmental exposures can trigger an autoimmune cascade that results in neuroinflammation and
198 Aristo Vojdani and Jama Lambert neuroautoimmunity, or these exposures can manifest in immune suppression leaving the patient susceptible to stealth organisms known to contribute to neuronal disorders. Today clinicians have tools to assess at-risk individuals. Autoantibodies to neuronal tissues can be detected in sera prior to the clinical onset of disease. Body burden of toxin exposure can be assessed using antibodies to the chemical bound to human tissue. These assessments, along with other pertinent clinical data, can improve the diagnosis and treatment of environmentally-triggered neuroautoimmune disorders. Screens for the detection of multiple autoimmune reactivity, neurological autoimmune reactivity, and chemical autoimmune reactivity are part of a very special menu offered by Cyrex Labs in Phoenix, AZ, as their Array 5, Array 7, and Array 11, respectively.
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Received: June 14 2013, Revised: June 21 2013, Accepted: June: 23 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):203-213 ISSN: 2156-941X © 2013 Nova Science Publishers, Inc.
TOXICANT LOSS OF IMMUNE TOLERANCE, NEUROLOGIC DISEASE, AND NUTRITIONAL STRATEGIES
Datis Kharrazian Bastyr University, San Diego, CA USA
ABSTRACT
This paper reviews immunology models of chemical tolerance and the role they may play with the pathogenesis of neurological autoimmune and neurodegenerative disease and how we may be able to reduce the impacts of these adverse reactions with various nutritional applications. The immune model of chemical tolerance describes how trace amounts of exposures to various chemicals commonly found within our environment lead to exaggerated immune responses turning on the cascade of immune dysregulation and systemic inflammation leading to neurological disease. Immune chemical tolerance is maintained by healthy integration of various immune cells that can be disrupted from toxicant exposure, chronic stress physiology, blood-brain barrier compromise, intestinal barrier compromise, hormone imbalances, antigenic models, oxidative stress models, and various mechanisms that induce loss of healthy immune integration. These mechanisms themselves have been shown to have the ability to be manipulated and modulated with various nutritional applications. With an increasing epidemic of toxicant load and virtually no conventional or pharmaceutical strategies to decrease their impacts on human systems evidence-based consideration leads us to the potential role of various natural compounds that exhibit activity that can decrease the expression NF-kappaB, optimize glutathione redox systems, improve barrier system impermeability, and support regulatory T-cell activity all which is essential to improve chemical immune tolerance environmental toxicants.
Keywords: Autoimmune, neurodegenerative disease, environment, chemical tolerance, oxidative stress, blood-brain barrier, nutrition
INTRODUCTION
There is no question that environmental pollution and toxins have potential for severe adverse impacts on both developmental brain health and inflammatory and autoimmune mechanisms of neurodegeneration [1]. We are living in a world that has changed dramatically within our lifetimes. We are now exposed to countless chemicals, hybridized foods, and genetically modified foods, all of which are very immune activating. Additionally, the increased use of pharmaceutical drugs is increasing rapidly. This polypharmacy model of various drugs potentially has diverse impacts on human physiology beyond known adverse reactions and iatrogenic causes of death and disability. The U.S. consumption of foods known as the Standard American Diet (SAD) is not only very
Correspondence: Dr. Datis Kharazian, 1001 Canvasback Court Carlsbad, CA 92011 Email [email protected]
204 Datis Kharrazian inflammatory but also very immune activating. The combination of chronic exposure to immune triggering pollutants, toxins, and inflammatory foods has potentially contributed to various inflammatory ailments that we as clinicians face today. Many have theorized that the growing development of autoimmunity, autism, and neurodegenerative diseases and other chronic inflammatory conditions may be result of our newly immune reactive environment [2-5].
Chemical Tolerance
Chemical tolerance is our immune system’s ability to react proportionately to compounds such as toxins, pollutants, and environmental proteins. The loss of chemical tolerance is a phenomenon both researchers and clinicians have identified as a mechanism leading to disease and inflammatory promoting reactions to commonly exposed pollutants within the environment that then lead to pathophysiological expression leading to chronic illness [6]. Immune chemical tolerance is dependent upon many overlapping physiological factors that include regulatory T-Cell integrity, antioxidant reserves, barrier system integrity, and integrity of hepatic biotransformation pathways. All of these systems can be compromised with various toxins; however these systems can also be compromised unrelated to toxin exposure from various etiologies and also lead to loss of chemical tolerance. Our immune system has some degree of tolerance to our environment however and loss of immune tolerance may lead to neurological autoimmunity involving known autoimmune diseases such as multiple sclerosis, autoimmune neuropathy, etc., but it may also be an underlying autoimmune factor for diseases such as Alzheimer’s, Parkinson’s, and autism [7-9]. The unprecedented levels of chemicals and heavy metals today, as well as hybridized, genetically modified, and industrially processed foods, all activate the immune system towards a proinflammatory expression. Only a minority of the synthetic compounds introduced to our environment have been researched individually, much less in conjunction with one another. The Environmental Protection Agency (EPA) doesn’t require testing on chemicals introduced to market unless evidence of potential harm exists, which means testing seldom happens. The EPA approves about 90 percent of new chemicals and only a quarter of more than 80,000 have been tested for toxicity [10]. Americans are born with increasingly high levels of chemical and toxin burdens. For example, a 2005 study of cord blood from newborns found almost 300 environmental compounds, including mercury and DDT. Another study showed first-time mothers in the United States had levels of flame retardants in their breast milk 75 times higher than in similar European studies. Environmental toxins have been linked with neurodegenerative conditions such as Alzheimer’s and Parkinson’s disease [13-15].
NF-κB and Chemical Immune Reactivity
Environmental toxicant activations of NF-kappaB is a powerful force capable of igniting relentless inflammatory cascades that play a role in neurological degeneration, autoimmunity, cancer, and loss of chemical tolerance. [16]. NF-κB is a protein inside of cells that acts as a switch to turn inflammation on and off in the body. It responds to whatever may be conceived as a threat to the cell, including environmental toxins, toxic metabolites, pollutants, and xenobiotics [17]. Systemic toxic load increase NF-κB activation promotion inflammation degradation of the barriers of the gut, brain and lungs, further increasing inflammation and loss of chemical tolerance [18]. Chronic activation of NF-κB also impairs cytochrome p45O hepatic biotransformation phase 1 oxidation/reduction reactions yielding compounds that are more immunoreactive and further perpetuating loss of chemical tolerance and perpetuation of inflammatory cascades that have potential to activate environmental hapten-induced neurodegeneration or autoimmunity [19-23].
Toxicant Loss of Immune Tolerance, Neurologic Disease, and Nutritional Strategies 205
It has been shown recently that NF-κB is required for activation of autoreactive T-cells, and its hyperactivity in monocytes and dendritic cells results in altered cytokine secretion and antigen presentation, which ultimately contribute to the initiation of autoimmunity [24]. An increasing number of studies indicate that NF-κB plays an important role in controlling the expression of genes relevant to the pathogenesis of autoimmunity. NF-κB is a protein complex that controls the transcription of DNA. It is found in all cell types and is involved in cellular responses to stimuli, such as stress, cytokines, free radicals, and antigens. NF-κB controls the expression of genes encoding the proinflammatory cytokines, chemokines, adhesion molecules, inducible enzymes (COX-2 and iNOS), and growth factors [25]. Once the NF-κB amplifying loop is activated, it may persist as an expression of chronic inflammation and autoimmunity, unless an active NF-κB inhibitor is provided. The two most naturally powerful supporters of a healthy NF-κB suppression are resveratrol and curcumin [26]. In recent studies, both curcumin and resveratrol have supported healthy numbers of T-cell cytokines [27, 28]. These results suggest the potential use of these select phytochemicals for supporting healthy immune responses. Research indicates that curcumin has the potential to support cardiovascular health through the minimization of IL-1beta, TNF-alpha, GATA-4 and NF-κB expression [29]. Curcumin has been shown to support healthy anti-inflammatory response. Studies show both compounds are effective in protecting the body from damage due to environmental toxins and for dampening NF-κB activation and inflammation [30-32].
Glutathione and Chemical Tolerance
Glutathione serves as key antioxidant to protect cells from environmental toxicants and pollutants by converting from reduced glutathione (GSH) to oxidized glutathione (GSSG), but even before the oxidation of glutathione occurs at the cellular level, glutathione is also involved with quenching oxidative stress occurring at our immune barrier to limit external chemical haptens exposure to our internal physiology [33]. Glutathione also supports both Phase I and Phase II hepatic biotransformation systems necessary for hepatic metabolic clearance of toxic metabolites [34]. Each of these mechanisms of glutathione protect us from toxicant induced neurological disease and neurological autoimmune disease to some degree and research has found that loss of chemical tolerance or autoimmunity may be kept in check at various levels by the pleiotropic impacts of glutathione [35,36]. GSH depletion is associated with environmental-induced inflammatory reactions. Researchers are now finding that environmental pollutants do not trigger an immune response until glutathione levels are depleted [37-39]. Continued oxidative stress from chemicals, immune-reactive proteins, and infections all deplete the glutathione protective system at our barriers. However, when glutathione becomes depleted there is no protection for the barrier system and free radicals can readily destroy them leading to exposure of chemicals and large particles to the underlying immune cells of the barrier system. This can lead to exaggerated inflammatory responses and be participating in a vicious cycle in those that suffer from chronic loss of immune tolerance integrity [40-45]. Glutathione doesn’t just protect cells from chemical oxidants is also possess natural chelation properties that allow the tripeptide to bind to environmental compounds and help remove them from the body without displacing them into other tissues, such as the brain that occurs with chelator [46- 50]. Numerous botanicals have been found to support glutathione levels in our body from various mechanisms. N-acetyl-cysteine is a key compound to glutathione activity. It is rapidly metabolized into intracellular glutathione [51-52]. Alpha-lipoic acid directly recycles and extends the metabolic life spans of vitamin C, glutathione, and coenzyme Q10, and it indirectly renews vitamin E, all of
206 Datis Kharrazian which support glutathione recycling [53-54]. L-glutamine is important for the generation of glutathione and oral ingestion is transported into the cell, converted to glutamate, and readily available to intracellular glutathione synthesis [55-57]. Selenium is a trace element nutrient that serves as the essential cofactor for the enzyme glutathione peroxidase, which converts GSH to GSSG so glutathione can quench free radicals in order to spare cells [58-60]. Cordyceps has been shown to activate both glutathione and peroxidase synthesis in the body and protect cells by engaging the glutathione enzyme cycle. Cordyceps increases glutathione levels in the cells by 300 percent within minutes [61-62]. Oral ingestion of Centella asiatica rapidly and dramatically increases the activity and amount of glutathione peroxidase and the quantity of glutathione [63]. Milk thistle has been shown to significantly increase glutathione, increase superoxide dismutase activity, and positively influence the ratios of reduced and oxidized glutathione [64,65]. In addition to the Pro-GSH compounds listed above that are useful in supporting glutathione recycling. Glutathione can also be taken directly, but only if it is the S-Acetyl-Glutathione. This form of glutathione has been shown to be efficiently absorbed unlike other versions [66-70].
Toxicants, Chemical Tolerance and Immune Barrier Systems
Many of the top ten Unites States list of hazardous substances, established by the Agency for Toxic Substances and Disease Registry, are found in such high levels that the chemicals themselves are leading to continued oxidative stress and breakdown of the barriers. Polychlorinated biphenyls (PCB), listed #4 on the top 10 list of hazardous substances, has been shown to disrupt the blood-brain barrier [71, 72]. Chronic exposure of arsenic in human water has been shown to alter the lung epithelial barrier and restrict wound repair [73]. Pesticides have also been found in food and drinking water and therefore are now considered a major route of exposure to the general population. The organo-photothionates in pesticides have been found to directly cause intestinal tight junction breakdown [74]. Polychlorniated biphenyls commonly found in the environment have also been found to cause alterations in tight junction integrity [75]. Unfortunately, it now appears that because of the commonly found chemicals in our environment, it itself is contributing to breakdown of our barrier system that is in turn leading to loss of chemical tolerance. The blood-brain barrier (BBB) maintains central nervous system homeostasis by preventing entry of substances that may alter or harm neuronal function, and also allows chemicals necessary for brain function to cross. The BBB is a membrane structure composed of endothelial cells surrounded by astrocyte cell projections tightly surrounded in brain capillaries. The BBB was first discovered by bacteriologist Ehrlich in the 19th century while he was performing tissue staining. When he injected animals with staining chemicals, all of the structures in the body would be stained except the brain. When he injected into the central nervous system he found that the stain would not penetrate outside of the central nervous system. These observations led him to conclude that there was a barrier between the central nervous system and the rest of the body. When the electron microscope was invented in the 1960s, the actual BBB membrane could be demonstrated. The structural composition of the BBB easily allows the entry of oxygen, carbon, dioxide, fatty acids, ethanol, and steroid hormones. Certain amino acids and sugars may also cross the BBB necessary for energy metabolism and neurotransmitter synthesis. However, neurotransmitters cannot cross the BBB with the exception of epinephrine and norepinephrine at thin areas of the BBB found in the hypothalamus. The BBB has special sites present with thinner membranes where its permeability is penetrated easier. These are a normal part of the BBB and include three important circumventricular organs, the subfornical organ, the area postrema, and organum vasculosum of the lamina terminalis. These hypothalamic integrative centers are very important for regulating fluid electrolyte balance,
Toxicant Loss of Immune Tolerance, Neurologic Disease, and Nutritional Strategies 207 sodium excretion, blood volume, regulation of vasopressin secretion, and detecting toxins in the blood to induce vomiting [76]. The BBB restricts B cell entry and protects the brain from general infections. Therefore, infections rarely occur in the brain, but when they do occur they are very difficult to manage. In cases of extreme infection, the BBB will lose its membrane integrity and immune cells from the peripheral system such as macrophages and bone marrow-derived progenitor cells will cross into the brain. Once the infection has been managed, the BBB membrane is reestablished [77]. Loss of BBB integrity has been proposed for the etiology of numerous disease processes including meningitis, multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease [78-80]. Loss of BBB integrity may lead to infiltration of environmental compounds (haptens), dietary proteins, or pathogenic organisms (antigens) to expose them to microglia and activate a neuroinflammatory response. The BBB has demonstrated loss of integrity from alcohol exposure [81], stress responses [82], elevated homocysteine [83,84], hyperglycemia [85], prostaglandin imbalances [86], and oxidative stress [87].
Regulatory T-Cells and Chemical Tolerance
Regulatory T cells, are a subpopulation of cells that downregulates the immune system, maintains tolerance to self-antigens, and down-regulates autoimmune disease. Regulatory cells are a component of the immune system that suppresses the immune responses of other cells. This is an important "self- check" built into the immune system to prevent excessive reactions. Regulatory T cells come in many forms, with the most well understood being those that express CD4, CD25, and Foxp3 (CD4+CD25+ regulatory T cells). These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms and also in preventing autoimmune TH1 and TH2 polar shifts. They play a critical role in both the modulation of autoimmunity and loss of chemical tolerance [88-90]. Regulatory T cell function can be supported with glutathione and vitamin D. When nutritionally supporting loss of chemical intolerance, vitamin D levels should always be addressed. Research shows vitamin D plays a critical role in the development of general tolerance, immune system defense, immune balance (regulatory T-cells) and immune barrier integrity [91-92]. On a 25-hydroxy vitamin D test, it is ideal to see a level no lower than 50 ng/mL. Several nutrients have been shown to support the regulatory T cells, such as vitamin D and glutathione support [93-97].
CONCLUSION
Toxicants, environmental pollutants, and inflammatory reactions lead to immune loss of chemical tolerance. Loss of immune chemical tolerance leads to increase oxidative, inflammatory, and immunoreactive responses to vulnerable tissues such as the brain and nervous system thereby promoting neurodevelopment disorders such as autism, neurodegenerative diseases such as Parkinson’s and Alzheimer’s, and neurological autoimmune disorders such as multiple sclerosis. Physiological depletion of glutathione redox systems, wind-up and amplification of NF-kappaB inflammatory expression, immune barrier system breakdown, and regulator T cell dysregulation all play key roles in maintaining healthy immune chemical tolerance. Nutritional strategies that may impact the integrity and the expression of these physiological systems may provide some potential support to address the growing concerns of environmental induced brain disease and neurological autoimmune disorders.
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Received: July 1 2013 Revised: July 3 2013 Accepted: July 7 2013
Funct Neurol Rehabil Ergon 2013;3(2-3):215-256 ISSN: 2156-941X © Nova Science Publishers, Inc.
THE POTENTIAL IMPACT OF VARIOUS PHYSIOLOGICAL MECHANISMS ON OUTCOMES IN TBI, MTBI, CONCUSSION AND PPCS
Joel Brandon Brock1,2,4, Samuel Yanuck3,4, Michael Pierce1,5, Michael Powell2,6, Steven Geanopulos7, Steven Noseworthy8, Datis Kharrazian9, Chris Turnpaugh3,11, Albert Comey1,12, and Glen Zielinski2,3,13 1Carrick Institute for Graduate Studies, Cape Canaveral, FL USA 2F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation and Applied Neurosciences, Garden City, NY USA 3The Yanuck Center, Chapel Hill, NC USA 4Cogence, LLC, Chapel Hill, NC USA 5Integrated Health Systems, Denver, CO USA 6Powell Chiropractic Clinic, Cedar Rapids, IO USA 7New Heights Integrated Health, New York, NY USA 8Essential Medicine, Lakewood Ranch, Florida USA 9Bastyr University, San Diego, CA USA 11Brain Balance Center of Mechanicsburg, Mechanicsburg, PA, USA 12Comey Chiropractic Clinic, Largo, FL USA 13Northwest Functional Neurology, Lake Oswega, OR USA
ABSTRACT
The need for effective clinical interventions in chronic neurological diseases such as TBI and other variants of chronic neurological conditions have been called for in the literature. The cellular and neurochemical mechanisms addressed in recent literature have focused around three common themes that traverse all of these condition classes: immune and autoimmune mechanisms, inflammatory pathways and oxidative phosphorylation or other energy production damage. Limits to the effectiveness of pharmaceutical and surgical approaches are apparent, and complicated by the physiological interconnectedness of such pathways. A growing call for non-drug, non-surgical options has evolved due to the dangers of poly-pharmacy, the lifestyle illnesses, and emerging evidence pointing to functional measures and methods. This paper surveys and links selected studies of specific, measurable effects of brain injury on several body systems, and it indicates an emerging path toward outcome-based multifactorial functional neurological assessment and treatment of some of the sequelae of chronic TBI and mTBI) (mild traumatic brain injury).
Correspondence: Dr. J. Brandon Brock, 105 Decker Court, Suite 120 Irving, TX 75062 E-mail: [email protected].
216 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al.
Keywords: Concussion, TBI, mTBI, autoimmune, inflammatory pathways, neuroinflammation, neurodegeneration, neuropsychological, neuroendocrine, vestibular
INTRODUCTION
While many people recover from common brain injuries during the first year of recovery, those who are left with chronic problems have been told to accept their fate according to the dogma of permanence. Brain plasticity research has brought this notion under scrutiny. Studies on the neurochemistry and sensorimotor consequences of chronic brain injury have revealed wide ranging and cross-disciplinary mechanisms. These measurable phenomena have increased the understanding of both pathological and dysfunctional syndromes within this category of illness. An increasing need for strong generalist thinking is therefore demanded in order to comprehend and utilize this bounty, and to avoid the traps of heuristic decision making and specialist-dumping in a clinical setting. Careful examination of many wide-ranging patient measures must be integrated in order to progress, such as reflexive eye movements, hormone panels, sensorimotor changes, immune and inflammatory markers, and mental and emotional states. History taking will need to expand to include lifestyle factors previously thought unrelated. The compartmentalization of diagnosis and treatment and the wanton medication of these populations of chronic brain injury may not be their only fate. Part I of this paper will survey mechanisms that span much of the above chronic neurological illness spectrum; first, through intracellular, and then, endocrine and tissue effects. This includes the underlying milieu prior to the injury, neurochemistry and receptors, fuel, immunity and inflammation, barriers, and endocrine effects. The CDC defines concussion as a subset within TBI and many sources consider it a form of mTBI (mild traumatic brain injury). There are several criteria for mTBI and concussion, so the reader is warned that each reference may define these with slightly different symptoms. Part II includes trauma effects, clinical neurological rehabilitation applications and mental health related to persistent post-concussion syndrome (PPCS).
PART I: MOLECULAR, RECEPTOR, SECRETORY AND CELLULAR DYNAMICS
Adding Insult to Injury: Non-Traumatic Brain Insults in the Total Picture of TBI and mTBI
Accumulated neuroinflammation and neurodegeneration from multiple concussions cause deleterious effects that are well established. The fact that non-traumatic mechanisms can create pro- inflammatory influences on the brain that influence the same cellular signaling mechanisms to those seen with trauma suggests that, in order to understand the total burden of brain pathology in a given patient, both traumatic (injury) and non-traumatic (insult) sources, and their interactions, must be considered. Non-traumatic sources of brain insult may be instigators of microglial priming in advance of TBI or mTBI, therefore worsening TBI or mTBI outcome.
The Potential Impact of Various Physiological Mechanisms … 217
Figure 1. Chronic TBI sequelae © Samuel Yanuck 2013.
Neuron-Microglial Interactions in the Healthy Brain
In the adult brain, there is a decline in gray matter density over time. For example, Sowell et al found a loss of gray matter density of approximately 32% between ages 7 and 60, and a 5% loss between 40 and 87 [186].. Thus neurons die every day. They need to be cleared, or they will drive damage associated molecular pattern (DAMP) mediated immune system activation, instigating a pro- inflammatory response in the brain [3,187]. Microglia are the predominant immune cells in the healthy brain [1]. In the normal, resting state, it is the job of ramified microglia to phagocytize the dead neurons, much like macrophages phagocytize apoptotic cells and tissue debris in peripheral tissues. In both cases, this housekeeping level of phagocytic activity drives the creation of anti-inflammatory mediators like IL-10 and TGFβ. Phagocytosis of apoptotic cells provides immune regulation through anti-inflammatory cytokines and regulatory T cells [2] However, since there is no appreciable drainage of lymph from the brain, except minimally at the cribriform plate, the option of clearing phagocytized debris from tissue via the lymph system, as occurs in the periphery, is not available in the brain. Therefore, microglia must fully degrade dead neurons and recycle them as building blocks and fuel. Given billions of neurons and an estimated ten microglia per neuron, and given a motif of continuous surveillance, the number of instantaneous events of microglial cells being activated or inhibited in the decision flow to instigate phagocytosis of a neuron is very large indeed. How do the microglia decide which neurons are dead? How is this process between microglia and neurons regulated in non-neutral circumstances like trauma, infection, inflammation, or neurodegeneration? Neurons control microglial activity [3]. ‘Off’ signals from neurons keep microglia in their resting state and reduce pro-inflammatory activity, while ‘On’ signals from neurons are inducible, including
218 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. purines, chemokines, and glutamate. Thus, neurons should be envisaged as key immune modulators in the brain [3]
Table 1. Inhibition of Glial Phagocytosis of Neurons (“OFF” Signals) [3]
OFF Signals Signal Effect Released TGFβ Inhibition of effector T cells; Promotion of immune tolerance & inflammatory resolution; loss of anti-pathogenic vigilance CD22 Inhibition of B cell activity CX3CL1 Inhibition of microglial neurotoxicity Neurotransmitters Multiple functions NGF Nerve growth factor BDNF Brain derived neurotrophic factor NT-3 Neurotrophin-3 Membrane CD200 Inhibition of glial inflammation Bound CD22 Inhibition of B cell activity CD47 Inhibition of glial inflammation CX3CL1 Inhibition of microglial neurotoxicity
Table 2. Activation of Glial Phagocytosis of Neurons (“ON” Signals) [3]
ON Signals Signal Effect Released CCL21 Glial chemoattraction CXCL10 Glial chemoattraction ATP & UTP Glial chemoattraction & IL-1beta release Glutamate TNF-alpha release & neuroexcitotoxicity MMP3 Induces glial release of TNF-alpha, IL-1beta, IL-6 (inflammatory) Membrane TREM2 ligand Promotes glial phagocytosis of neurons Bound
In a healthy brain, the interplay of neurons and microglia is balanced. Healthy, viable neurons produce adequate OFF signals to repel microglial phagocytic interest. In addition, healthy neurons produce abundant electrical activity. The electrical activity of neurons is itself a potent inhibitor of microglial activation [4]. In the healthy, non-inflamed brain, ramified microglia secrete TGFbeta, which promotes a tolerogenic and anti-inflammatory tissue environment [5]. In addition, in a healthy brain, microglia and astrocytes express FasL, which induces apoptosis in T cells that migrate from the periphery into the brain [6]. Neurons and glia express cellular death signals, including CD95Fas/CD95L, FasL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and TNF receptor (TNFR), through which they can trigger apoptosis in T cells and other infiltrating cells [2].
Factors Affecting Neuronal-Microglial ‘On’ or ‘Off’ Signaling
The capacity of neurons to maintain robust frequency of firing (FOF) is essential for sustained electrical activity and neurotransmitter (NT) output, two essential ‘OFF’ signals. The central integrative state (CIS) of the neuron depends on presynaptic stimulation, neuronal oxygen and neuronal glucose. Physiological factors that have the capacity to impair these three factors can contribute to changes in neuronal FOF, thereby changing the neuron-microglial ON/OFF equation.
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The capacity of neurons to maintain robust FOF also depends on the metabolic integrity of the neurons themselves. A host of factors contribute to neuronal metabolic integrity. Among the variables that can perturb function and lead to diminished FOF are a lack of exercise, excessive accumulation of mitochondrial ROS, diminished thyroid hormone signaling, and CoQ10 deficiency (statin-induced or other). The accumulation of ROS in mitochondria depends on the balance between electron accumulation from excessive caloric consumption versus the utilization of electrons via exercise. Too much caloric intake combined with a lack of exercise yields an overabundance of electrons (general biology). They react with oxygen, creating superoxide. If this occurs in amount in excess of what can be cleared by mitochondrial antioxidant mechanisms, the mitochondria are damaged. Mitochondrial damage from ROS may be more common in patients with single nucleotide polymorphisms (snips) for glutathione or SOD. Approximately half the population has a snip for GSTM-1, the primary gene for the production of glutathione s-transferase) [188]. Sensory stimulation factors like lack of exercise, destruction of joint mechanoreceptors in arthritic conditions, poor muscular tone, diminished rib movement with respiratory disorders and other such changes can alter the neurosensory environment. Glycemic dysregulation in diabetes, hypoglycemia, insulin resistance and other such conditions can impair systemic and consequently CNS glucose levels. Many of these patients have microcirculatory problems exacerbating inadequate blood glucose levels with poor delivery to brain. Likewise, CNS oxygen levels can be impaired by respiratory disorders, disorders of microcirculation and other such problems.
Figure 2. Factors Potentially Affecting the Neuron-Microglial ON/OFF Equation © Samuel Yanuck 2013.
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Clearance and Inflammation in Injury
When the brain is injured, however, the resulting inflammatory chemistry can change the equation. With inflammation, neurons and microglia both change in ways that promote microglial phagocytosis of neurons. As with any cell, inflammation compromises metabolic integrity. In neurons, this yields diminished production of neurotransmitters and reduced electrical activity. Thus, two potent “Off” signals are lost. Meanwhile, inflamed microglia change their morphology. Brain inflammation differs from inflammation in the periphery by the relative absence of leukocytes and antibodies. There is a limited traffic across this barrier and this traffic can be increased by inflammation which can recruit leukocytes into the brain [1]. However, in the inflamed brain, microglia (which are after all a specialized form of macrophage) acquire antigen presenting cell capacity [4]. Instead of inducing apoptosis in invading T cells, inflamed microglia present antigen to invading T cells. Antigenic material can be fragments of processed pathogens. This is a useful antimicrobial effect, favoring clearance of pathogen. However, microglia can also present fragments of neuronal tissue debris as antigen, promoting a self-antigenic response in the T cells to which the antigen is presented. A mild and transient form of this T cell self- antigenic activation appears to be reparative. However, prolonged or overly exuberant self-antigenic T cell activation can cause irreversible damage to brain [4]. It is noteworthy that some of the research in this field occurred before there was a full appreciation of the role of TH17 polarization in T cell/microglial interactions. Inflammation is known to induce mitochondrial uncoupling, diminishing mitochondrial integrity in all cells. Inflammation is therefore also a driver of diminished mitochondrial integrity and FOF of neurons. In a variety of inflammatory and neurodegenerative diseases, glial cells such as microglia gain antigen-presenting capacity through the expression of MHC molecules. The pro-inflammatory cytokines stimulate microglial MHC expression in the lesioned CNS areas only [4]. Neuronal signaling, a strong “Off” signal, works to suppress the immune system’s inflammatory activation in the brain so that induction of brain immunity is strongly counterregulated in intact CNS areas. The signaling activity of neurons also constitutes an inhibitory signal. The control of MHC expression by neurons is dependent on their electrical activity. Immunity in the CNS is inhibited by the local microenvironment, in particular by physiologically active neurons, to prevent unwanted immune mediated damage of neurons [4] (emphasis not original). Research on the role of T cells and peripheral innate immune cells in the brain is evolving. Most authors suggest that maintenance of the non-inflamed CNS environment depends on the ability of microglial cells to induce apoptosis in peripheral T cells that gain access to the brain. However, the failure of systemic anti-inflammatory medications to yield improvement in neuroinflammatory disorders has led some authors to a view that CNS-infiltrating T cells provide crucial anti- inflammatory cytokine signals that are essential for the resolution of neuroinflammation [7]. It is noteworthy that non-steroidal, anti-inflammatory medications have been described in the literature as “resolution toxic” because they inhibit signaling mechanisms involved in the resolution of inflammation [8]. This insight may prove useful in understanding the failure of anti-inflammatories as a viable therapy to address chronic neuroinflammation. In the presence of systemic inflammation, T cells invading the CNS are likely to be influenced by pro-inflammatory cytokines and other factors into a pro-inflammatory morphology, as they are in the periphery. Once so influenced, they are likely to produce pro-inflammatory cytokines, further promoting the pro-inflammatory CNS environment. Pathogens in tissue create pathogen associated molecular patterns (PAMPs). Damaged tissue creates damage associated molecular patterns (DAMPs). Microglial pattern recognition receptors (PRRs) sense PAMPs and DAMPs, triggering phagocyte NADPH oxidase (PHOX), which turns
The Potential Impact of Various Physiological Mechanisms … 221 molecular oxygen into reactive oxygen species (ROS). This conversion depletes the tissue of molecular oxygen, yielding hypoxia, driving hypoxia inducible factor 1α (HIF-1α), driving NF-κB, driving IL-1beta and TNF-alpha, which increase gene expression of NF-κB. NF-κB drives iNOS (inducible nitric oxide synthase) expression. Though nitric oxide (NO) is cytoprotective, the combination of NO and hypoxia impair cellular respiration, yielding excitotoxicity. Though balanced amounts of ROS are normal to microglial function, ROS in combination with NO yields peroxynitrite, driving neuronal apoptosis. In patients with antioxidant depletion, from glutathione (gsh) snips or other factors, the likelihood of microglia producing neurotoxic amounts of ROS is increased.
Figure 3. Factors Contributing to Perpetuation or Resolution of Neuroinflammation [11] © Samuel Yanuck 2013.
Microglial Priming and the Contribution of Non-Traumatic Influences to Neuroinflammation
Microglial priming is a condition in which microglia move from the ramified state in which they perform housekeeping functions and reduce neuro-inflammation to a state in which they swell and fill with pro-inflammatory cytokines [9,10,11,12] Priming can be induced by aging, trauma, infection, or other stimuli. Microglia can remain in this state for long periods of time, without returning to the ramified state, but without releasing their bolus of cytokines. However, further insult to the brain will cause a flooding release of pro-inflammatory cytokines that can be damaging to the brain [9,10,11,12]. It has been established that increases in pro-inflammatory cytokines in the periphery yield upregulation of brain inflammation and potentiate neuronal death [13,14] It has also been shown that increasing the peripheral LPS (lipopolysaccharide) level can induce the activation of central pro- inflammatory mechanisms, even when the amount of LPS used for stimulation is minimal or when the peripheral inflammatory cytokine levels are suppressed artificially. Both central and peripheral inflammation can exacerbate local brain inflammation and neuronal death [15]. Once neuroinflammation occurs, the key question is whether it will resolve quickly or yield a chronically activated state, in which greater neuronal loss occurs. Microglia alter their morphology and activate in response to pathophysiological brain insults. Microglial phenotype is also modified by systemic infection or inflammation. Chronic systemic inflammatory components are risk factors for Alzheimer disease. This implies that crosstalk occurs between systemic inflammation and microglia in the CNS [16]. Pathogens, protein aggregates, or damaged neurons may inflammatorily activate glia, which may then kill neurons. IL-1b has been
222 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. shown to be the main activator of microglia during brain disturbances. Systemic IL-1b can cause CNS inflammation once it enters the brain, thus linking systemic inflammation and immune activation [12]. Microglia can become over-activated through two mechanisms. First, microglia can initiate neuron damage by recognizing pro-inflammatory stimuli, such as lipopolysaccharide (LPS)). Second, microglia can become overactivated in response to neuronal damage [11]. LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation [9,10]. Many of the pathological events described in traumatic brain injuries can also be seen with excitotoxicity [12]. Receptor stimulation by pathogens or neuron damage contributes to nuclear factor-kappaB (NF- κB) activation. Simultaneous activation of PHOX (Phagocyte NADPH oxidase) and iNOS (inducible nitric oxide synthase) in microglia resulted in the disappearance of NO, appearance of peroxynitrite and apoptosis. However, the chronic state of activation may progress to “resolution phase” where microglia are amoeboid, highly phagocytic, and produce anti-inflammatory cytokines (including IL- 10 and TGFb) in order to resolve the inflammation and clear up the mess [1] With successful, non-phlogistic microglial phagocytosis of apoptotic neurons, the neuron is engulfed and digested without release of additional damage associated molecular patterns (DAMPs) into the tissue environment. This favors the production of anti-inflammatory cytokines and a movement toward resolution of tissue inflammation in the brain parenchyma. If instead the neuron dies by necrosis through direct or indirect trauma, or is triggered into necrosis by a pathogen or toxin, its death releases cell fragments and cytosolic contents into the tissue environment, triggering a pro- inflammatory response in surrounding microglia. Neuroinflammation favors a more aggressive microglial cell phenotype and a more exuberant phagocytosis of neurons, yielding neuronal loss in excess of that necessary to bring about resolution of the initial condition.
SIDS, SIRS and CARS
Acute neuroimmunological syndromes such as central nervous system injury-induced immune deficiency syndrome (SIDS), systemic inflammatory response syndrome (SIRS) and compensatory anti-inflammatory response syndrome (CARS) have been reviewed elsewhere [17]. It is unclear in the literature, however, whether a gradient of severity exists in these syndromes. For example, it is unclear whether a patient with mTBI (mild traumatic brain injury) might be expected to manifest a modest version of the apoptosis of innate immune cells and TH1 cells seen in SIDS. If this were the case, the patient might be incrementally more susceptible to chronic infection, promoting systemic and therefore neuroinflammatory mechanisms. From a clinical perspective, whether or not mild forms of these syndromes pertain, the clinician faced with a patient with a TBI or mTBI should be alert for indications of suppressed immune vigilance against pathogens. Such a circumstance would have the potential to yield chronic infection, a known driver of microglial priming and neuroinflammation.
The Injured Neuron
In the realm of traumatic brain injury, the neuron is the center point of the physiological story [18]. Factors including the preexisting central integrated state of various neuronal pools, the integrity of existing neuronal circuitry, peripheral receptor integrity, level of circulating cytokine populations, polarization status of a dynamic immune system, level of glial priming and function, balance and integrity of the endocrine system, various underlying infectious organisms, genetic predisposition, associated comorbidities and the extent of damage sustained as well as related biomechanics of a
The Potential Impact of Various Physiological Mechanisms … 223 given injury all determine neuronal integrity and probability of recovery post-injury [19]. Other factors that can impact the neuron are the nutritional and digestive status of the patient as well as vascular perfusion and autonomic integrity. The neuron’s ability to survive and maintain optimum functional capacity and appropriate cellular plasticity is vital to recovery and sustaining humanism and vitality post-neurological insult. Understanding and evaluating all converging physiological scenarios that can impact the health of the neuron and how it relates to head injury and damage to the CNS is vital when determining the extent of injury, creating appropriate treatment plans and care of patients suffering from traumatic brain injury or neurodegeneration [20]. The intracellular cascade after head injury is complex and involves organelle function, metabolic and ionic fluctuations and surface receptor interplay. This gross level interplay impacts cellular plasticity, immunoexcitotoxicty, intracellular calcium and binding proteins, caspase cascades, apoptosis, cerebral blood flow, glucose metabolism, phospholipase and free radical production, protease and cytoskeleton breakdown, endonuclease and DNA damage, nitric oxide isomers and superoxide anions [12]. On a smaller intracellular scale, organelle involvement includes changes in mitochondrial function, neurofilaments and microtubules, lysosomes, epigenetic function, protein replication, secretory vesicle production and synaptic capacity. The eventual consequence of intracellular and organelle variations will impact cellular energy, axonal and myelin integrity, cellular swelling, synaptic transmission, lipid membrane stability, synaptic transmission, and cellular summation capabilities. When damage occurs in the CNS, neurons are impacted, glial cells are altered, glutamate receptors can become sensitized, GABA receptors can become internalized, the immunological system is impacted, vasculature is compromised and the blood-brain barrier becomes damaged. This combination of events can lead to cellular damage, microglial priming and sustained inflammation within the CNS, antigen presentation of neural tissues and possible autoimmunity and compromise in the resolution process post-injury [21]. Surface receptor types, densities and their sensitivities also contribute to metabolism [22]. There are many receptor types; however, of particular interest are the ionotropic receptors including NMDA, AMPA, Kainate and voltage gated calcium channels. These receptors types allow a regulated influx of calcium into the cell that impacts multiple intracellular pathways allowing for intracellular cascades, cellular function, cellular plasticity and long term potentiation. The ultimate promotion of NMDAr(define) (N-methyl-D-aspartate, a specific type of ionotropic glutamate receptor) promotes the extracellular influx of calcium and calcium stores within the cell. The increase and appropriate regulation of cytosolic calcium leads to the proper activation of kinase dependent signaling cascades leading to cAMP (cyclic adenosine monophosphate) element binding protein activation. The activation of CREB (cAMP Response Element-Binding protein) ultimately generates the phosphorylation at SER 133 (serine 133) leading the generation of protein synthesis within the nucleus. This generates the ability for the cell to innately generate more surface receptors, intracellular structures, cytokines, neurotrophic factors, cellular efficiency, dendritic development and repair cycles vital for cell survival. The ultimate outcome of this process is synaptic plasticity and long term potentiation. This process is a large part of learning and memory and is a major mechanism of repair after damaged neural circuitry is created after head injury or in a neurodegenerative process [23]. The dysregulation of intracellular calcium, however, can lead to degenerative and excitotoxic mechanisms that are damaging. Under certain circumstance, cell surface receptors become more permeable to calcium while intracellular calcium-buffering proteins become aberrant thus causing the intracellular calcium levels to become dysregulated. Multiple neurodegenerative conditions, inflammatory scenarios and disease processes as well as excitotoxin loads and glutamate levels have the ability to alter NMDA receptors activation and skew AMPA:NMDA receptor ratios allowing a greater influx of extracellular calcium into the cell [18]. The resultant intracellular calcium dysregulation triggers pathology. The triggering of intracellular lipases causes cell membrane damage.
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Triggered nucleases destroy DNA. Calcium induced phospholipase activation promotes prostaglandins, arachidonic acid and leukotrienes which generate inflammation, vascular dysfunction, white matter disease, myelin damage, axonal damage and further free radical generation [24]. Energy uncoupling allows for protein phosphorylation, which alters gene expression and ion channel activity and changes the central integrated state and firing capacity of the neuron. Calcium induced proteolysis occurs which breaks down the cytoskeletal structure of the neuron thus altering transporting mechanisms and supportive structures of the cell body and axonal projections. This has the potential to alter antero- and retrograde function, which can alter the transportation of synaptic vesicles thus reducing synaptic activity. Activation of reactive oxygen and nitrogen species generates mitochondrial damage, NFκB activation and ultimately cellular apoptosis if persistent. A continuation of inflammation, oxidative damage and excitotoxicity can generate a situation where glial cells remain primed, neurons fail to function, plasticity is diminished and the neurochemical environment is altered. This continued process can lead to post concussive syndromes, second impact syndromes and repeat concussive symptoms despite not having another physical injury.
Figure 4. The balance of life and death receptors is epigenetically primed much like the muscle spindle system © Joel Brandon Brock 2013.
During times of oxidative stress, inflammation or neurodegeneration, energetic failure emerges among normal mitochondrial function and overall energy production of the cell [25]. This can lead to
The Potential Impact of Various Physiological Mechanisms … 225 a breakdown in the electron transport chain and decrease mitochondrial calcium loading capacity through an activated mitochondrial permeability exchanger. The exchanger opens mitochondrial pores and allows the deposition of calcium within the mitochondria into the cellular cytosol disrupting intracellular calcium regulation. Respiratory chain uncoupling and the release of intermembrane space proteins as a result of MPT (membrane permeability transition) activation causes multiple cascades to occur [26]. These include the release of intracellular caspases, caspase independent cell death effectors, NLRP3 inflammasomes, NFκB and interferon regulatory factors. The release of cytochrome C from the mitochondria activates caspase three which programs cell death and apoptosis. These cascades collectively lead to the development of inflammation, loss of cellular energy production and perpetuate further mitochondrial and cellular dysfunction. Thus the milieu of the cell primes the receptor sensitivity even before death or life receptors are triggered. This phenomenon of “setting receptor tone” is conceptually similar to how the tympanum tension is preset to perceive or protect from sound prior to the event, and the muscle spindle tone is preset before a perturbation. The implications of this for clinical prognosis and cellular apoptosis indicate some potential for leverage through clinical cell mediator manipulation. Such manipulation could be through substances administered as well as evoked potentials. In a normal cell, when there is abnormal stress, organelle damage, accumulation of misfolded proteins or damaged mitochondria, the cell removes the damaged organelles or unwanted proteins [27]. These processes include autophagy and mitophagy. Under periods of aging, inflammation, oxidative stress, mitochondrial damage, intracellular calcium dysregulation or a decrease in cellular activation, appropriate autophagy and mitophagy is impaired. When these cellular processes are impaired after head injury, various diseases can manifest, the health of the neuron can fail and ultimately lead to cellular death and premature neurodegeneration.
Copyright ©Joel Brandon Brock 2013 Mechanism of Injury Will vary depending Age / Sex / Other PAST MEDICAL On time bodily injury HISTORY
Axonal damage Cellular damage Second impact / Changes to CNS Post concussive Depends on area of Synaptic Neurofilaments prone Will vary depending trauma, extent of force Damage on severity on the head, amount of tissue ischemia, other Mechanical and ionic comorbidities Deformation Glial priming Inflammation Lysosome Energy loss Second impact / Damage to Mitochondrial Intracellular Post concussive Terminal or Relates to comorbidities Twisting, Shearing, Compression Structural Damage Autophagy debris prone transporters And number of injuries Bleeding, Diffuse and Focal Damage Neurochemical Biomechanical forces Damage Apoptosis Second impact / Chemical PON Knockout NMDA Post concussive Cascade iNOS Caspase prone Coup SOA Calpain Contra Coup Excitotoxicity Rotational Shearing Head Injury Linear force Reuptake Bleeding transporter loss Glutamate ↑ Unconscious GABA↓ Hyperkinetic Second impact / Chemical TND Post Cascade Excitotoxic concussiveprone
Bleeding / stroke / watershed Transmitter changes Twisting Rotation Shearing force Golgi Depression Serotonin ↓ Blunt trauma ↓Fuel causes Vascular changes Packaging damage Pain Emotional changes Cellular Dopamine ↓ Traction Oxidative stress Emotional Head and body pain Failure Monoamine issue To changes Peripheral Vestibular Synaptic vesicle loss System Reactive Vasconstriction
Contusion or Ischemia Excitotoxicty damage to the To tissue Decrease in peripheral Decrease in fuel for Prone for loss in Without therapy synaptic vestibular delivery plasticity Recovery ↓ transmission apparatus
Damage to TM / round / oval Or Damage to hair cells window Or Displacement of Fracture to temporal Inflammation or Or Otoconia bone Autoimmunity Delineate vestibular And Auditory loss or Damage to PVN Hearing loss both Fistula / TM BPPV Conditions Damage to PV Hydrops Canal / Otoliths apparatus
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Figure 5. How physical forces transmute into cellular changes and clinical conditions © Joel Brandon Brock 2013.
Head injury or uncontrolled inflammation or imbalanced immunological responses can trigger abnormal neuronal surface receptor activation. This can lead to dysregulated intracellular calcium, which can cause oxidative stress, cell structure breakdown, energy production loss and activation of inflammatory cytokines. Inflammation and cellular apoptosis can ultimately lead to the released of glutamate and proinflammatory cytokines that generate more surrounding excitotoxicity to nearby cells. This can create plasticity related to abnormal circuitry activation and lead to seizure, hyperkinetic function, ischemia and GABA receptor internalization. This mechanism is the cornerstone to the onset and perpetuation of many neurodegenerative diseases that might arise or be triggered post TBI.
Neuronal Energetics and TBI
Traumatic brain injury alters neuronal membrane potentials amking them more sensitive thus placing greater energy demand on a compromised system. Glucose is the obligate fuel source of the mammalian brain. While the brain can use alternate fuels, such as lactate and ketones, the efficiency with which the brain can do so varies with development stage/age as well as whether or not the brain is operating under normal physiological conditions [28]. While the brain accounts for only 2% of a human’s entire biomass it is responsible for 50% of total glucose utilization [29]. Under normal physiological conditions approximately 85% of brain glucose utilization is directed toward fueling the Na/K pumps that restore resting membrane potentials in active neurons [30]. Like the periphery, cellular uptake of glucose in the brain can be accomplished through both insulin-independent and insulin-dependent mechanisms. And while central neurons can synthesize their own insulin the majority of brain-based insulin is derived from peripheral supply [31]. The brain environment is sequestered and barriers exist to free flow of nutrients and glucose from the periphery. The two main obstacles to delivering nutrients and glucose to active neural tissue in the CNS are the blood-brain barrier (BBB) and the lack of local carbohydrate storage in neurons themselves [31]. Under conditions of concussion and traumatic brain injury, energy demands increase while glucose utilization decreasesresulting in a significant neuroenergetic mismatch [32].
Glucose Transport Across the Blood-Brain Barrier
The neuronal cell membrane is an impermeable barrier that requires insulin for transport across the cell membrane. Neurons express high amounts of insulin receptors, however the majority of brain insulin is derived from peripheral production, although some evidence does exist that neurons can produce small amounts of insulin themselves [33]. Beyond the cell membrane the neurovascular unit functions not only as a static barrier but can adapt to physiological changes by altering transport systems in order to modify and facilitate ion and nutrient flux. There are two primary classes of active glucose transporters that can express on both luminal (blood facing) and abluminal (brain facing) surfaces of the neurovascular unit. These two mechanisms are dedicated glucose transporters (GLUT1) and sodium-glucose co-transporters (SGLT). GLUT1 is a member of the glucose transport molecule family, is highly expressed in the brain, and can upregulate or down-regulate nutrient transport depending on the pathophysiological state of the system [33] [33]. It is a facilitated transport system that moves glucose along a gradient and is both Na+ and insulin independent. SGLT, on the other hand, is a Na-dependent symporter (integral membrane protein involved in transport of molecules across phospholipid membrane), moving one
The Potential Impact of Various Physiological Mechanisms … 227 glucose molecule along with two Na+ molecules in the same direction across the cell membrane in a co-transport relationship, against the glucose gradient [31]. SGLT is a secondary active transport mechanism that uses ATP generated from ion gradients. SGLT can also function in reverse, moving accumulated Na+ out of the cell into the extracellular space [34]. While GLUT1 is considered the primary glucose transport system studies have shown upregulation of the sodium-dependent glucose transporter SGLT1 in conditions of ischemia-hypoxia [33]. Because of these limitations (cellular and tissue level barriers coupled with a lack of passive diffusion and local neuronal glucose storage) the brain relies heavily on the expression of glucose transporters on the blood-brain barrier as well as the storage capacity of astrocytes. Both of these glucose transporters can be insulin sensitive or insensitive, hormonally regulated or driven by glucose concentrations [31] Other GLUT and SGLT isoforms (GLUT3, GLUT4, SGLT1, SGLT2) exist in the brain, but in lower concentrations and contribute to a lesser degree to neuroenergetics [5].
Energy Compartmentalization
In the brain, energy metabolism is highly compartmentalized [35]. While neurons have both aerobic and anaerobic pathways they have little capacity to store energy. As such neurons rely heavily on glucose delivery from the periphery as well as the participation of astroglial cells, which function as the brain’s glycogen repository. This presents several problems since there are significant barriers to consistent and stable glucose supply to the brain. Furthermore astrocytic glycogenesis and glycogenolysis as well as neuronal mitochondrial function can be influenced by TBI. Since neurons do not store glycogen, neuronal glucose utilization is intimately yoked to astroglial compartmentalization of glycogen. In the absence of its own localized glycogen neurons must communicate energetically with astrocytes in order to replenish energy substrates. This allows for resetting of membrane potentials and continued neuronal viability and functionality. Astrocytes support neuronal energetics via multiple pathways, the most notable and well-studied being the Glutamine-Glutamate Cycle and the Astrocyte Neuron Lactate Shuttle (ANLS). In the former, glutamate produced by neuronal Citric Acid Cycle (TCA) mechanics passes into the extracellular space and is taken up by astroglial cells where it is converted to glutamine [36]. Astroglial glutamine then exits the astrocyte and can be taken up again by a nearby neuron where it can resupply the neurotransmitter pool or reenter the TCA cycle by being converted into either alpha- ketoglutarate or succinate [37]. The Astrocyte Neuron Lactate Shuttle provides substrate for neurons to engage the glycolytic pathway. Extracellular glutamate, from active neuronal signaling, increases astroglial uptake of glucose by upregulating GLUT1 [38]. Astroglial cells then drive the glycolytic process creating lactate as a metabolic byproduct. This lactate is transported out of the astroglia into neurons by a monocarboxylate transporters, MCT1 and MCT 2 respectively. Neurons express several isoforms of lactate dehydrogenase (LDH) causing the conversion of lactate to pyruvate and the initiation of neuronal glycolysis, which eventually yields more glutamate to continue the ANLS. These two systems, Glutamine-Glutamate Cycling and the Lactate Shuttle, bind astroglial cells and central neurons in a symbiotic relationship that ultimately determines the ATP potential of both functional and injured brains.
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TBI Alters Brain Energy Metabolism
In 2001, Giza and Hovda outlined the neurometabolic cascade of concussion. The injured brain shifts into “hypermetabolism”, which increases the demand for ATP. At the same time energy production pathways shift away from the highly efficient oxidative phosphorylation to the much less efficient glycolysis. The net effect is neuronal acidosis, membrane dysfunction and BBB permeability. In addition evidence suggests that in the context of TBI lactate-consuming pathways that would otherwise drive ATP production via the ANLS are compromised [32]. What follows is diminished cerebral blood flow, which may be reduced by as much as 50%. This cellular energy crisis predisposes the injured brain to second injury and prolongs functional deficits associated with the injury [39]. Beyond the direct effects upon ATP producing pathways, post-injury depolarization and K efflux opens NMDA receptors. Calcium influx further impairs neuronal ATP production by impairing both oxidative phosphorylation and glycolysis. This promotes activation of apoptotic pathways, neurofilament compaction, microtubule disassembly, axonotomy and increases the production of inducible nitric oxide synthase [39]. Due to its high lipid content, the brain is highly susceptible to oxidative damage. TBI leads to a significant decrease in glutathione and ascorbic acid, the two primary intracellular antioxidants. Rat brains subjected to TBI showed a three-fold reduction in the reduced-to-oxidized glutathione ratio. Concomitant reductions in cerebral NAD+ promote mitochondrial dysfunction [32]. Reduced glutathione has been shown to impair astroglial glucose metabolism and glycogen utilization [40].
Hypoxia
Epidemiological studies reveal that up to 44% of severe TBI patients experience brain hypoxia that is a direct consequence of hypoperfusion. Proinflammatory cytokine upregulation induces BBB dysfunction via IL-6 and IL-1b and an overall significant hypoglycemia, with brain glucose levels dropping by 50% in injury-induced hypoxia [41].
Peripheral Metabolic Impacts on Injured Brain Fuel Status
Ives et al explored evidence of hypopituitarism following multiple concussions. Growth hormone was the most vulnerable to successive brain injury followed by gonadotropins, TSH and finally ACTH. Furthermore these hormonal imbalances may not be evident until well after the initiating injury [42]. Agha et al explored Glucagon Stimulation and Insulin Tolerance tests in a population of brain injured patients with a median interval of 7 months post-injury. Approximately 28% of patients exhibited at least one anterior pituitary hormone deficiency, 22% showed isolated deficiencies involving either GH, LH/FSH (follicle-stimulating hormone) or ACTH (adrenocorticotropic hormone) and 6% showed evidence of multiple deficiencies [43]. Both GH and ACTH exert significant influence over the action of both glucagon and insulin, and GH deficiency can impair glucose tolerance by decreasing beta cell mass and insulin production [44]. These conditions can have impacts on the injured brain primarily due to the brain’s reliance on peripherally derived insulin for glucose uptake.
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Post-Synaptic Contributions in TBI
TBI and Central Processing of Viscera Traumatic brain injury can lead to various mechanisms of gastrointestinal dysfunction. These mechanisms include: impairment of digestive enzyme production, impairment of intestinal motility, disruption intestinal autonomics related to circulation, promotion of intestinal permeability, and altered interoceptive processing. Disruption of the brain-gut axis involving the cortico-pontine circuit has been demonstrated with brain imaging studies as a central mechanism of irritable bowel syndrome [45]. Central integration of cortico-pontine circuit is critical for proper vagal temporal summation and autonomic regulation necessary for regulating proper intestinal afferent and efferent communication. Additionally, traumatic brain injury can lead to significant changes of brain-gut peptides in both plasma and small intestine, which may be involved in the pathogenesis of complicated gastrointestinal dysfunction [46]. These cortico-pontine and pontine-cortical central integrations may be altered in TBI. Cortical integration is critical for proper bowel function and bowel disorders associated with lack of cortical level integration of visceral inputs have been demonstrated with percept-related fMRI [47]. Therefore it appears that TBI may potentially lead to altered gastrointestinal function from loss of cortico-pontine central processing.
TBI and Intestinal Permeability One of the major consequences of TBI is lack of cortical activation of the pontine vagal system leading to altered postsynaptic autonomic changes that promote decreased intestinal autonomics and inflammatory reactions leading to intestinal permeability. Intestinal permeability induced from TBI may be a consequence of lack of post-syanaptic activation of the vagal nuclei. In a mouse model of TBI, vagal stimulation prevented TBI-induced intestinal permeability and also increased enteric glial activity [48]. This study supported the notion that the vagal nuclei disruption from TBI was the central mechanism for intestinal permeability development and that vagal activation has modulating activity on the enteric glia neuroinflammatory responses. Additionally, TBI can induce an increase in intestinal permeability, which may lead to bacterial translocation, sepsis, and system inflammation [49,50]. TBI induced intestinal permeability thus has the potential to promote a vicious inflammatory cascade involving the brain to gut axis and the gut to brain axis. Intestinal permeability has been found to increase proinflammatory cytokines at the intestinal mucosal level and cause lipopolysaccharide translocation that can disrupt brain function [51,52]. Therefore, the alteration of cortico-pontine integration from TBI can lead to gastrointestinal inflammatory consequences from intestinal permeability that then potentially further suppress brain function leading to chronic inflammatory vicious cycles between the brain and the gastrointestinal system. Traumatic brain injury can also lead to pro-inflammatory immune activation in the peripheral blood stream leading to systemic inflammatory response syndrome [53]
TBI and Intestinal Mucosa Compromise At the intestinal level many changes take place in the intestinal mucosa directly after brain injury including mucosal ischemia, mucosal atrophy, and activation of intestinal inflammatory cascades. These reactions occur rapidly as early as 3 hours following brain injury and last for more than 7 days with marked mucosal atrophy [54]. Additionally, TBI induces profound effects including gastrointestinal mucosa ischemia and motility dysfunction [55]. The inflammatory reactions that occur in the intestinal mucosa following traumatic brain injury appear to increase the expression of intestinal nuclear factor kappa B and intercellular adhesion molecule-1 in the intestine leading to acute gut mucosal injury following TBI [56,57]. There is also rapid and persistent up-regulation of myeloid differentiation primary response protein 88 (Myd88) in combination with systemic inflammatory cytokine activation [58]. These inflammatory changes that occur after TBI are immediate and
230 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. illustrate how cortical injury can lead to inflammatory consequences in the peripheral gastrointestinal mucosa lining.
TBI and Breakdown of the Blood-Brain Barrier The blood-brain barrier plays a critical role in protecting the brain from immune activating substances. However, widespread breakdown of the blood-brain barrier occurs immediately after brain trauma leading to susceptibility of circulating proteins and the promotion of inflammatory sequelae [59]. It appears the blood-brain barrier breakdown occurs rapidly within hours. TBI disruption of the blood-brain barrier occurs and cerebral vascular permeability can increase fourfold within six hours of the initiating trauma. It was also found that vagal nerve stimulation attenuated cerebral vascular permeability and decreased up-regulation of perivascular aquaporin 4 after TBI [60]. Therefore TBI loss of cortico-pontine dysregulation of the vagal nuclei appears to be a central mechanism for both intestinal and blood-brain permeability. Specifically TBI induces profound breakdown of the blood- brain and blood cerebrospinal fluid barriers (BCSFB) and release into the CSF a major chemoattractant for monocytes, CCL2, by the choroid plexus epithelium at the side of the BCSFB (blood cerebrospinal fluid barriers) leading to post-traumatic invasion of monocytes promoting the recruitment of inflammatory cells to the injured brain [61]. These inflammatory changes in the blood- brain barrier neurovascular network have been found to ultimately lead to delayed neuronal dysfunction and degeneration [62]. In summary, in TBI loss of cortico-pontine processing disrupts vagal network integration and inflammatory sequelea that promotes breakdown of the neurovascular blood-brain barrier network leading to loss of brain barrier protection and susceptibility to further neuroinflammation.
Joel Brock © copyright2013 TBI Dietary Plasticity Supplements Vestibular input Canals Nutritional Receptor based Diet Otoliths Concerns therapy
PMRF Neuron Autonomics MRF Glial Glial Cells Trigeminal Brain Immune interaction
Blood flow Control immune activation Transmitters Can prime or turn off
Reticular Transmitters PyramidalGlial Hypothalamic Fuel ParaventricularImmune Astrocytes Muscle tone Inflammation Cerebellum Delivery Left Right Mesencephalic Cytokines Microglial Posture Brain activation Efficiency Basal Ganglia Oligodendro
Proprioceptive Good and bad Transmitters Feedback Needs balance Brainstem output
Success Gait Innate Immune Response Inflammatory Parasympathetic Stability Astrocyte barrier Barriers Endocrine / Cortisol Non‐inflam Sympathetic balance Agility Resolution protection BDNF Biomechanics Adaptive Response Success Inflammation Vagal output Pathogen Not Pathogen Barrier breakdown Inadequate Excessive Killed. Tissue Killed. Tissue Non or inflammatory Inflamed. Inflamed. Vestibulospinal Cytokines Excitotoxic Organ Splenic cytokines Gut Glutamate↑ gaba↓ interaction Brain Stress Lung Tissue Becomes Neuroinflammation Tissue Becomes Cell growth Posture Antigen Neurodegeneration Antigen reactions Central integrated state Inflammatory respons Glial cells
Vestibulo Cell growth or death Vagal output Immune activation ocular Factors Influencing Neuroimmunological Outcomes... Biotransformation Regulation of Control of hormone Immune separation Neuron – Microglial Apoptosis vs. Necrosis Blood sugar output ROS / PON NMDA / Vagal control over Ocular function Cytokine Interactions Mit failure Death receptors LIver T Cell Polarization Death Caspase Dynamic connectivity Cytokines, Hormones, NT’s Loss of brain mass P450 Immune borders cascade ROS, RNS, Other Tissue Factors Organ output ↓Inflammation & ↓Pathogen Cytochrome Killing vs. Self / Alt‐Self / Pathogen Gain and sensitivity Caspase Toxin removal ↑Inflammation & ↑Pathogen Antigen Apoptosis Killing Glial health / NFKB or Biotransformation Adrenal‐ thyroid Protection of tissues Epigenetic changes Chemical sensitivity insulin
Spindle feedback Tissue Health / death Deafferentated Cellular health / death Energy failure Ability to be plastic / TND Glial Priming / Glial coding
Figure 6. Stepwise progression toward immune dysfunction in brain injury © Joel Brandon Brock 2013.
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TBI Dysautonomia Various autonomic imbalances may occur after brain injury impaired cortico-pontine integration called dysautonomia [63]. It is a common consequence of TBI and has been found in 8 to 33% of TBI individuals [64]. Dysautonomia after brain injury is characterized by episodes of increased heart rate, temperature, blood pressure, muscle tone, posturing, and profuse sweating [65]. A common presentation of dysautonomia is persistent sympathetic overactivity in response to nociceptive stimuli and development of chronic pain after TBI [66,67]. In addition to chronic pain, many individuals that suffer from TBI also demonstrate prolonged uncoupling of heart rate and heart rate variability postulated to occur from cortical-pontine disconnection [68]. These outcomes have also found to be worse with those that suffer from post-traumatic hypertonia and have been linked to poor long-term outcome [69]. It appears that TBI leads may lead to altered cortico-pontine integrations leading to various types of autonomic consequences such as chronic pain, hear rate variability, abnormal sweating, and various types of imbalanced sympathetic and parasympathetic responses.
TBI and Systemic Immune Dysregulation Immune system dysregulation may occur from traumatic brain injury, specifically TBI can lead to immunodeficiency and vulnerability to infections [70,71]. It appears brain injury leads to systemic immune responses from which chemokine signals from the central nervous system activate the production of hepatic immune responses and changes in systemic immunity [72]. TBI can alter immune homeostastis contributing to immunosuppression from decreased phagocytic functions of neutrophils and macrophages as well as monocyte deactivation resulting in decreased capacity of antigen presentation to lymphocytes [73]. These immune suppressive reactions may have long-term expressions. It was found that brain injury leads to immunodepression for months and to chronic central nervous system and systemic immune activation for years after the initial injury [74]. Animal lesion studies have been able to demonstrate the pre and post immunological changes that occur after brain injury. Animal induced lesion studies of the cerebellum with localized kainic acid microinjections resulted in reduction of lymphocyte percentage in peripheral white blood cells and an inhibition on the number and functions of T-cells, B-cells, and natural killer cells suggesting a role the cerebellum may play in neuroimmunomodulation [75,76]. These immune compromise changes secondary to brain lesions were also evaluated with kainate lesions of the vestibulocerebellum. The chemical lesion induced depressed secretion of hematopoietic cytokines in tissue cultures of bone marrow and thymus [77]. It appears that the brain and immune system are intimately connected and neuroimmunomodulation may be impaired after TBI leading to immunological compromise and susceptibility to infection.
The Blood-Brain Barrier
Blood–Brain Barrier Role in TBI The term “leaky brain” is the jargon used to describe the increased permeability across the astrocytes that make up the blood-brain barrier. This is described as the increased passage of molecules through pericellular and transcellular permeability [78]. Shrinkage of endothelial cells causes a mechanical disarray of the tight junctional complex. This is due to drastic yet reversible changes in cell morphology leading to spatial reorganization of the junctions [78]. Brain infiltration of cells, ions, or molecules may initiate, amplify, procrastinate, repair or disrupt a CNS response [78]. It is also well understood that a fundamental principle of a mTBI is a breach in the BBB. The severity or ability to recover from a TBI may be intimately related to the pre-existing state or the severity of the breach of the BBB. Glial cell types are all capable of producing typical
232 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. proinflammatory molecules [78]. Inflammatory cytokines have been implicated as modulators of BBB function [79]. TBI induced breaches in the BBB cause an extravasation or movement of albumin from the capillaries to the surrounding tissue in brain, changing the ion channels. This may be an independent activator of astrocytes and result in long-term neocortical abnormalities and functional decline [80]. The brain has a highly specialized glioneuronal system to buffer extracellular potassium [81]. Increased levels of potassium will cause massive reduction in blood flow. This reduction will shift the brain toward hypoxia and loss of metabolic support.
Figure 7. Cellular and barrier changes from TBI © Joel Brandon Brock 2013.
Glutamate is more concentrated in the blood. A breach in the BBB will lead to increased glutamate in brain causing an excitotoxic response and an increase in firing. Adenosine helps to maintain neurovascular control. When the BBB is breached, a complex synergy of adenosine and glutamate transporters and catalytic enzymes is altered, leading to an overall drop in adenosine availability to curb neuronal firing and increased glutamate [78]. In these examples it is reasonable to understand how a breach in the BBB, from multiple mechanisms, can lead to chronic states of neuronal compromise and predispose the brain to TBI and inhibit the recovery of a TBI. Vagal nerve stimulation attenuates the effects of TBI by protecting hippocampal neurons. Vagal nerve stimulation also attenuates the breakdown of the BBB post TBI. The attenuation of the BBB breakdown may be the mechanism of hippocampal protection [60]. This mechanism may be further described as vagal nerve stimulation induction of the cholinergic anti-inflammatory pathway, effectively inhibiting pro-inflammatory cytokines. This has been partially confirmed by vagal nerve stimulation decreasing systemic tumor necrosis factor alpha hours after TBI [82]. Some disagree and state it is due to a more localized central nervous system-specific effects of vagal nerve stimulation [83]. What is agreed on is the fact that vagal nerve stimulation attenuates post TBI BBB breakdown [82]. Not only is this a potential therapy, but also further implicates the importance of BBB integrity as an independent risk factor with regard to TBI. In adult brains, oligodendrocyte precursor cells (OPCs) are thought to maintain homeostasis and mediate long term repair in white matter after disease [79]. The activation of OPCs is supposed to represent a protective response in the damaged or diseased brain. Recently, however, reactive glia are now recognized to mediate complex mechanisms, including both beneficial and deleterious effects after brain injury and neurodegeneration [84,85]. For example, depending on context, astrocytes can either promote neuroplasticity or secrete inhibitory matrix molecules that inhibit axons [86,87]. Similarly, microglia are now known to release both pro-recovery and neurotoxic factors [88,89,90].
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OPCs can also release multiple factors to modulate neighboring cells and the microenvironment [91] These intercellular signals may be especially important, since perturbations in the blood-brain barrier (BBB) are known to be a critical part of white matter pathology in a wide range of CNS disorders [92,93]. OPCs in adult brain are precursor cells for white matter remodeling, and repair injury and demyelination. They can play a surprisingly deleterious role in cerebrovascular injury and demyelination in white matter [79]. With TBI or other mechanisms causing inflammatory changes in brain, even before demyelination occurs, BBB leakage and neutrophil infiltration can be observed [79]. MMP2 (matrix metalloproteinase-2) and -9, are known to mediate BBB injury [94,95]. In studies after an initiating trauma or event causing a BBB breach, the early phase of BBB leakage at 3 days, white matter MMP9 expression is increased, mostly in OPCs and at 7 or 14 days, a secondary expression of MMP9 occurs in cerebral endothelial cells [79]. No other glial cell types (mature oligodendrocytes, astrocytes, microglia) appear to produce MMP9 in the model of cerebral hypoperfusion and chronic hypoxic stress [82]. No significant MMP9 increases occur in blood neutrophils nor plasma at day 3. Importantly, MMP9 expressing OPCs were located close to cerebral endothelial cells and OPCs existed near the BBB leakage areas at the acute phase of white matter injury [79]. After brain injury and disease, progenitor/precursor cells in the adult brain are believed to help compensate for lost brain function [96,97]. OPCs can be triggered to become mature oligodendrocytes or cortical projection neurons after white matter injury [98]. OPCs can rapidly respond to white matter injury and produce MMP9 that appears to open the BBB and trigger secondary cascades of cerebrovascular injury and demyelination [79]. This could serve as a model to explain a more severe consequence of a “seemingly” mild injury/event causing severe effects on brain function. Inhibition of the early MMP9 phase in OPCs also prevented the secondary expression of MMP9 in cerebral endothelium on day 7 and subsequently the development of white matter injury and demyelination as well as cognitive deficits in cerebral hypoperfusion. OPC-derived MMP9 in the acute phase may trigger further secondary cascades of cerebrovascular damage in white matter [79].
Figure 8. Oligodendrocyte cascade [79].
OPCs do not produce MMP9 under normal conditions, but after treatment with nonlethal levels of the inflammatory cytokine IL-1beta (similar to that in a TBI), MMP9 secretion is markedly increased. IL-1beta–treated OPCs degrade the tight-junction protein ZO-1 in cerebral endothelial cells without affecting cell survival. Consistent with this effect on tight junctions, conditioned medium from IL- 1beta–stimulated OPCs significantly increased endothelial permeability and neutrophil transmigration [79]. This effect is dependent on MMP. This suggests that stimulated OPCs (potentially from TBI) release MMP9, which degrades the BBB in white matter. This represents a mechanism for white
234 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. matter disease at an early stage, and creates further damage and downstream inflammation and demyelination. The state of the BBB both prior to and immediately after injury plays a major role in the probability of, the severity, and the long-term consequences a TBI.
TBI and Its Effect on the Adrenals and Hormones Deficiencies in circulating hormones may not be apparent immediately after injury but can be demonstrated days to weeks thereafter. Aimaretti et al. reported an incidence of pituitary dysfunction in 33% of TBI patients 3 months after injury, complete panhypopituitarism in 5.7%, multiple defects in another 5.7% and a single hormone deficit in 21%. Secondary hypoadrenalism was found in 8.5% but considering those with panhypopituitarism or multiple hormone abnormalities that might include the adrenal hormones, this incidence may be as high as 20% [99]. In a prospective comparison of 80 TBI patients to 41 trauma patients without TBI, measuring cortisol and ACTH levels twice daily for 9 days after injury, adrenal failure, which was defined as two consecutive cortisols of ≤ 15µg/dL or one cortisol of ≤ 5µg/dL, occurred in 53% of the TBI patients at a mean time of 2.4 days and suggested a secondary cause. Patients with adrenal failure were more severely injured, demonstrated more episodes of hypotension and more often required vasoactive drug support [100]. From such data, it would appear that the risk of secondary hypoadrenalism after TBI is somewhat higher than 25%. Recently published guidelines recommend acute endocrine evaluation only for patients with documented fractures in the sella turcica or diabetes insipidus. Other authors, however, suggest early endocrine assessment for all patients with moderate-to-severe TBI and routine endocrine testing for all TBI patients at 3 and 12 months. It is also suggested that evaluation be performed for primary and secondary adrenal failure in patients that demonstrate continuing hyponatremia or hypoglycemia or require persistent vasoactive drug treatment during acute care [99]. Endocrine evaluation should include a baseline blood cortisol concentration, a serum ACTH measurement and thyroid studies before the administration of any preparation containing steroids. Although some authors recommend a morning cortisol blood test, stress decreases the normal diurnal variation in cortisol release, making random values acceptable. In both primary and secondary adrenal failure this measurement should be low. The actual concentration that defines a low value is somewhat controversial because of the expected increase in cortisol during ‘stress’ caused by TBI. Therefore, values between 200 and 700 nmol/l or over 15mgm/dl are suggested as minimal basal concentrations expected after trauma [100]. HPA (hypothalamic-pituitary-adrenal) injury may also produce underproduction of thyroid stimulating hormone (TSH) as ‘central’ hypothyroidism, indicated by low TSH and tetraiodothyronine (T4) blood concentrations. The ‘euthyroid sick syndrome’ is expected in such critically injured patients, but in that condition the TSH remains normal. Growth hormone and the several gonadal hormones produced by the pituitary gland may also be low but do not require acute replacement, although treatment during later recovery will be important [100]. Utilization of the traditional ‘high-dose’ (250 mg) versus ‘low-dose’ (1 mg) ACTH stimulation test remains controversial. The higher pharmacological amount may allow a partially dysfunctional gland to release a sufficient amount of hormone to appear falsely normal, while the lower dose is perhaps more difficult to accurately administer. Similarly, criteria regarding the magnitude of response that confirms a responsive adrenal gland have been controversial. Criteria include either a specific post-stimulation (usually 60 min) cortisol concentration (e.g., above 500 nmol/l, or 25 mg/dl) or a specified incremental increase from basal levels (e.g., >250 nmol/l or >9 mg/dl). Bernard et al. found 78% of their TBI patients had a basal cortisol value of under 414 nmol/l, but after a 250 mg ACTH stimulation, only 13% failed to increase the serum cortisol concentration by less than 250 nmol/l [101]. These data again emphasize that the diagnosis of hypoadrenalism often depends upon the criteria selected [100].
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Cortisol is measured in the blood as both an unbound (‘free’) form, which is the biologically active hormone, and as cortisol bound with cortisol-binding globulin (CBG). CBG is commonly low in critical illness/injury, especially when the serum albumin is less than 2.5 gm/dl and may be one cause of an apparent low cortisol serum concentration. Measurement of free-cortisol, therefore, has been suggested as the more accurate assessment of adrenal output. Testing methods for CBG and free cortisol, however, are rarely available [99]. Acute hypoadrenalism after TBI may contribute to hypotension, hyponatremia or hypoglycemia during patient care. Its incidence remains unclear due to variable definitions and testing methods, but appears to be approximately 25%, including both secondary causes related to injury to the central hypothalamic-pituitary axis and primary adrenal failure. We recommend serum testing of basal cortisol, ACTH, and post-ACTH stimulation cortisol at 60 min when hypoadrenalism is suspected. Basal cortisol below 15 mg/dl suggests either primary or secondary adrenal failure and may warrant treatment. Failure of the cortisol concentration to increase by at least 9 mg/dl after stimulation suggests primary adrenal gland hypoadrenalism. Treatment with intravenous hydrocortisone during acute care should be initiated if clinical circumstances warrant. Thyroid function should also be evaluated and, if needed, hormone replacement should be provided if adrenal insufficiency is treated. It is generally recommended that even if acute treatment is not given, all patients should be evaluated for adrenal, thyroid and growth hormone deficiency 3 months after severe TBI [99]. It has been previously reported that experimental mild traumatic brain injury results in increased sensitivity to stressful events during the first post-injury weeks, as determined by analyzing the hypothalamic-pituitary-adrenal (HPA) axis regulation following restraint-induced stress. This is the same time period when rehabilitative exercise has proven to be ineffective after a mild fluid- percussion injury (FPI) [100]. These findings suggest that the increased sensitivity to stressful events during the first post-injury weeks, after a mild FPI, has an impact on hippocampal neuroplasticity [100]. An earlier paper described an increased sensitivity to restraint-induced stress during the first two post-injury weeks as indicated by increases in corticosterone (CORT) and ACTH compared to uninjured rats [100]. The stress response involves the activation of the HPA axis resulting in the release of ACTH from pituitary cells. ACTH stimulates the adrenal gland to release glucocorticoids, such as CORT, which in turn results in the inhibition of ACTH secretion [102]. It has been well characterized that stress decreases neuronal plasticity and favors neurodegeneration [103]. The effects of stress on the central nervous system are most notable within the hippocampus where it substantially influences neuronal excitability and long-term potentiation (LTP). The hippocampus has a high density of glucocorticoid receptors [104]. These receptors exert a variety of effects besides the autoregulation of the stress response, such as influencing mood, learning and memory [105]. Moreover, stress-related increases in glucocorticoids have been associated with cell death and cognitive impairments [106]. Among the effects of stress is the inhibition of hippocampal brain-derived neurotrophic factor (BDNF) [107]. The anatomical and vascular characteristics of the hypothalamic-pituitary complex increase its vulnerability during TBI. Particularly, diffuse TBI, where metabolism and neural connectivity are compromised [108]. Given the above-mentioned effects of glucocorticoids on hippocampal synaptic plasticity and BDNF expression, it is feasible that impaired neuroendocrine function interferes with BDNF- mediated restorative processes after TBI. For example, a hyper-response to stress following TBI may play a role in the inability to increase BDNF during the subacute period, as seen in rats with a mild injury [109]. Affective disorders and cognitive impairments after TBI play a substantial part in decreasing quality of life. A dysregulation of the stress response has been linked to affective disorders in TBI patients. In effect, alterations in the regulation of the HPA axis contribute to negative mood states
236 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. associated with depression [110]. In addition to showing a hyper-responsiveness to stress after TBI, we now provide evidence that post-injury stress has an effect on BDNF regulation within the hippocampus. The effects of stress on cognitive abilities also need to be considered, particularly given BDNF’s effects on plasticity. An increase in glucocorticoids, in human subjects, is associated with impaired memory and hippocampal deterioration [111]. These data add some pieces to the puzzle in understanding the hyper-response and the delay of exercise-induced increases in BDNF during the subacute period. However, they also emphasize the need for more studies regarding HPA dysregulation after a mild TBI. Understanding some of the molecular mechanisms influencing the response to stress will allow us to better address posttraumatic affective and behavioral disorders as well as enhancing rehabilitative therapies. There were 113 charts that were retrospectively reviewed of traumatic brain injury patients within 10 days of their injury. They all had a high-dose corticotropin stimulation test performed because of haemodynamic instability. Blood cortisol concentrations were measured at baseline, 30 and 60 minutes after the administration of high-dose corticotropin. The incidence of adrenal insufficiency was determined according to various definitions used in the literature [101]. Primary adrenal insufficiency defined by an abnormal baseline cortisol concentration and an abnormal response to the high-dose corticotropin stimulation test was present in 13–28% of patients according to the cut-off values used. The incidence of adrenal insufficiency varies from 25 to 100% in the first 10 days after traumatic brain injury when the charts of 113 traumatic brain injury patients were reviewed [101]. Adrenal insufficiency has emerged in recent years to be a crucial and prevalent problem in intensive care. Hypopituitarism has recently been reported to occur in 35–80% of patients in rehabilitation following head injury. Adrenal insufficiency accounts for 30–50% of these cases [101]. Underestimation of the true incidence of adrenal insufficiency and potentially under-treated patients may be occurring by using only the low-dose stimulation test to define adrenal insufficiency [101]. A concentration of 414 nmol/l is considered to be the normal minimum value in response to severe stress, particularly hypotension. Hence, it is viewed as the minimal appropriate concentration for intensive care patients. A concentration below 690 nmol/l has been suggested instead since patients undergoing surgery or sustaining trauma almost invariably have cortisol concentrations above this value. The intensive care literature tends to support this view. Response to high-dose corticotropin stimulation test, in a study by Annane and colleagues, suggested a rise in plasma cortisol concentration by >250 nmol/l was the appropriate response of the adrenal glands in intensive care patients with sepsis [112]. This definition is probably the most widely used cut-off to interpret a stimulation test in intensive care. Classically, a rise above 500 or 550 nmol/l is considered normal based on the response of non-critically ill patients to insulin-induced hypoglycaemia [101]. Primary adrenal insufficiency defined by an abnormal baseline and abnormal post high-dose corticotropin stimulation test cortisol concentration was present in 13–28% of patients depending on whether a 60 or 30 min sampling time after high-dose corticotropin was used, respectively. Whichever definition was used, the incidence of primary adrenal insufficiency is markedly reduced if the 60 min (rather than the 30 min) cortisol values were used to define adrenal insufficiency [101].This study showed that the incidence of adrenal insufficiency in severe traumatic brain injury varies enormously depending on the definition used. The incidence of adrenal insufficiency defined by baseline cortisol concentrations may be as high as 100%. Primary adrenal insufficiency accounts for 13–25% of the cases. It also demonstrated that sampling for cortisol at 60 min after a high-dose corticotropin stimulation test is more appropriate than doing so at 30 min. 414 mmol/l is probably a more useful cut off in a traumatic brain injury population [103]. Although fatigue is a common experience in the general population it is particularly bothersome to those with TBI [113]. Depending on the scales used to measure fatigue and time since injury, its
The Potential Impact of Various Physiological Mechanisms … 237 prevalence has been reported in 16–80% of individuals after injury. Associated symptoms include depression, sleep disturbance, pain, cognitive and motor disturbances [113]. Neuroendocrine abnormalities as manifested by pituitary dysfunction can occur after TBI. One- to-several hypothalamic-pituitary axes may be affected; posterior pituitary dysfunction typically resolves during the first several months post-injury, whereas anterior pituitary problems are more likely to persist [113]. Although several lines of evidence indicate that TBI may predispose the pituitary to injury, neuroendocrine dysfunction is rarely considered in current TBI management. Autopsy studies of fatal head-injury victims confirm that up to one third sustain anterior pituitary gland necrosis. Moreover, numerous case reports, retrospective reviews, and recent prospective cohort studies have documented acute and chronic posttraumatic hypopituitarism [100]. Activation of the HPA axis is an important protective response during critical illness. Untreated adrenal insufficiency (AI) may lead to hemodynamic instability and poor outcome. [100] The molecular mechanism of the effects of glucocorticoids on chronic inflammation is not well understood, but there is increasing evidence that they inhibit the action of transcription factors such as AP-1 and NF-kappaB [114]. Glucocorticoids are potent inhibitors of the activation of NF-kappaB, which may account for most of their anti-inflammatory actions [115]. Glucocorticoids are effective inhibitors of NF-kappaB, but they have endocrine and metabolic side effects when given systemically [115]. Activation of NF-kappaB, for example by cytokines, is blocked by glucocorticoids. Glucocorticoid-receptor complexes bind to the p65 subunit of NF-kappaB, and this prevents NF- kappaB activation of the inflammatory genes. Synthesis of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBα) is stimulated by the binding of glucocorticoid- glucocorticoid-receptor complexes to a glucocorticoid response element in the promoter region of the IkBα gene [115]. It may be unwise to block the activation of NF-kappaB for prolonged periods, because the factor plays such a critical part in the immune response and other defensive responses [115]. Part I revealed a wide range and number of cellular and tissue/hormone processes that can be measured and manipulated. Part II describes clinical level measures and interventions.
PART II: CLINICAL CONSEQUENCES AFFECTING SPECIFIC BRAIN SYSTEMS
Neuroanatomical Considerations
Evidence of anatomical brain damage has long been a hallmark in diagnosis of brain injury. For the chronic post-concussion patient this has historically been elusive. Researchers consider concussion to be the result of mechanical trauma to the head or neck that leads to functional impairment without overt structural damage [115]. This results in no gross changes or brain abnormalities seen on imaging [116,117]. A traumatic head injury mechanism combined with a lack of positive findings on imaging is the primary diagnostic scenario. This, the symptom checklists, the opinion of a physician familiar with the patient and ongoing observation by family, coaches or the patient themselves, are standard diagnostic tools. These are commonly used strategies in identifying the presence of concussion and are relied upon for clinical, return to activity and legal purposes in most settings [118,119,120,121]. Current neuroscience has reached a point where evidence of the neuroanatomical consequences of concussion can be identified. The initiating structural damage appears to result from stretching and
238 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. disruption of neuronal, glial and axonal cell membranes; while cell bodies and myelin sheaths are less affected [122,123]. These injuries are microscopic, involving cellular structures, as well as microvasculature and the blood-brain barrier. Although techniques to identify microscopic structural damage are not readily available to clinicians, the pursuit of this information is clinically relevant. Investigators looking at extent of tissue damage using advance imaging techniques have been able to use the data in predicting individuals who will likely have an uncomplicated recovery from concussion versus those who progress to chronic post-concussion syndrome [124] Postmortem studies of individuals who survived concussion and later died due to apparently unrelated circumstances have provided early evidence of microscopic brain damage in concussion. These types of studies, performed as early as the 1950’s and 1960’s, continue to provide evidence of damage post-concussion. Historically, the overall impression has been that post-concussion brain damage occurs diffusely in the white matter [155,126] More recently diffusion tensor imaging, tractography, perfusion studies and functional neuroimaging have been utilized in identifying areas of damage in individuals with mild traumatic brain injury. These advanced neuroimaging techniques support the notion of axonal and vascular lesions [128,129,130, 131]. Additionally, a mouse model of concussion has provided evidence that degeneration in the gray matter, involving extensive dendrite degeneration and synapse reduction with very minimal cell death, may be a major neuropathological feature in mTBI [132]. Chronic head injury at the concussive or subconcussive level has been associated with morphological change in the brain that is similar to those seen in Alzheimer’s disease and other neurodegenerative disorders. Cortical degeneration with neurofibrillary tangles, neurite heads, neuronal dropout and accumulation of Tau and transactive response DNA-binding protein 43 (TDP-34) proteins are found the human brain chronically after repetitive concussion and subconcussion trauma [133,134,135,136]
Figure 9. Neuroanatomical damage at the cellular level © Joel Brandon Brock 2013.
Work has been done to identify which regions of the brain are most often affected in concussion. In severe and moderate brain injury the location of damage is fairly consistent with proximity to mechanical trauma, contrecoup deformation, areas of the brain in contact with more rigid structures and those displaced by swelling [137,138]. For the chronic post-concussion patient there is less predictability in the specific region of damage. Medial frontal, dorsolateral frontal, occipital, subcortical and corpus callosum have all been reported as damaged in this population [113,
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139,140,141] In a subset of chronic post-concussion patients with depression, the frontal and temporal white matter have been identified as injured [142]. Corticocerebellar circuitry disruption has been found as well [115,124,143] Structural involvement of the thalamus was inferred using graph theory analysis and proposed as a useful marker in identifying mTBI [144]. Sheering stresses around the brainstem have been investigated by recreating a series of recorded head to head collisions in football and analyzing the threshold of force that may be necessary to produce a lasting concussion syndrome [145]. Additionally, the tissue stressor from concussive trauma has been associated with vascular damage to both the small vessels and integrity of the blood-brain barrier [146,147] The immediate trauma associated concussion results in a host of other changes at the cellular and molecular levels. They include involvement of the immune and endocrine systems. They affect the metabolism and biochemistry of the brain, as well as distant sites in the body [148,149]. There is very strong and growing evidence that both the immediate and ongoing “non-anatomical” consequences are associated with the vast majority of the difficulties faced by the post-concussion patient [150,151,152].
Visual and Vestibular Dysfunction in the mTBI Patient Beyond neurocognitive testing, many additional methodologies have been evaluated to assess the consequences and natural history of mTBI. These forms of functional analysis offer new windows for the clinician to assess the severity of mTBI and monitor response to treatment and level of recovery. Further, they imply promising new avenues of treatment for the mTBI patient.
Vestibular dysfunction in mTBI Vestibular impairment is a common consequence of mTBI. As many as 65% of mTBI pateints will experience some form of vestibular dysfunction during their recovery [153]. Vestibular lesions have been shown to directly produce central inflammatory changes. Unilateral vestibular deafferentation has been demonstrated to result in significant microglial and astroglial activation in the vestibular nuclei [154]. Rat models of vestibular lesion via arsanilate transtympanic injection manifest significant central vestibular inflammatory changes. Elevations in the number of tumor necrosis factor alpha immunoreactive (TNF-alpha-Ir) cells in the bilateral medial and inferior vestibular nuclei can be seen as early as 4 hours after vestibular lesion, with NF-kappaB upregulation following 8 hours after the lesion, and manganese superoxide dismutase (MnSOD) elevation after 24 hours. Similar changes have been demonstrated in rat models of mechanical unilateral vestibular deafferentation [140]. As a consequence, thorough evaluation and management of vestibular dysfunction in mTBI patients may show promise as a means of limiting central inflammatory processes. Benign paroxysmal positional vertigo is the most common form of posttraumatic vertigo [139]. As this is a relatively straightforward condition to evaluate via Dix-Hallpike testing, and manage with canalith repositioning maneuvers, Dix-Hallpike testing should be employed in all mTBI patients with vestibular complaints [139]. Sherer et al. evaluated blast-induced mTBI patients reporting persistent dizziness via videonystagmography (VNG), rotational chair, cervical vestibular-evoked myogenic potentials, computerized dynamic posturography, and self-report measures [155]. Evidence of central and peripheral vestibular dysfunction was identified at a higher frequency in symptomatic patients. Abnormal nystagmus or oculomotor findings were present in 50% of symptomatic subjects. Rotational chair testing found evidence of peripheral vestibulopathy in 25% of symptomatic patients, and central vestibular pathology in 17% of symptomatic subjects [141]. Computerized dynamic posturography (CDP) has been proposed as a means to monitor the status of vestibular function. CDP testing assesses the patient’s ability to maintain postural stability against a standardized series of balance and postural challenges. Approximate entropy (ApEn), a measurement of how likely a postural correction is to recur within a time series, is thought to decrease with mTBI
240 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al.
[156]. A person swaying in a predictable manner represents a lowered capacity to adapt to subtle changes in environmental stability, and thus lower postural control dynamics. ApEn has been shown to decrease with mTBI, and shifts in stabilization strategies toward greater anterior-posterior and decreased medial-lateral control [142]. This raises the likelihood that concussed patients have a chronic risk of falls without appropriate neurorehabilitation. Treven et al. demonstrated the utility of CDP to assess and quantify balance deficits in ambulatory mTBI. They revealed that standardized functional measures utilized for determining release from acute mTBI rehabilitation settings do not consistently and specifically assess balance. Many patients that have reached discharge level from acute rehab setting maintain a high degree of balance deficit [157]. This persistent instability raises the risk of reinjury and further trauma. Assessment of vestibular dysfunction has been effectively demonstrated through the use of vestibular-visual-cognitive interaction tasks [158]. Changes in static visual acuity, perception time, target acquisition, target following (TF), dynamic visual acuity (DVA), and gaze stabilization have been demonstrated in blast-induced mTBI patients. Rehabilitation procedures involving the vestibulo- ocular reflex, cervico-ocular reflex, and depth perception, as well as somatosensory balance exercises, dynamic gait, and aerobic function exercises have been employed to effectively manage these systems [144]. Vestibular rehabilitation therapy (VRT) has been shown to be helpful for patients with persistent dizziness and balance dysfunction for whom gait and balance dysfunction did not resolve with rest alone [159]. Subjective dizziness and objective measures of gait and balance have shown to be improved after protocols of rehabilitation involving gaze stabilization exercises, standing and dynamic balance exercises, and canalith repositioning maneuvers where indicated [145]. Similarly, target following and dynamic visual acuity scores returned to normative levels after an 8-week vestibular physical therapy protocol. Gaze stabilization similarly improved after 8 weeks of VRT [144].
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Figure 10. mTBI progression to visual and vestibular dysfunction © Joel Brandon Brock 2013.
Visual Dysfunction in mTBI Visual dysfunction has been shown to be extremely prevalent in the mTBI population. Ciuffreda et al. assessed for frequency of occurrence of oculomotor dysfunction in TBI, considering accommodation, version, vergence, strabismus, and cranial nerve palsy. They found that oculomotor dysfunction is the norm in TBI [160]. Convergence insufficiency (CI) has been shown to be present in roughly 9% of the visually symptomatic TBI population without simultaneous vestibular dysfunction, saccade or pursuit dysfunction, cranial nerve palsies, visual field deficits, visuospatial neglect, or nystagmus. In many cases it appears that CI may occur in the absence of obvious dysfunction in visual and vestibular systems, rendering a thorough evaluation even more necessary [161]. The neural substrates of eye movements involve diffuse networks including the frontal lobes, parietal lobes, and cerebellar cortices. These systems also serve within networks that facilitate executive functions and higher cognitive experience. Impairments of eye movements have thus been demonstrated to have considerable clinical utility in both diagnosing and rehabilitating the mTBI patient. TBI patients demonstrate aberrancies in predictive components of smooth pursuit eye movements [162]. These deficits in average target prediction, eye position error, and eye position variability positively correlated with executive function and attentional measures on the California Verbal Learning test (CVLT-II), without apparent reduction in IQ noted on the Weschler Abbreviated Scale of Intelligence (WASI). Impairment of predictive smooth pursuit eye movements thus may be a sensitive indicator of impaired attention processing. Smooth pursuit movements coupled with target blanking, wherein the target being pursued is intermittently obscured, necessitates the generation of greater predictive eye movements [163]. This process requires greater reliance on brain regions involved in cognitive processing. Deficits in CVLT- II performance have been shown to more positively correlate with oculomotor variability during target blanking than during target tracking [163]. Maruta et al. demonstrated the presence of diffuse axonal injury (DAI) within the frontal lobes in mTBI via diffusion tensor imaging. Fractional Anisotropy indicates frequent involvement of the anterior corona radiata, the uncinate fasciculus, the genu of the corpus callosum, and the cingulum bundle. They compared various measures of eye movement performance to fractional anisotropy (FA) and diffusion tensor imaging (DTI), as well as to neurocognitive tests. Variability of gaze position errors during predictive smooth pursuit proved to be a sensitive measure that correlated with neurocognitive testing data and DTI findings. The degree of variability correlated with the mTBI spectrum severity [164]. They determined that performance variability during predictive visual tracking is a valid and useful indicator of damage to frontal white matter tracts, and is similarly indicative of impaired cognitive function [164]. Similar correlations have been shown between dysfunction in saccade eye movements and measures of neurocognition. Mulhall indicated that bedside tests of saccades utilizing infrared oculography (IRO) produced saccadic impairment data that positively correlated with impairments on neurocognitive tests [165]. Recovering TBI patients were shown to have decreased rates of self-paced saccades, impaired ability to suppress inappropriate saccades in single memory-guided and antisaccade tests, prolonged saccadic latencies, and hypometric saccades in visually guided reflex saccade tests. This implies that IRO testing should be part of any mTBI management protocol [165]. Increased duration of reflexive saccade latencies has also been shown to be present in mTBI [166]. Portable saccadometry has been utilized to evaluate boxers pre- and post-bouts. Latency distributions have been shown to be significantly altered after blows to the head, with these effects
242 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. reversible over a short period of time. Latency requires cortical decision mechanisms, and is directly affected by processes that affect cerebral function [166]. Drew et al. investigated the relationship between dysfunctional visuospatial orientation processes and difficulty with orienting attention. Saccadic targets were presented with varying temporal gaps and reaction times were assessed. They found that mTBI patients demonstrated significantly longer saccadic reaction times than controls when the time gap between saccades was short, but not when the temporal gap was long. Shifts in attention require disengagement from the point of fixation, both cognitively and visually. This process appears impaired in mTBI [167]. Heitger found that eye movement function was impaired in post-concussion syndrome, with eye movement deficits found on measures relating to motor functions executed under both conscious and semi-conscious control, as well as on several eye movement functions that are beyond conscious control and indicative of sub-cortical brain function [168]. They demonstrated specific deficits in antisaccade performance, a task that in non-mTBI individuals that requires attentional focus, inhibitory control, working memory, and the ability to generate voluntary goal-directed behavior [169]. They recommended that eye movement testing be utilized with post-concussion syndrome patients to evaluate for incomplete recovery of function [169]. Given the interaction between visual and vestibular function within the maintenance of balance and gait, it is perhaps unsurprising that TBI patients demonstrate abnormal caloric irrigation and optokinetic circularvection testing, as well as lower anterior and posterior and higher medial and lateral center of mass displacements and velocities during gait assessment [170]. Rehabilitation of eye movement dysfunction has been shown to be effective in mTBI patients. Ciuffreda et al. demonstrated a 90% rate of improvement from oculomotor rehabilitation, with reduction in both symptoms and objective findings that persisted at a 2- to 3-month follow-up, demonstrating both the efficacy of optometric rehabilitation and significant neural plasticity in mTBI patients [171]. Novel forms of rehabilitation have been shown to have efficacy in treating the visual and vestibular dysfunction, and may hold promise in the treatment of those same dysfunctions in mTBI patients. Optokinetic stimulation has been shown to activate areas often involved in mTBI, including the prefrontal cortex/frontal eye fields, areas involved in generation of saccades, and modulation of the parieto-insular vestibular cortex, an area involved in visual-vestibular interaction [172]. Repetitive optokinetic stimulation has been shown to be useful for rehabilitation of vestibular deficits and in causing adaptive changes in locomotion in healthy subjects [173,174,175]. Optokinetic stimulation has shown efficacy restoration of mobility in acute stroke patients [176,177]. Vagal nerve stimulation has been shown to be effective in limiting the vasogenic edema that develops secondary to the disruption of the blood-brain barrier in TBI, thus limiting central inflammation and neuronal damage [60,178]. Within a virtual reality environment, combinations of optokinetic stimulation and habituation, visual and physical perturbations, and postural stability exercises have been shown to decrease visual and physical motion intolerance and impairment in static balance [179]. Further research is needed with respect to these interventions. Given the interaction between the visual and vestibular systems, the frequency of impairment noted in these systems, and their potential influence on central inflammatory processes, thorough and sensitive evaluation of these systems is a prerequisite for effective management of mTBI.
Neuropsychological Effects: Multi-Systems Approach to Persistent Post-Concussion Syndrome (PPCS) Neurocognitive effects of concussion/TBI are unpredictable. Research to date has given us a wealth of information concerning the mechanism of injury, acute pathophysiology, chronic pathophysiology, imaging, neuro-immune and HPA axis contribution. With all of this information there are still few tools available for clinicians to diagnose the extent of cognitive impact and even
The Potential Impact of Various Physiological Mechanisms … 243 fewer tools available for prognosis and treatment. Why is it that some who have suffered more severe TBI have complete resolution of cognitive symptoms but those with a relatively mild history of injury have such great difficulty with executive function, attention, anxiety, pain, fatigue, and depression? This leaves clinicians with little choice but to react to symptoms as they occur, thus allowing the potential harm of unrecognized, undiagnosed chronic pathophysiology and dysfunction to fester. The treatment for persistent post-concussion syndrome (PPCS) due to mTBI does not address the cause, and mostly consists of rest and cognitive behavioral therapy with limited results for those suffering from PPCS [180]. Medications to treat concomitant depression, attention deficit and anxiety are often prescribed. There are two current sets of research criteria for the post-concussive disorder: the International Classification of Diseases, 10th Edition (ICD-10), and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). According to the DSM-IV the individual with post- concussion syndrome will have trouble paying attention, concentrating, changing focus from one activity to another, performing more than one mental activity at the same time, remembering information, and learning new information. Three or more of the following symptoms occur after the trauma and last at least 3 months: fatigue; insomnia; headache; vertigo or dizziness; anger that occurs without a good reason; anxiety, depression, or mood swings; and personality changes such as inappropriate behavior, apathy, or lack of spontaneity. The impairment represents a significant decline from pre-trauma functioning and causes significant difficulty with school or workplace performance. According to the ICD-10, a person must have a history of “head trauma with loss of consciousness” preceding the onset of symptoms by a period of up to 4 weeks and at least three of six symptom categories. These include:
Headaches, dizziness, general malaise, excessive fatigue, or noise intolerance. Irritability, emotional lability, depression, or anxiety. Subjective complaints of concentration or memory difficulty. Insomnia. Reduced tolerance to alcohol. Preoccupation with these symptoms and fear of permanent brain damage.
The ICD-10 criteria do not require “objective” evidence of cognitive problems. Both models attempt to clearly state the symptoms and parameters for diagnosis, however they do not offer much of a direction for understanding pathophysiology once the diagnosis has been made. A clear understanding of the pathophysiology as it relates to multiple systems and circuits will guide research toward better models of prognosis, care and prevention. Complete or nearly complete recovery from concussion occurs in a timely manner in the majority of individuals, however there is a minority of those who have symptoms that persist for months to years [181]. The research is not clear as to how to predict who will be more likely to experience chronic symptoms. Bigler et al. described PPCS as it is related to structural damage to specific predictable or likely brain regions impacted by brain injury using biomechanical models. Recent advances in imaging using DTI have detected axonal damage previously undetectable. The anatomical regions most likely to suffer structural damage with concussion include the posterior frontal lobe, medial temporal lobe, midbrain structures, fornix, hypothalamus, pituitary, cerebral peduncle, entorhinal cortex and hypothalamus. So, within a few centimeters are critical brain structures that, if affected, could represent the structural basis to many symptoms associated with concussion [182]. Rao and Lyketsos indicate that the PPCS nomenclature is too vague and that the more accurate description is ‘frontotemporal syndrome’ as this better describes the regions most affected by injury. There is considerable evidence linking the vestibular system and objective findings utilizing digital
244 Joel Brandon Brock, Samuel Yanuck, Michael Pierce et al. posturography and videonystagmography for ocular involvement and precise evaluation of central circuits involved [183] We recognize that the same symptoms classified as PPCS can be seen in people without history of concussion or trauma [184]. This is possibly involving the same pathophysiological characteristics with a different etiology. The methodological quality of neuropsychological research for concussion, although plentiful over the past decade, has lacked scientific rigor [185]. When looking at the confounding factors that must be considered in the design of PPCS research, Bigler notes that the major symptoms of PPCS; fatigue, sleep disorder, headache, dizziness/vertigo, irritability, affective lability, anxiety, apathy and personality changes, share such great overlap that exist with other psychiatric disorders such as depression [182] [182].
Figure 11. Development of mental health problems in the context of mTBI milieu © Joel Brandon Brock 2013.
It appears, as is noted in the research cited above, that PPCS shares a great deal of similarity with depression, anxiety, attention deficit disorder (ADD) and OCD. The common thread that holds PPCS, depression, anxiety, OCD and ADD may be a chronic, immune mediated, inflammatory process also known as immuno-excitotoxicity as well as shared anatomical circuitry [12]. Research conducted which points out the effect peripheral musculoskeletal injury has on cognition is similar to that seen with concussion, indicating that injury itself, regardless of anatomical location can affect objective test scores previously attributed to concussion alone. Thus a narrow assessment of pre- and post-injury neuropsychological scores should be avoided [185]. This finding may indicate that systemic inflammation occurring outside the CNS may play a role in the function of cognitive circuitry. There appear to be significant shortcomings in conceiving PPCS, mTBI and chronic TBI as a wholly neuropsychological condition requiring a neuropsychological approach to researching treatment, diagnosis and prognosis. A comprehensive model that addresses multi-system physiology including but not limited to sensorimotor processing and neuro-immune function is likely to emerge. The probability of chronic immune inflammatory processes being involved and the likelihood of compromised neural circuitry may be discovered with sensitive analysis of sensorimotor function of neural circuitry shared by cognitive and behavioral centers. A research model can be crafted that incorporates a multisystem approach to function as opposed to simply ameliorating symptoms. With
The Potential Impact of Various Physiological Mechanisms … 245 this in mind the direction research can take regarding care must be tangible, quantifiable and very different from rest and cognitive therapy. Research needs to address sensorimotor function of specific circuits underlying cognitive and behavioral symptoms within PPCS (i.e., vestibular aspects of posture and ocular function). Recognizing the pathophysiology as it relates to past medical history, family history, genetics, multiple system involvement and systemic peripheral contributions to central nervous system (CNS) function will yield new directions in research, preventive and post-injury care. Research in several disciplines has indicated that blending the study of the evolutionarily conserved, shared underlying neural circuitry common to the visual, vestibular, memory, immune and autonomic regulatory nuclei have been fruitful and are needed if we are to make progress in chronic brain injury outcomes. There appear to be significant shortcomings in conceiving PPCS, mTBI and chronic TBI as a wholly neuropsychological condition requiring a neuropsychological approach to researching treatment, diagnosis and prognosis. A comprehensive model that addresses multi-system physiology including but not limited to sensorimotor processing and neuro-immune function is likely to emerge, which addresses compromised cognitive and behavioral neural circuits that reciprocally affect each other’s frequency of firing. Generating productive clinical questions to investigate must be a disciplined thinking process starting at the molecular level, progressing up through the cellular, receptor, tissue, and sensorimotor, visual and vestibular systems. Only after this Socratic querying can the collection of quantifiable evidence begin and have meaning. Further, both laboratory based neurochemical-immune assessments as well as comprehensive functional neurological examination must be collected and considered. This will necessarily lead to more precise rehab methods and chemical management of chronic brain injuries.
Figure 12. Overview of clinical Socratic thinking in chronic brain injury assessment and care © Joel Brandon Brock 2013.
CONCLUSION
Many factors in a given patient’s physiology can influence the outcome of TBI or mTBI, yielding widely divergent potential outcomes from head trauma, including PPCS. The clinician’s ability to understand a given patient depends upon skilled assessment and appreciation of these variables, their potential interconnections, and their impact at cellular and systems levels. An increasing need for strong generalist thinking is therefore required in order to comprehend and utilize the bounty of recent research, and to avoid the traps of heuristic decision-making and over- emphasis on specialized niches in both the research and clinical settings.
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Recognizing pathophysiology as it relates to past medical history, family history, genetics, multiple system involvement and systemic peripheral contributions to central nervous system (CNS) function will yield new directions in research, preventive and post-injury clinical care. Research in several disciplines has indicated that blending the study of the evolutionarily conserved, shared underlying neural circuitry common to the visual, vestibular, memory, immune and autonomic regulatory nuclei have been fruitful. Their expansion and integration are needed if we are to make progress in improving chronic brain injury outcomes. In both research and clinical settings, careful examination of many wide-ranging patient measures must be integrated in order to progress, including reflexive eye movements, hormone panels, sensorimotor changes, immune and inflammatory markers, mental and emotional states, and other factors required to appreciate each patient’s uniqueness. History taking will need to expand to include lifestyle factors previously thought unrelated. The health status of individuals pre-concussion will be a significant factor in determining PPCS risk in any individual. In the research setting, accounting for physiological variables that can impact TBI and mTBI outcomes is essential in appreciating potential non-homogeneity of patient populations enrolled in a given study. In the clinical setting, accounting for the same physiological variables creates the opportunity to identify key clinical targets that can markedly improve outcomes or, if ignored, stall progress. Once identified, these clinical targets must be addressed with best-matched methodologies, not all of which will be pharmacological. Understanding the post-injury, and ideally the pre-injury status of these patients, utilizing outcome-based multifactorial neurological assessment and treatment are key in the emerging path for effective concussion care.
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Received: June 23 2013. Revised: July 2 2013 Accepted: Jul 3 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):257-273 ISSN: 2156-941X © Nova Science Publishers, Inc.
DIME (DIPLOMATIC, INFORMATION, MILITARY AND ECONOMIC POWER) EFFECTS MODELING SYSTEM: APPLICATIONS FOR THE MODELING OF THE BRAIN
Newton Howard1 and Gerry Leisman2,3,4 1Mind-Brain Institute, Massachusetts Institute of Technology, Cambridge 2F.R. Carrick Institute for Clinical Ergonomics, Rehabilitation & Applied Neurosciences CERAN, Garden City, NY USA 3The National Institute for Brain & Rehabilitation Sciences, Nazareth, Israel 4Biomedical Engineering, Department of Biomechanics, ORT-Braude College of Engineering, Karmiel, Israel
ABSTRACT
This paper describes an analysis framework for estimating the effects of Diplomatic, Informational, Military, and Economic (DIME) activities in the context the brain. We are proposing to evaluate and recommend a set of candidate models of the flow and evolution of cognition and intention as the starting point for developing a DIME Effects Modeling System (DEMS) for command and control by the brain and nervous system. We identified the needs as: (1) understanding and representing the underlying causality within the population, (2) formulating models that are both sensitive and computable, and (3) validating the predictions of cognitions, intentions, and behaviors by model.
Keywords: DIME, intention awareness, DEM, SOA, PMSEII
INTRODUCTION
Can computational models of human behavior and of the nervous system be useful in facilitating our understanding of how networks of the brain communicate? Can seemingly non-related fields of science offer insights in understanding the nature of neural processing and rehabilitation. Understanding the development of human brain organization is critical for gaining insight into brain organization and functions in adulthood as well as for investigating disorders such as autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD), where normal developmental processes are disrupted. Neuroimaging studies of development have primarily focused on structural changes from childhood, to adolescence, and into adulthood. Studies have suggested that the human brain undergoes vast developmental changes in grey and white matter structure between childhood and adulthood. These changes are thought to reflect synaptic pruning and myelination observed at the
Correspondence: Dr. Newton Howard E-Mail: [email protected]
258 Newton Howard and Gerry Leisman neuronal level [1,2]. In spite of growing for patterned brain development, the functional organization of the human brain in childhood is not well understood and it is also not clear how the above structural changes translate to differences in functional brain organization between children and adults. Changes in the functional modeling of the brain and nervous system is a potential useful approach to better understand the nature of normal and abnormal processing as well as being able to generate hypotheses for subsequent empirical study. Modeling techniques from the defense industry hold promise for assisting in a better understanding of nervous system function and dysfunction. These graph-theoretic metrics have also proven useful in modeling the large-scale functional and structural organization of the human brain [3-6]. In a graphical representation of a brain network, a node corresponds to a brain region while an edge corresponds to the functional connectivity between two brain regions. Functional connectivity networks of the human brain derived from electroencephalograms (EEGs), magnetoencephalograms (MEGs), and task-free functional magnetic resonance imaging (fMRI) data have been shown to exhibit small-world characteristics [4,7,8]. These studies suggest that small-world metrics are suited to quantify the global topological properties of large-scale organization of the human brain. Recently, in addition to small-world metrics, Bassett and colleagues used graph theoretic metrics such as hierarchy to characterize local topological properties of large-scale organization of the human brain. Using structural brain imaging data and modeling of interregional covariance in cortical thickness, they reported that hierarchical organization in anatomical human brain networks is characterized by the presence of frontal hubs [9]. A recent study of aging by Meunier and colleagues investigated the modular organization of large-scale functional brain networks using Newman’s graph-based modularity metric. They reported that while both young and older adults showed modularity of network organization, the topological roles of the specific brain regions as well as the inter-modular connectivity was significantly different between the two groups [10]. The use of small-world metrics along with more advanced graph theoretic metrics to characterize local organization of complex networks provides a new approach for investigating large- scale functional organization of the human brain at multiple levels of granularity. The development and evaluation of computable models for assessing the flow and evolution of a population’s beliefs, intentions, and behaviors within the diplomatic, informational, military, and economic (DIME) aspects of regional conflicts is not fundamentally unlike the nature of brain organization and reorganization as a result of experience. These military models may, in turn, have value in allowing us to better understand the nature of brain organization and reorganization as a result of experience. These models were part of a quest by the US Army to assess and manage the social aspects of stability operations in overseas conflict. The resulting collective models are hereafter referred to as the DIME Effects Model (DEM). We identify and characterized at least five classes of models that could be applicable to the DEMS. The identification of possible models was supported by a broad, but necessarily limited, literature search that spanned political theory, demographics, group behavior research, biostatistics, genetic theory, social networking and group beliefs and motivations. From this search, a classification of models into five types was made. These model classes are broad, with considerable variation in breadth, depth of detail and time span across the model instances found. Each of the model classes was intended to provide an approach to modeling the population, its beliefs and motives and its likely behaviors, as well as the underlying state of the Political, Military, Economic, Social and Informational Infrastructure (PMESII). The five classes we defined are:
System Dynamic Models
This class of model generally consists of a system of differential equations that describe the relationships between attributes of the system state as the system evolves through time. Given an initial state X(0), a future state X(t) can be calculated. In practice, only the smallest systems of up to a
DIME (Diplomatic, Information, Military and Economic Power) Effects Modeling System 259 few dozen equations can be solved unless the systems are assumed to be linear (all higher order derivatives = 0). Much larger systems can be represented and solved under the assumption of linearity, which often is acceptable for short time periods and small variations in the state attributes. An example of such a model is represented in Figure 1.
Figure 1. Represents dynamical causal modeling for fMRI. Dynamical causal modeling (DCM) tries to infer directed connectivity among brain regions or sources. These models distinguish between a neuronal level, which models neuronal interactions among regions and an observation level, which, for fMRI, models the ensuing hemodynamic responses. Here, we look at the attentional modulation of evoked responses (in the context of visual motion processing) and see that it is best explained by an increased sensitivity of excitatory populations of neurons in V5 to forward afferents from earlier visual areas. Left: This example uses a DCM with two neuronal states (populations) per region which affords an explicit model of intrinsic (between-population) connectivity within a region. In addition, by using positivity constraints (through the exponential in the neuronal state equation), the model reflects the organization of real cortical hierarchies, whose extrinsic connections are excitatory (glutamatergic). Excitatory and inhibitory neuronal states for the ith region are denoted by x(i)⊇{xE(i), xI(i)} and exogenous (experimental) inputs (such as photic stimulation, motion or attention) are encoded by u⊇{u1, u2, …}. By comparing these sorts of DCM, one can disambiguate among competing hypotheses about the locus of context-sensitive changes in coupling, I(u). Middle: In all three models considered here, photic stimulation enters V1 and motion modulates the connection from V1 to V5, and all assume reciprocal and hierarchical extrinsic (between region) connections. The models differ in how attention modulates the influences on the excitatory population in V5 (green ellipses): model 1 assumes modulation of backward extrinsic connections, model 2 assumes modulation of intrinsic connections and model 3 assumes modulation of forward connections. Right: The results of Bayesian model comparison (upper graph) are shown in terms of the log evidence for each model: Model 3 (modulation of the forward connections by attention) is selected over other two models. The lower graph shows the predicted and observed regional responses under this model. In all, photic stimulation enters V1 and the motion variable modulates the connection from V1 to V5. Models 1, 2 and 3 all assume reciprocally and hierarchically organized connections. They differ in how attention modulates the influences on V5; Model 1 assumes modulation of the backward extrinsic connection, Model 2 assumes modulation of intrinsic connections in V5 and Model 3 assumes modulation of the forward connection. (See Marreiros and colleagues [11] for details).
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State Transition Models
A state transition model exemplified in Figure 2 represents the state of the population beliefs and PMESII as a hierarchical state graph with nodes representing system state and links representing transition probabilities between the states. The hierarchical structure of the graph embeds sub-graphs within nodes, so that substrates can be defined within a state and so on. A node in a sub-graph represents a total state for the population system being modeled, and a system can be in only one state at a time. A state transition model may also be composed of a number of disconnected state graphs, each representing state transitions for an independent part of the system.
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Figure 2. (A) is a block diagram of a neural prosthetic system including a cognitive state machine which illustrates a control system for a prosthetic device in which neural signals originating in the brain may be recorded from a neural implant and transmitted for processing. The neural activity decoded from a subject may transition through different stages between forming an intention to reach and executing the reach. Reach execution may not involve movement of the arm itself, but may involve movement of a virtual arm instead. (B) Represents a schematic block diagram of a cognitive state model of three movement types see the patent of Andersen et al., 2005 [12].
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Rehabilitation applications might include limb prostheses which may operate in response to muscle contractions performed by the user. Some of these prostheses are purely mechanical systems. Other prostheses may incorporate electronic sensors to measure muscle activity and use the measured signals to operate the prosthesis. These types of prostheses may provide only crude control to users that have control over some remaining limb musculature. Prosthetic devices and other assistive aids that require control over some remaining limb musculature may not be useful for individuals who have suffered from upper spinal cord injury, strokes, and neurodegenerative diseases. Prosthetic devices that operate in response to electrical signals measured by a sensor implanted in the subject's brain are being contemplated for assisting these individuals. A prosthetic system may use a decoder to predict an intended action, such as a reach, from processed signals generated from measured neural activity. The decoder may include a cognitive state machine, which transitions between cognitive states based on transition rules. Mathematically, this corresponds to a state space model for cognitive processes. States may be continuously or discretely valued and may be observable or hidden. The transition rules may be described by a matrix of probabilities. Classifiers may classify the processed signals into period and direction classifications. The period classifications may correspond to neural/behavioral periods and the direction classifications may correspond to intended directions. The state machine may transition between cognitive states in response to receiving certain classifications for a predetermined period of time. For example, for a reach, the state machine may transition between a planning state and a reach state in response to receiving a planning classification for a predetermined period of time, e.g., 500 ms. Other state transition models may additionally require that a direction classification is received for the duration of a planning period and/or that a cognitive “go” signal is received. The cognitive states in the state transition model may be defined based on observation, hypothesis, and experimentation. The cognitive states may also be developed using mathematical modeling techniques such as hidden Markov modeling techniques.
Social Network Models
These are graph-structured models of relationships between people or groups of people. Nodes represent the individuals or groups and vertices represent relationships such as communication or influence. A nervous system-based exemplar is provided in Figure 3(D). If one were to make a picture of one’s social network, what would it look like? Would it look like a regular structure, like a lattice as represented in 3(C)? Or would there be strange detours and long- range connections between friends’ friends as represented in Figure 3(A) or 3(B)? It would probably be something more like the irregular graph than the lattice as represented in Figure 3(C). People do not form friendships in a regular, orderly manner conforming to strict rules of structure. Instead, people form local clusters of friends or cliques and some people act as bridges between cliques to connect them and form the small-world topography familiar to social networks as represented in Figures 3(A) and (B). This is one of the points Watts and Strogatz [13] illustrated with their social network models. A ring lattice may be a poor analog for a real-life friendship network, but a ring lattice with a few perturbations of the edges does a good job of capturing two characteristics of social graphs: local structure and random edges that allow a small world. Figure 3(D) represents such an example with applications of connectography represented in Figure 3(D).
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Figure 3. Graph-structured models of relationships between people or groups of people employing the (A) Watts- Strogatz model (B) Sociometry (C) Lattice Models and (D) Connectography of short and long range connections. Multimodal studies have shown that cellular and whole-brain networks demonstrate consistent topological features.
Group Ideology Models. This type of model represents the beliefs and intentions of groups within a population and suggests what actions the groups are likely to take in the future. The model is implemented using one or more symbolic reasoner to provide an “analyze-plan-act-coordinate” loop for each group. The groups are goal-driven with goals defined by their adopted ideology, and may be in conflict with the goals of other groups. The groups have beliefs which may be inaccurate, incomplete and inconsistent. Groups take actions to fulfill their goals, and actions may be directly mediated by the state of the PMESII. Again, brain applications are provided in Figure 4.
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Figure 4. Continued on next page.
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Figure 4. Provides an illustration of a simplified path model of inmate group behavior with nonrecursive and duplicate paths not shown to reduce visual complexity as illustrated in (A), these control processes are the result of three other sets of processes in the organization: (B) conflictive, (C) structural, and (D) normative. Additionally, the extent of controls used will result in a comparison of actual inmate behavior to that level desired by the organization [14]. The use of material control will also be affected by inmate efforts to control the allocation of material resources such as job allocations and other scarce resources [15]. The conflictive, structural, and normative controls used, whether positive or negative, interact dynamically with inmate compliance and these other processes [see 16].
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Group Dynamics Models
The DEM is situated at the brigade level because that is where the necessary operational and architectural resources exist today. The DEM model should be able to run its full analysis cycle in roughly one hour to accommodate the current status reporting procedure at the brigade level. The analysis should include high fidelity predictions within a time frame of days, accompanied by lower fidelity predictions that span months. The system should facilitate situation assessment when one brigade relieves another on station, as well as sharing information between cooperating brigades. Finally, the DEM should be granular enough to represent cultural differences in different theaters and adaptive as the theater evolves. This type of model represents the behaviors and intentions of groups within a population and suggests what actions the groups are likely to take in the future based on their internal and external dynamic relationships. Although similar to the Group Ideology model in mechanization, the knowledge within this class of model is focused on group dynamics rather than ideology, and is therefore more general and more re-usable. Figure 5 provides such an example of this model applied to the brain.
Figure 5. Group Dynamic Models: A group consists of two or more people with a common relationship. If the group members shared leadership, developed their own purpose or goal or worked together continuously, rather than occasionally, it could become a team. In 1965, Tuckman [17] proposed The Forming – Storming – Norming – Performing model of stages of group development. In 1977, Tuckman added a fifth stage called Adjourning (reproduced from Langton & Robbins [18] in [Fig. 5]). Forming- is the first stage, characterized by uncertainty. Members of a group do not know each other well. Through communication connectivities become stronger in ways similar to those found in Fig. 3(D). Storming- is the second stage characterized by conflict when group members know each other better. It happens often, that at this stage many conflicts occur, the motor learning equivalent might be piano lessons where the motor skills have not reached levels of automaticity. It is at this stage that the need of a leader becomes higher. Norming- is the third stage characterized by cohesiveness. At this stage, the team becomes organized as in brain connectivity function in adolescence as opposed to early childhood [19]. Team members effectively begin working together, helping each other and asking for others’ opinion. The team started fulfilling its purpose. Performing- is the fourth stage in which group energy has moved from acquaintanceship to performance, where tasks can now be optimized. This concept can also be represented in brain dynamics as optimized functional connectivities.
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Figure 6. Represents the evaluation of unconscious body movement synchrony and implicit interpersonal interactions between two participants examined by observing the neural correlates and functional connectivities within and among the brain regions of interacting participants. Results of unconscious fingertip movements between two participants are represented while simultaneously recording EEG in a face-to-face setting. Participants were asked to straighten their arms, point and hold their index fingers toward each other, and look at the other participant's fingertip. Face-to-face interactions closely approximate real-life situations and reinforce the social nature of interpersonal interactions. (A) Represents the total number of functional connections that showed significant phase synchrony of inter- and intra-brain in theta (4~7.5 Hz) and beta (12~30 Hz) frequency range. The overall number of significant phase synchrony increased after training in inter-brain connections, but not in intra. (B) Represents the topography of the phase synchrony connections between all 168 cortical ROIs of the two participants (Left brain: leader, right brain: follower) when contrasting post- against pre-training in theta (4~7.5 Hz) and (C) beta (12~30 Hz). Inter-brain connections were found mainly in the inferior frontal gyrus (IFG), anterior cingulate (AC), parahippocampal gyrus (PHG), and postcentral gyrus (PoCG) (see Yun et al 2012). (D) Functional connectivity captures brain interactions via fluctuations in the observed activity; graphical modeling can extract connectomes, i.e. graphs of brain connectivity, with statistically well-posed and controlled methods. Learning brain connectivity faces the complexity of brain graphs that contrasts with the small amount of data at the subject level. At the group level, connectivity information can be convolved with inter-subject variability (see Ng et al. [20]).
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SYSTEM ARCHITECTURE
The DEMS is meant to be a state-of-the-art tool for analysts at the brigade level to use for planning and evaluating the effectiveness of the effects-based operations, particularly focused on integration of diplomatic, informational, military, and economic effects. Because the DEM is an integration of ideas from several disciplines of science, a component based framework approach is the best investment for the DEM. A component-oriented framework allows the DEM to evolve as data visualization technologies evolve. Our research confirmed that the initial framework necessary to setup the DEM exists and is already integrated with the major defense programs we are tending to as commercialization opportunities for the DEM.
Development Methods
Our development methods followed Xtreme programming methodology, working in short iterations to reach through all layers of the architecture to implement a small, well-defined use case. We elicited feedback on each iteration’sprototype to further integrate the look and feel with which the analyst expects to work.
Figure 7. Extreme program methodology.
Service Frameworks
The envisioned architecture is a distributed infrastructure promoting application integration and collaboration across services and applications. It uses the Service Oriented Architecture (SOA) style exemplified in Figure 8 to define, govern, and implement core service interfaces including discovery. It uses an event-driven architecture style for message routing and collaboration between users. It contains a suite of tools specifically designed to aid tying intelligence applications together. The value of this architecture lies specifically in its collaborative potential and in its open architecture.
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Figure 8. Distributed Infrastructure in a service oriented architecture.
Collaborative Framework
The collaboration framework is an event-based service integration framework, or more simply, a service bus. Systems are composed of compliant applications and services that interact via the collaboration framework. The framework supports peer-to-peer and client-server configurations and runs on laptops or almost any Windows hardware. The value of the collaborative framework in the architecture is that it allows end-users to collaborate and share their data. More than just a screen-scraping technique, two collaborating usersare actually sharing data, while maintaining separate presentation mechanisms. For example, suppose two analysts are collaborating on new intelligence data about a person of interest. The collaboration framework allows them to share their data about the person with each other, even though one analyst is using that data to evaluate the link analysis network for that person while the other analyst is using the data to simulate a belief model for that person. The following services make up the collaboration framework.
Collaboration Data Manager Service. The CDM is an in-process object management and event notification service. It handles activities such as creation and deletion of objects and client subscriptions.
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Session Manager Service. The SM is a Windowed Client Adapter that provides the user interface for connecting to local or remote Session Brokers, managing their sessions, subscribing to sessions and connecting the collaboration to the subscribed session. Session Broker Service. The SB manages available sessions on a single system. It handles activities such as keeping track of available sessions, session types, channel types, subscriptions, and session creation and deletion. Interop Services. IS is responsible for providing information about available Collaboration Sessions on a system, bridging message traffic between heterogeneous Collaboration channels. Channel Adapter Service. CA enables collaboration messages to be sent and received across process (or system) boundaries. It is responsible for serializing and de-serializing collaboration and session messages into a format appropriate for the Collaboration Channel that they are communicating on.
Solution Framework
Complementing the collaboration framework, the solution framework is an object-oriented execution environment (Figure 9) for integrating components to form a Windows application, including service discovery.
Figure 9. Object oriented execution environment providing a collaboration framework.
It provides basic components and mechanisms for connecting them together and defining their interaction. Ultimately, it is the framework that allows a user to work with related elements across multiple data sources. A PMESII element in the link analysis component window can be dragged and dropped into the belief value model component window and analyzed immediately, even though the components are different applications. This ability allows the framework to integrate multiple vendors seamlessly to boost the analyst’s view into the data.
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TESTING AND EVALUATION
The value of a suite of models such as the DIME Effects Modeling System is directly related to the extent to which the models can be tested and evaluated against the real world they purport to model. But the testing and evaluation of models such as DEMS is not an easy task. This section will provide a background for the complex issues facing evaluation of DEMS, and provide a set of recommendations to guide further work. When the output of a model is compared to the observations of the real world, discrepancies can arise in two ways: (1) the model has an error in its implementation, but may otherwise be properly founded, or (2) the model was implemented completely as desired, but the underlying foundations of the model were flawed. Outcome (1) is the area of test and evaluation known as verification testing, while outcome (2) is the problem of validation. Verification testing is normally conducted with pre-defined and pre-certified test cases whose expected outputs are thought to be “correct” with respect to the real world. A second issue in verification testing is the extent to which the system under test is fully exercised. It may take a very large number of pre-certified test cases to provide coverage of all aspects of the system under test. Validation testing of models requires head-to-head comparison with the real world. If the output of the models agrees reasonably with the observations of the real world, the model can claim at least local (for a particular case) validity. After many trials over a broad range of conditions, the outputs of the suite of models may continue to agree reasonably with the observations of the real world, thus establishing convergent validity. It is important to note that a system may have known faults (not fully verified) and still be valid. However verified or valid the suite of models might be, utility is still a separate question. Does the DEMS benefit the users? If the outputs of the model are no more refined than the average educated estimates of the user, it is of no real help. The DEMS is useful to the extent that it can lead users to better decisions with better outcomes. To measure this, the utility tests must be fully interactive with real users in a real and dynamic world. For all these test processes (verification, validation and utility testing), a rich set of formal experimental methods exists. But for testing the DEMS, a set of deep and difficult challenges also exists. Underlying all of the elegant and useful work in formal experimental design are two important ideas: the experimental unit, and replication. The experimental unit defines that chunk of reality that can be sufficiently isolated from its surroundings and controlled against external factors so that the observation of its outcome can be cleanly linked to its inputs. In many sciences, the experimental unit is easy: a test tube with culture medium and organisms, a plot of land, an aluminum bar. But for DEMS, how is a part of an interconnected social, political and economic system isolated without disrupting its very nature? Even if an experimental unit can be reasonably defined, replication is an even harder challenge. Many experimental units must be found, all of them “identical” for the purposes of an experiment. Because social systems carry the memory of their past, it requires special care if any living experimental unit will be used more than once. Further complicating the evaluation of the DEMS is the issue of correctness. How should a unit of a social system behave if manipulated in some planned way? Is the way a social system responded in the past a reasonable guide to how another similar social system will respond in the present? For now, political science and sociology provide only weak guidance as to what would be “correct” behaviors for DIME manipulations. Lastly, one of the fundamental issues in testing is the ability to isolate and repair the sources of discrepancies between the outcome that was expected and the outcome that is observed. Even with a solid notion of correctness of model predictions, this can be a difficult problem. For DEMS, evolution
DIME (Diplomatic, Information, Military and Economic Power) Effects Modeling System 271 of a set of useful models will require a strong approach to separating the effects of initial conditions, model parameter settings and model structure.
CONCLUSION
We have reported on the requirements and technology-base for a suite of models to support in- theater assessment and prediction of the effects of Diplomatic, Informational, Military and Economic (DIME) activities on the political, economic and social infrastructure. Of particular interest is the ability to model the spread of ideas, motivations and beliefs within the non-combatant population and how to apply these models to the nature of brain function and in rehabilitation applications. The challenges associated with this research area include understanding the causality between elements of the population, formulating models that are both sensitive and computable, and validating the predictions of a population’s beliefs and intentions at some future time. This research focuses on providing insight on the specification of a DEM model. It proposes what the desired properties would be and describes the architecture the DEM would be situated in. Additionally, this report evaluated 24 sources regarding the most promising uses of social modeling in computer science, biology, sociology, and political science to derive the most desirable characteristics of the DEM model and to anticipate where it would present challenges. The report also evaluated how such a system would be verified and validated. Biswal and associates [21] compiled the largest publicly-accessible fMRI dataset, consisting of over 1,400 scans from 35 different centers. All of the data, along with some tools for analysis, are freely available for download from NITRC [22]. One might wonder why an fMRI dataset of this scope has not been assembled until now; after all, fMRI isn’t that new a technique, having been around for about 20 years now. The answer (or at least, one answer) is that it’s not so easy–and often flatly impossible–to combine raw fMRI datasets in any straightforward way. What allowed Biswal to consolidate datasets to such a degree is that they focused exclusively on one particular kind of cognitive task. Or rather, they focused on a non-task: all 1400+ scans in the 1000 Functional Connectomes Project are from participants being scanned during the “resting state”. The typical finding is that, when you contrast this resting state with activation during virtually any kind of goal-directed processing, you get widespread activation increases in a network that’s come to be referred to as the default network. One of the main (and increasingly important) applications of resting state fMRI data is in functional connectivity analyses, which aim to identify patterns of co-activation across different regions rather than mean-level changes associated with some task. The fundamental idea is that one can get traction on how the brain operates by studying how different brain regions interact with one another spontaneously over time, without having to impose an external task set. The newly released data is ideal for this kind of exploration, since you have a simply massive dataset that includes participants from all over the world scanned in a range of different settings using different scanners. Biswal et al. report that functional parcellation of the brain using seed-based connectivity (i.e., identifying brain regions that co-activate with a particular “seed” or target region shows marked consistency across different sites, revealing what Biswal et al. call a “universal architecture”. This type of approach by itself isn’t particularly novel, as similar techniques have been used before. But no one’s done it on anything approaching this scale as it has been in computer science with the results reported in Figure 10.
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Figure 10. Functional parcellation of the brain using seed-based connectivity [see Biswall et al.].
One can observe that different seeds produce difference functional parcellations across the brain (the brighter areas denote ostensive boundaries).
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[7] Micheloyannis S, Pachou E, Stam CJ, Vourkas M, Erimaki S, Tsirka V. Using graph theoretical analysis of multi channel EEG to evaluate the neural efficiency hypothesis. Neurosci Lett. 2006;402:273–277. [8] Stam CJ. Functional connectivity patterns of human magnetoencephalographic recordings: a ‘small-world’ network? Neurosci Lett. 2004;355:25–28. [9] Bassett DS, Bullmore E, Verchinski BA, Mattay VS, Weinberger DR, et al. Hierarchical organization of human cortical networks in health and schizophrenia. J. Neurosci. 2008;28:9239–9248. [10] Meunier D, Achard S, Morcom A, Bullmore E. Age-related changes in modular organization of human brain functional networks. Neuroimage. 2009;44:715–723. [11] Marreiros SJ, Kiebel KJ, Friston. Dynamic causal modelling for fMRI: a two-state model. NeuroImage. 2008;39(1):269–278. [12] Andersen RA, Pesaran, B, Mitra P, Meeker D, Shenoy KV, Cao S, Burdick JW. Cognitive state machine for prosthetic systems. US Pat. 6,952,687 B2 Oct. 4, 2005. [13] Watts DJ, Strogatz SH. Collective dynamics of 'small-world' networks. Nature. 1998;393(6684):409–410. [14] Toch, H. Violence from without and within: safety. In: Braswell M, Montgomary Jr R, Lombardo L, editors. Prison violence in America. 2nd ed. Cincinnati, OH: Anderson Publishing; 1994. p. 11-26. [15] Marquart J, Crouch B. Judicial reform and prison control: The impact of Ruiz vs Estellean on Texas penitentiary. In: Braswell M, Montgomary Jr R, Lombardo L, editors. Prison violence in America. 2nd ed. Cincinnati, OH: Anderson Publishing; 1994. p. 265-290. [16] Patrick S, Dorman PM, Marsh RL. Simulating correctional disturbances: The application of organization control theory to correctional organizations via computer simulation. J Artif Societies Soc Sim. 1999;2(1). http://jasss.soc.surrey.ac.uk/2/1/1.html [17] Tuckman, BW. Developmental sequence in small groups. Psychol Bull. 1965;63:384-399. [18] Langton N, Robbins SP. Fundamentals of Organizational Behaviour. 3rd ed. Ontario, Canada: Pearson Education; 2006. [19] Leisman G. Children’s language production: How cognitive neuroscience and industrial engineering can inform public education policy and practice Forum on Public Policy. A Journal of the Oxford Roundtable. 2012;2012(1):1-14. [20] Ng B, Varoquaux G, Poline J-B, Thirion B. A novel sparse graphical approach for multimodal brain connectivity inference. Med Image Comput Comput Assist Interv. 2012;15(Pt 1):707-714. [21] Biswal BB, Mennes M, Zuo XN, Gohel S, Kelly C, Smith SM, Beckmann CF, Adelstein JS, Buckner RL, Colcombe S, Dogonowski AM, Ernst M, Fair D, Hampson M, Hoptman MJ, Hyde JS, Kiviniemi VJ, Kötter R, Li SJ, Lin CP, Lowe MJ, Mackay C, Madden DJ, Madsen KH, Margulies DS, Mayberg HS, McMahon K, Monk CS, Mostofsky SH, Nagel BJ, Pekar JJ, Peltier SJ, Petersen SE, Riedl V, Rombouts SA, Rypma B, Schlaggar BL, Schmidt S, Seidler RD, Siegle GJ, Sorg C, Teng GJ, Veijola J, Villringer A, Walter M, Wang L, Weng XC, Whitfield- Gabrieli S, Williamson P, Windischberger C, Zang YF, Zhang HY, Castellanos FX, Milham MP. Toward discovery science of human brain function. Proc Natl Acad Sci USA. 2010 Mar 9;107(10):4734-4739. [22] Neuroimaging Informatics Tools and Resources Clearinghouse (NITRC). (cited 2012 Aug 15). Available from: http://www.nitrc.org/projects/fcon_1000/.
Received: January 31 2012 Revised: August 15, 2012 Accepted: February 15 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):275-293 ISSN: 2156-941X © Nova Science Publishers, Inc.
ANATOMICALLY ACCURATE HEAD MODELS AND THEIR DERIVATIVES FOR DENSE ARRAY EEG SOURCE LOCALIZATION
Jasmine Song1, Kyle Morgan1, Sergei Turovets1, 2, Kai Li1, Colin Davey1, Pavel Govyadinov2, Phan Luu1, 3, Kirk Smith4, Fred Prior4, Linda Larson-Prior4, and Don M. Tucker1, 3 1Electrical Geodesics, Inc., Eugene, OR USA 2Neuroinformatics Center, University of Oregon, Eugene, OR USA 3Department of Psychology, University of Oregon, Eugene, OR USA 4Electrical and Optical Imaging, Neuroimaging Laboratory, Washington University, St. Louis, MO USA
ABSTRACT
Electroencephalography (EEG) is a brain imaging technology that is noninvasive, cost effective, and provides millisecond temporal resolution. Improved spatial resolution of EEG measures can benefit multiple clinical and research applications, including the assessment of Traumatic Brain Injury (TBI), stroke, and neurodevelopmental disorders. Recent advances in electrode arrays have made it feasible to achieve dense array sampling (128, 256 and 512 channels) of brain potentials on the head surface, and then localize the sources of the measured fields to the surface of the cortex to provide spatially resolved information. Accurate dense array source localization requires i) moving beyond simplistic models of the human head (such as homogeneous multi-shell spheres) and ii) accurate knowledge of regional conductivities of head tissues. These requirements are particularly important for children because the size, shape and electrical properties of the head tissues undergo rapid developmental changes from infancy through adolescence. In this paper we apply high performance computing with finite difference methods (FDM) to solve the forward EEG problem with skull and head conductivity models that are appropriate for children as well as adults. We show that the improved structural (MRI and CT based) head models may improve high-resolution EEG source localization by correcting systematic biases in EEG source localization due to conductivity misspecifications and structural uncertainties. We also demonstrate how these same advances in electromagnetic head models may be used to model effects of non-invasive brain stimulation such as Transcranial Magnetic Stimulation (TMS) and Transcranial Electrical Stimulation (TES).
Keywords: EEG, pediatric, atlases, models, source localization, MRI, CT, SEP, mismatch
Correspondence: Sergei Turovets, PhD, Electrical Geodesics, Inc., 1600 Millrace Dr. Suite 200. Eugene, OR, 97403, USA E-Mail: [email protected].
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INTRODUCTION
Electroencephalography (EEG) provides important information on brain activity for a range of applications, including research on normal cognitive development in children, brain monitoring of neonates in intensive care, and early detection of brain pathology such as epilepsy. In adults, imaging technologies may use ionizing radiation (computed tomography (CT) or radionucleotides (positron emission tomography (PET), single photon emission tomography (SPECT), or they may require that the subject remains still during image acquisition (magnetic resonance imaging (MRI) or CT). In children, radiation exposure and sedation are particularly problematic. Better spatial resolution for the inexpensive and noninvasive EEG measure, such as through accurate source localization, could improve both research and health care [1]. A fundamental limitation to the use of source localization techniques lies in the relatively sparse sensor arrays used in standard EEG monitoring systems (19-21 electrodes in the standard 10-20 system). These conventional recording arrays provide inadequate spatial coverage [2] both in terms of the inter-electrode distances (~5 cm) and the coverage of basal regions of the head [3]. Many laboratories now acquire data from dense arrays of 64, 128, or 256 channels [4]. By increasing the spatial sampling of the volume and decreasing the inter-electrode distance, dEEG has been shown to provide a significantly improved spatial resolution from scalp recorded data [5]. At present, the use and validation of dEEG and Electromagnetic Source Imaging (ESI) in infants and children is hindered by the lack of accurate pediatric head models. To generate an ESI solution, two independently specified problems must be solved: (1) the forward problem, or volume conduction head model, which includes a set of conditions that specify the way in which currents propagate from their site of generation at the cortex to the site of measurement at the scalp, and (2) the inverse problem. The inverse problem requires mapping the recorded surface potentials to the cortical sources space in the volume conductor model, and this is a problem for EEG because it is highly underspecified. While many studies have shown that “realistic” volume conductor head models generate more accurate ESI solutions [2, 3, 6], the impact of the structural head tissue geometry, conductivity specifications, computability and necessity of additional variables such as tissue anisotropy or inhomogeneity remain poorly understood [7, 8]. These parameters are particularly critical for infants and children, where both shape and density of the skull and the structure of the cortex cannot be approximated by adult head models [9, 10]. The human skull and brain undergo rapid and significant growth from birth to about 2 years of age, with slower but continued growth through the 6th postnatal year [9-11]. Ossification of the skull begins at approximately 11 weeks gestational age [12] and is not fully complete until the 3rd to 4th decade of life [11]. While adult bone represents a layering of cortical (external and internal) and diploic bone, infant cranial bone (birth – 6 months of age) is primarily cortical bone [13]. This difference can be expected to lead to a significant change in skull resistivity from infancy to adulthood [14]. In addition, the developing skull exhibits large discontinuities, the fontanels (Figure 2a, 3a and 5 in this paper), which form at the intersection of 3 or more ossifying bone edges. These usually ossify over the first 2 years after birth, but the cranial sutures remain incompletely ossified at least until early adulthood. The open sutures and fontanels, as well as the unique shape of infant heads, must be modeled for accurate source localization [6 -8,18-23]. In addition to differences in the bony cranium, significant changes in brain volume, regional tissue composition and ventricular volume are seen in infants and children. The few imaging studies of normal brain development in children from birth to 2 years report that this is a period of significant dynamic micro- and macro-structural change [9,10]. During this period, brain volume increases 115%, lateral ventricular volume increases an amazing 288%, and white matter volume, a reflection of axonal myelination, increases substantially. This rapid growth trajectory is maintained into the 10th
Head Models for dEEG Source Localization 277 year and is further reflected in differences in fractional anisotropy and mean diffusivity across the developmental period [15]. The importance of including age-specific regional brain anisotropy is not fully understood. The human brain exhibits large changes in regional anisotropy between the ages of 0-9, in addition to major changes in brain and tissue volumes from ages 0-2 that almost certainly are of critical importance to accurate modeling. In the course of creating accurate and useful pediatric head models, it would be useful to evaluate the age ranges in which changes in brain and tissue volume, in addition to regional anisotropies, significantly impact the accuracy of electrical source localization. Several studies have addressed the issue of conductivity parameter misspecifications in adult head models including anisotropy and inhomogeneity. The effects of these parameters have been studied using analytic forward solutions in multi-shell spheres or MRI-based boundary element models (BEM) and finite element models (FEM) [18, 19, 38]. For example, Pohlmeier et al. [20] showed that by using an equivalent dipole approach (continuous dipole fit) one can obtain up to a 6 mm error increase with 20% skull misspecifications in both spherical and realistically shaped models. The uncertainty in the reported skull conductivity data range, in fact, can be up to a factor of 10. On the other hand, simulations by Huiscamp et al. [21] showed source localization error up to 20 mm for conductivity misspecification. More recently, Acar and Makeig [22] reported effects of forward model variation and mismatch on EEG source localization in adults using the BEM and equivalent dipole techniques. They compared models derived from subject specific MR images and models warped to digitized individual head shapes from the MNI adult atlases [24] as well as the best fit spherical models. The four-layer (warped to electrodes) MNI models were found to be the best approximations to the ground truth of the individual head models for four adult subjects. We are unaware of similar studies in children across the developmental spectrum, except the paper by Roche-Labarbe et al. [23] on neonatal head BEM simulations with structural variations (fontanels, the whole skull layer). In our approach, the subject head model geometry is created through: (1) high-resolution segmentation of head tissues, (2) cortical ribbon surface extraction with topology correction (to insure a correct and continuous surface), and (3) tessellation of the cortical surface (for example, 1 cm squares) for dipole seeding. This detailed geometric model is then populated with the estimated conductivity for each tissue. At this point the forward model can be used to create the subject specific Lead Field Matrix (LFM) by individually activating each current dipole with unit magnitude and calculating the resultant scalp electrical potentials at the sensor locations. A complete formal description of the forward and inverse problems has been presented previously [1,27, 28, 40]. The structural changes that mark the development of the skull and brain are accompanied by changes in brain function and cognition [29]. While simple cognitive functions such as processing of sensory information and responses to sound and language are present at birth, the integration of higher order cognitive coordinating centers such as the prefrontal cortex show a protracted course of development [30]. Anomalies in the development of cerebral connections are relevant to a number of developmental disorders, including attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and schizophrenia (SZP). At least some of the characteristic features of these disorders have been attributed to disruptions in dynamic neural network interactions [31], a full elucidation of which requires neuroimaging with adequate temporal resolution. Although changes in network dynamics might be quantifiable using electrophysiological methods alone, the greatest benefit would derive from a clear definition of regional components of such networks. For that reason, accurate head models that would enable finer scale resolution of anatomical regions involved in network interactions using dEEG represent a much-needed tool. Furthermore, such head models would aid in the development of non-invasive multi-modal imaging by enabling the co-registration of age-specific anatomical images. This need, which is currently being addressed in adult populations, is particularly wanting in infants and children.
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In this paper we conducted a simulation study based on Finite Difference Modeling (FDM) to examine the error when a rescaled or warped adult head model, an older child’s head model, or inaccurate skull conductivities, are used in pediatric ESI. Specifically, we analyzed several pediatric head models based on: (1) the reference model, a 6 month old infant MRI co-registered with the infant’s own CT; (2) the same MRI with warped adult CT atlas skull, with no fontanels but with adjusted thickness; (3) a child head model from a preschool age group warped to the 6 month old infant head shape; (4) a child head model from a teenage group warped to the reference infant head shape; and (5) an adult male head model warped to the reference infant head. In contrast to previous studies, where a skull compartment was derived from MRI, we used the infant’s or children’s own CT in all models. The CT provides an excellent representation of bone structure and density of the skull, the most resistive tissue of the head and therefore having the largest impact in electrical modeling. All models have differentiated five tissue layers: scalp, skull, CSF, brain grey matter (GM) and white matter (WM), as well as internal air pockets in sinuses and throats. The effects of geometry variations (such as the presence or absence of fontanels) and the skull conductivity variations were also examined systematically. All models were analyzed for six skull conductivity values, ranging from the lowest value reported in the literature 0.004 S/m through the average adult value 0.018 S/m to the average scalp conductivity (effectively no skull). The "synthetic ground truth" EEG was generated separately in each model for the “true” conductivity value. In the model mismatch studies, the ground truth EEG was generated in the reference infant model. Inverse solutions were examined in the true, warped, or modified models using minimum norm (MN) and sLORETA methods of distributed linear inverse source localization [8]. In addition, we examined the impact of different resolutions in medical images and FDM computation on ESI accuracy comparing the source localization results in the reference infant models for 0.5 mm, 1 mm, and 2 mm FDM resolutions. Finally, we illustrated the impact of model mismatch on source localization accuracy with a Somatosensory Evoked Potential (SEP) experiment with two adults. The mismatched models were created intentionally by warping or geometry swapping with a different subject’s head model.
METHODS
All research retrospective and prospective protocols involving human subjects were approved by Institutional Review Boards (IRB) at both project sites (Eugene, OR and Saint Louis, MO), with informed consent obtained from the subjects recruited in the prospective studies. Figure 1 summarizes the head model creation, data collection, and model analysis path. Each of the steps starting with structural anatomical data and ending with source localization on cortex is outlined in Figure 1 and described in detail below. MRI and CT data collection: The reference models of soft head tissues for adult subjects were derived from T1-weighted MR images of the heads of a 36-year-old healthy Asian male (subject A1) and two healthy Caucasian males: a 42-year-old (subject A2), and the Atlas Man (subject A0, also known as Colin27 at the MNI website [24]). The first two images were obtained with a 3T Allegra and the third with 1.5 T Magnetom Symphony scanners (Siemens Healthcare, Erlangen, Germany). The bone structure for these three subjects was derived from CT scans recorded with a GE CT scanner (General Electrics, Fairfield, United States). The acquisition matrix was 256 × 256 × 256 with a voxel size of 1mm × 1mm × 1mm in both the CT and T1 scans. Retrospective pediatric CT and MRI data were acquired by data mining the clinical image repository of the Washington University BJC Health System in St. Louis, Missouri, United States. A query preparatory to research was conducted against a system that indexes Radiology reports [37]. This initial query identified 174,000 possible pediatric records. The more focused search on recent years 2006-2012 and based on the search string “CT+MR+CH (Children’s Hospital)” was submitted
Head Models for dEEG Source Localization 279 to the repository and yielded 11,000 potentially useful cases. Based on an initial sampling of this data, we predicted a 5% acceptance rate of data appropriate for constructing pediatric head models. An additional search term indicating head/brain (CT + MR + brain + head + CH) resulted in a total 2,500 exam reports. Search criteria were iteratively refined by review of radiology report text for actual presence of both MRI and CT scans, and by no more than a 6 month time interval between the two scans. As a result, 385 subjects were selected for retrieval and visual examination using a research PACS (Philips Healthcare, Andover, MA). Exclusion criteria were further refined through visual inspection for gross anomalies, resulting in data for 131 subjects being selected, de-identified, and entered into the study. Further reduction in the subject population occurred during morphometric analysis and visual inspection due to factors such as clipped field of view and subtle motion artifacts. Ultimately a total of 63 usable pediatric subjects (covering the age range between 0 to 18 years old) were entered into analysis. This represents 16% of the 385 subjects that passed initial screening or 0.04% of the initially identified potential subjects available in the clinical repository.
Figure 1. The diagram showing the data and workflow in source localization. MRI and CT may be subject- specific or warped from atlases. Sensor locations may be also subject-specific from Geodesic Photogrammetry System [36], or based on average sensor locations. Conductivities may be estimated [28] or values from the literature may be used. Lead fields calculation performed with FDM (this paper) or other known methods (FEM, BEM) [7]. Inverse matrix may be one of the published methods, e.g.: Minimum Norm, LORETA, sLORETA and LAURA [8].
Somatosensory EEG data collection experimental paradigm and recording: Two adult male subjects (A1 and A2) were positioned in a comfortable chair with their feet flat on the floor and rested their head on a chin-rest to avoid head movement artifacts. Each participant was instructed to remain relaxed and refrain from blinking as much as possible while staring at a fixation point throughout the
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EEG recording. Digit I of the left and right hands were stimulated individually using a custom-made piezo-electric stimulator. During the recording, the piezo was lightly taped to the digit of interest, and the participant’s hand was placed between two cotton towels to muffle the “tap” sound created by the stimulator. The stimulations were segmented into blocks in which each digit was stimulated at a rate of 2Hz for 200 seconds, resulting in 400 trials per block. Each digit was stimulated for one block before the tapper was moved to the other hand, and then was moved back once, resulting in 4 staggered blocks and 800 trials per digit. EEG was acquired using a 256-channel array EGI EEG 300 system and sensor positions were determined using the Geodesic Photogrammetry System (GPS) [36]. Head Model Construction: To build anatomically accurate head model geometry, the T1 MRI images were automatically segmented into seven tissue types (brain gray matter, brain white matter, CSF, scalp, eyeballs, air and skull), and then the CT images were coregistered (or warped) to the MRI using EGI’s segmentation and image processing package, BrainK [32,33]. BrainK is a set of automated procedures for characterizing the tissues of the human head from MRI, CT, and photogrammetry [36] images. BrainK achieves five major tasks: (1) image segmentation, (2) registration of head model components (MRI, CT, and EEG sensor positions from Geodesic Photogrammetry), (3) cortical surface extraction, (4) tessellation of the cortical surface for oriented dipoles, or generation of dipole triples on the gray matter grid, and (5) Talairach transformation (not used in the present analyses). BrainK MRI segmentation recognizes the white matter (WM) and the gray matter (GM). It partitions these into two hemispheres and it differentiates cerebellum from cerebrum. In addition, an entire head mask and the two eyeballs are recognized as well in the segmentation component. The eyeballs are important for the electrical head model because of the large far fields generated by their cornea-retinal potentials. In the development of BrainK, Li [32] introduced a novel Relative Thresholding (RT) method for accurate tissue segmentation in the presence of MRI field inhomogeneity. Given the results of RT performed on a region of interest (ROI), BrainK also implements a novel sophisticated morphological image analysis (SMIA) technique and a cell complex based morphometric image analysis (CCMIA) method for white matter extraction, gray matter extraction, scalp extraction, and, topology correction of the cortical surface mesh. BrainK uses a priori knowledge (including structural, geometrical, and morphological observations on the neuroanatomy, and radiological observations on the structural imaging) to enable automated, accurate, and fast segmentation (performed by a trained technician in 20-30 minutes). Once the initial tissue segmentation has been conducted, there are several workflow paths that can be chosen based on the available subject specific data. Each workflow scenario represents a different way in which a skull can be registered. For example, the scenario Atlas to MRI is used when an individual CT scan is unavailable but an individual T1 MRI is. In this scenario, an adult atlas skull will be registered to the MRI geometry and will act as a guide for bone placement within the head. Due to the developmental differences in skull geometries in infants (i.e. presence of fontanels), an individual CT is always preferred. In this study, the workflow CT to MRI was used to generate all subject specific head models; a scenario that takes a subject’s own CT and warps it to the geometry defined in the MRI. In all scenarios, when the skull registration is conducted, the resulting head segmentation includes the following tissue types: WM, GM, CSF, bone, flesh, eyeball and air, in which the WM and the GM are further partitioned into two cerebral hemispheres and the cerebellum (Figure 2a). For all workflow scenarios, following skull registration, a generic Geodesic Sensor Net spherical sensor cloud is warped onto the head contour of the subject. For the scenarios of Atlas to MRI, MRI to CT, and CT to MRI, an additional sensors-to-head registration procedure is conducted to register the EEG sensor position cloud onto the head surface using several fiducial landmarks. For the scenario Atlas to EEG sensors, an individual sensor cloud from Geodesic Photogrammetry acts as a template
Head Models for dEEG Source Localization 281 for which any given head model warps to the physical positions of the sensors measured with photogrammetry. This allows users to rescale a generic head model atlas to the individual’s actual head shape. A head model (one that has a full brain segmentation and skull registration) is required to be completed before sensor transformation can be accomplished. After sensor registration, dipoles are allocated in two modes: oriented or triples. If the individual’s MRI is available, the cortical surface is extracted, tessellated into patches, and an oriented dipole is fitted to the vector sum of the normals of all the triangles in the surface mesh of each patch, thereby describing an equivalent dipole model for that surface patch. If the individual’s MRI is not available, then triple dipoles (fitting x, y, z components of the unknown orientation) are distributed evenly throughout the cortical gray matter of an atlas brain on a regular grid with a user specified spacing (typically 7 mm or 5 mm).
Figure 2. (a) BrainK Segmentation and CT to MRI coregistration differentiating scalp, skull, CSF, GM and WM in model C1 (a 6 month old subject). (b) A 128 sensor net registered on the same infant head. (c) Cortical surface generated. (d) Oriented dipoles set assigned to each cortical. Forward Problem: The relevant frequency spectrum in EEG and MEG is well below 1 kHz, and most studies deal with frequencies between 0.1 and 70 Hz. Therefore, the volume conduction in EEG/MEG can be well described by the quasi-static approximation of Maxwell’s equations, the Poisson equation. The electrical forward problem can be stated as follows: given the positions, orientations and magnitudes of current sources, as well as geometry and electrical conductivity of the head volume Ω calculate the distribution of the electrical potential on the surface of the head (scalp) ΓΩ. Mathematically, it means solving the linear Poisson equation [7]:
()=S, in (1) with no-flux Neumann boundary conditions on the scalp:
() n = 0, on ΓΩ . (2)
Here = ij(x,y,z) is an inhomogeneous tensor of the head tissues conductivity and S = -I ( r-r+)
+I ( r-r-) is the source current configuration constructed in the simplest case from a source and a sink of strength I at the vector locations r+ and r- . Having computed potentials (x,y,z) and current densities J=- (), the magnetic field B can be found through the Biot-Savart law. In this paper, we do not consider anisotropy or capacitance effects (the latter because the frequencies of interest are too small), but they can be included in a straightforward manner. Eq. (1) becomes complex-valued, and complex admittivity should be used [7, 38].
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Lead Fields Calculations and Numerical Implementation: Lead Fields are defined as forward projections of unit strength dipoles’ potential fields from cortex to scalp sensors. It is a matrix with the dimension: number of sensors (typically 256 or 128) by number of dipoles (typically 2400). The EEG session specific LFM requires a session specific set of sensor coordinates. A generic LFM for a given subject head volume can be calculated for more dense coverage of scalp (several thousand points) and then potentials for session specific sensor locations interpolated from this generic LFM on scalp. It can be accomplished by the “brute force” approach launching separately the forward solver for each dipole position. However, one can reduce the required number of forward solutions drastically by using the reciprocity principle for LFM calculations [7, 38, 40]. We have implemented both these approaches as they can be parallelized effectively in a multi-core cluster environment or desktops with modern Graphic Processing Units (GPUs: http://www.gpgpu.org/). To solve Eq. (1) numerically we built a finite difference forward problem solver for the volume conduction based on the multi-component alternating directions implicit (ADI) algorithm [27,28, 40]. The numerical method is a generalization of the classic ADI algorithm, but with improved stability in 3D. We chose the FDM approach over FEM and BEM methods for its simplicity of implementation from the MRI/CT tissue segmentation map that produces a cubed lattice of nodes. Therefore, meshes are easy to construct (once segmentation is accomplished) as the cubic/rectangular elements can be mapped directly from the voxels of the medical images (3D MRI/CT scans), including all relevant anatomical details (in contrast to BEM and FEM). To set up the boundary conditions in the heterogeneous biological media within a complex geometry like the human head, the method of the embedded boundaries is used in FDM. Here an object of interest is embedded into a cubic computational domain with extremely low conductivity values in the external complimentary regions. This effectively guarantees there are no current flows out of the physical area (the Neumann boundary conditions, Eq. (2), is naturally satisfied). The forward computations using high resolution structural models and the inverse conductivity search, which is composed of multiple forward solutions, represent computationally intensive tasks and require high performance computing. The electrical forward and inverse conductivity optimization models have been implemented in a parallel C/C++ code (OpenMP and MPI) and CUDA to run on multi-core cluster and GPGPU platforms [27,40]. EEG Source Localization: Estimating the source of EEG with distributed source models consists in first, allocating a grid of unit strength dipole sources with fixed locations and orientations in the whole brain volume or on the cortical surface, computing LFM for this dipole set, and then, estimating inverse solution for amplitudes of dipoles on this grid using the computed LFM and the scalp EEG data. For fixed positions and orientations, at a given time, the relation between source moments and the data can be stated as:
KJ , (3)
N 1 N 1 where ° e is the electric potential;J ° j is the (unknown) amplitude and orientation of N N source distribution;K ° e j is the lead field matrix linking the current sources to the electric Ne 1 potential; ° is the additive noise component (perturbation); Ne is the number of electrodes;
N j is the size of source distribution; N d is the number of dipoles. Estimating the source amplitudes consists in solving this noisy linear system. Considering the physics of data formation in EEG, source estimation is ill-posed ( N = N ). For a given data set, e j there is no unique source distribution. Further, after discretizing to a limited number of sensors, the corresponding K operator is ill conditioned, thus the solution is highly sensitive to small perturbations
Head Models for dEEG Source Localization 283 in data and the model. This problem belongs to the linear ill-posed inverse problems. Methods for solving this problem, called inverse procedures, must take regularizing schemes into account to prevent the oscillatory behavior of the solutions in presence of noise. The basic regularization methods range from constrained Minimum Norm (MN) [2-5,8] to minimization of regularized least-square cost functions such as:
2 Jˆ argmin KJ L(J) , J where is a positive scalar that is called the regularization parameter, and balances the data fidelity 2 2 term KJ and prior term L(J) ; represents the square of the l -norm. The prior 2 regularization operator L(g) contains the priors that one wishes to take into account. For example, this operator can be taken in the form of the identity operator, which produces solutions with a minimum norm (MN), the gradient or weighted Laplacian operators (LORETA), local autoregressive average
(LAURA), cortical surface laplacian (CSL), l1 -norm of the source amplitudes. In this paper, the MN and sLORETA [8] methods for the EEG inverse problem are used. The analytic solution for the MN 1 ˆ T T ˆ 1/2 ˆ method is J K KK I . The sLORETA solution is following: J C ˆ J , Ne l J ll l ˆ th th where J is the current density estimate at the l dipole and C ˆ is the l diagonal of l J ll 1 T C ˆ KKK I K J Ne , for l= 1, …, Nj. The distributed inverse problems can be divided into two scenarios. Scenario 1 (triple dipoles) estimates an unknown current density distribution, including both orientations and amplitudes of the source distribution. Scenario 1 assumes N 3N and K ° Ne 3Nd in Eq. (3). The root mean j d T 2 2 2 square (RMS) R R ,L , R ° Nd 1 is defined as R J J J 3, where 1 Nd i i,x i,y i,z T T J J ,L , J ° N j 1 , J J J J ° 31 , for i 1,L , N . 1 Nd i i,x i,y i,z d Scenario 2 (oriented dipoles) estimates only unknown amplitudes of the source distribution given known orientations of dipoles. Since Scenario 2 assumes N j Nd in Eq. (3), there is no need in calculation of RMS.
RESULTS
Model Warping
Several head models based on 3 original retrospective pediatric MRI/CT volumes (C1, C2, C3), and 3 prospective adult MRI/CT volumes (A0, A1 and A2) were created (see Table 1). The pediatric models represent the most distinct developmental age clusters [37]: infants 0 – 2 years old (C1), preschoolers 2- 6 years old (C2) and school age children 6 – 17 years old (C3). In most studies presented here, an infant model (C1, see Figure 2) for a 6 month-old was chosen as the ground-truth reference model. It was compared with derivative models from a preschooler pediatric model (C2) (6
284 Jasmine Song, Kyle Morgan, Sergei Turovets et al. years old), a teenager head model (C3) (14 years old), and an adult model (A1) to assess the effects of head model mismatch on source estimation results. The notations for those rescaled models (warped to the physical size of C1, but retaining the original morphology and having LFMs recalculated) are: C2’, C3’, A1’ (see Table 2). We also created a 6 month old model with only the adult skull atlas (A0) warped and adjusted by thickness to match subject C1’s specific MRI (notation A0s) and an adult mismatched model (A2 warped to A1, A2’). In all cases of warping the older age models to the reference infant model C1 the fontanel structure was lost (see Figure 3).
Figure 3. Skulls of three typical geometries. (a) The reference infant model C1 contains frontal and occipital fontanels. (b) Skull of the warped model A0s (only skull of A0 warped and adjusted to C1 MRI). (c) Skull of the warped model A1’ (the whole adult head rescaled to the infant size). Notice that warped models have no fontanels. Table 1. The original human subject models C1 C2 C3 A0 A1 A2 Age (years) 0.5 6 14 NA 36 42 Gender NA NA NA M M M Original MRI/CT yes yes yes yes yes yes
Table 2. Derivative head models C2’ C3’ A1’ A2’ A0s Warped Target Model C1 C1 C1 A1 C1 All Tissue Warped Yes Yes Yes Yes No (skull only) Average Literature Values Yes Yes Yes Yes Yes for Tissue Conductivity Derivative LFM Yes Yes Yes Yes Yes
The quality of the warping process can be evaluated based on the data presented in Tables 3 and 4, which show distances between left and right prearicular fiducial landmarks in the original models and after rescaling. The distances after warping match the original C1 model fiducial distance with accuracy better than 1% and about 0.1% in warping A2 to A1.
Table 3. Distance between Fiducial Landmarks for Original Head Models Model C1 C2 C3 A1 A2 Distance (cm) 12.24 13.73 14.81 15.88 15.64
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Table 4. Distance between Fiducial Landmarks for Warped Head Models Model C2 C3’ A1’ A2’ Distance (cm) 12.20 12.12 12.16 15.90
Effect of Head Geometry Mismatch on Source Estimation Accuracy
For this evaluation, a forward projection from a dipole source (near the occipital fontanel) oriented perpendicular to its corresponding cortical patch was generated (Figures 4a and 4b). For all head models used to estimate the source shown in Figure 4a, LFMs were generated using three orthogonal moments for each dipole location (“triples”). For all LFM calculations, the following conductivity values were used based on the average literature values: 0.46 S/m (scalp), 0.018 S/m (skull), 1.79 S/m (CSF), 0.25 S/m (GM), 0.33 S/m (WM). To investigate the model mismatch effects we compared estimated source solutions obtained from the original model (C1) and the derivative models (C2’, C3’, and A1’). The MN technique was used to estimate the sources. The metric employed for source localization accuracy in this paper is the localization error distance (LED). The LED is the Euclidean distance between the locations of the true dipole and the dipole with maximum intensity in the source estimation. Smaller LEDs represent more accurate estimates.
Figure 4. Source estimates as a function of head model. (a) Location of source generator from C1; (b) Forward projection of scalp potential for dipole shown in (a); (c) ESI solution obtained with C1 model; (d) ESI solution obtained with C2’ model; (e) ESI solution obtained with C3’ model; (f) ESI solution obtained with A1’ model.
Table 5. LED of ESI solutions as a function of head geometry Model C1 C2’ C3’ A1’ LED 10.5 mm 16.5 mm 15.6 mm 32.7 mm
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As shown in Table 5, the LED is minimal when a head model matches the model that generated the scalp potential data. When a subject specific head models are not available, the warped older pediatric group models (C2’ and C3’) are still reasonable for EEG source localization (LEDs are increasing in this case up to 16 mm). The warped adult model, A1’ resulted in the large localization error of ~33 mm.
Effect of Head Model Resolution on Source Estimation Accuracy
The motivation of this study is the fact that an infant head is about twice as small as an adult head and the skull is thinner. Therefore, it is reasonable to expect that a higher resolution model would be required for an infant head to match the same finite difference node density per skull voxel in adults captured by 1 mm resolution images. Another reason is that a current dipole is approximated in FDM as two monopoles at adjacent finite difference grid nodes with the amplitude I (Eq. 1) divided by the voxel volume. Therefore, the overall forward projection will be more accurate for the higher FDM resolution. Resampled subject C1 head volumes were created from the original 1 mm resolution C1 head model. In order to manipulate image resolution of the original head model (.88 mm × .88 mm × .9 mm), each voxel of the post-processed data is either merged with its 6 neighboring voxels or subdivided into 8 separate voxels, thus decreasing and increasing image resolution respectively (Figure 5).
Figure 5. Head models of a 6-month-old infant (C1) at 2 mm (left), 1 mm (center) and 0.5 mm (right) resolutions. Sagittal slices (top), sensors on scalp (bottom).
When decreasing resolution, sets of merged voxels were given a uniform tissue type based on the tissue type that was most common amongst the group before the merge. Due to aliasing, dipoles that were located in WM as a result of voxel merging were automatically deleted and not used for analysis. When increasing resolution, the subdivided voxels were assigned a single tissue type that matches the tissue of the voxel from which they were derived.
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Figure 5 shows the effect of the mesh resolution variations for the reference infant model, C1. Sagittal slices show the different FDM grid voxel size of 2 mm3, 1 mm3, and 0.5 mm3. It can be seen in Figure 5 that reduction of resolution to 2 mm leads to visible bumps on the scalp surface (bottom left corner) and disruption in skull morphology (upper left corner sagittal view), as the actual anatomical resolution was decreased in this case along with FDM resolution, while transition from the original 1 mm resolution to the interpolated 0.5 mm resolution simply made FDM grid denser but actually did not improve the original image resolution. In this evaluation, the same 128-sensor positions were registered to all three C1 resolution models. A forward projection for one dipole (Figure 6a) using the 0.5 mm resolution model served as the ground-truth location. The forward projections (lead fields) of this dipole in three resolution cases were calculated and plotted versus sensor number (Figure 6b).
Figure 6. Resolution variation effects on source localization: (a) ground truth dipole location near the occipital fontanel on the cortex; (b) forward projection of potentials to EEG sensors (128 channels) as a function of model resolution; (c-e) 3D views of forward projections to scalp; (f-h) ESI solutions (sLORETA) as a function of model resolution.
One can see that the dipole projection to the scalp is tighter (the full width at half maximum (FWHM) is smaller) for the 0.5 mm resolution, while projections of the same dipole forward fields at 1 mm and 2 mm are more diffused as expected. The ESI solutions (Table 6) using the sLORETA technique derived from the 0.5 mm resolution model correctly localized the dipole (LED is 0 mm, no
288 Jasmine Song, Kyle Morgan, Sergei Turovets et al. resolution mismatch). The source distributions for the lower resolutions are more diffuse, as expected (the error is of 12 mm for this dipole in both mismatched resolutions).
Table 6. LED of ESI solutions as a function of model resolution Model Resolution 0.5 mm 1 mm 2 mm LED 0 mm 12.15 mm 11.91 mm
Effect of Tissue Conductivities on Source Estimation Accuracy
To evaluate how inaccurate assumptions of tissue conductivities will impact ESI solutions, LFMs were generated for three different models (C1, A0s, and A1’) while varying the skull conductivity (which is the most resistive tissue) across six values (0.004 S/m, 0.018 S/m, 0.1 S/m, 0.2 S/m, 0.35 S/m and 0.45 S/m). This resulted in 18 LFMs. The model with skull conductivity set to 0.1 S/m in each model (assuming that infant bones are more conductive on average than in adults) served as the ground truth. From the ground-truth model, forward projections were generated for each dipole and ESI solutions were derived using MN and sLORETA. The LEDs presented in Table 7 represent the mean LED (i.e., averaged ESI solutions for all dipoles) for each condition.
Table 7. Errors of ESI depending from conductivity and/or model mismatch. The mean LEDs are given in mm. The ground truth LFMs for skull conductivity of 0.1 S/m results in the minimal LED in all three geometries with both MN and sLORETA. Method Head Skull Conductivity (S/m) Geometry 0.004 0.018 0.1* 0.2 0.35 0.45 MN C1 17.25 15.49 15.06 15.12 15.19 15.19 A0s 18.42 16.22 15.18 15.34 15.39 15.46 A1’ 19.75 18.26 13.97 14.98 16.27 16.63 sLORETA C1 3.72 0.27 0 0 0 0.003 A0s 7.63 1.14 0 0 0.017 0.066 A1’ 10.56 4.60 0 0.08 0.54 1.045
As can be seen, LED is minimal for both MN and sLORETA solutions when the conductivity values used in the head model matches with those used to generate the synthetic EEG data. Use of the head models with the correct skull conductivity values results in the minimal LEDs. When skull conductivity is set to be low (skull is more resistive), the LEDs are larger. On the other hand, when skull is effectively replaced bypio soft tissues (conductivity values approaching conductivity of surrounding tissues), the effect is small. The steepest change in LED was observed in the range of conductivities between 0.004 S/m and 0.1 S/m and more pronounced for the rescaled adult head models, A1’. We believe this is due to the fact that the relative skull thickness of adult model A1, even after rescaling, is larger than in the reference infant model C1, therefore the thicker skull conductivity misspecifications have more impact on the forward solution.
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Model Mismatch in SEP experiment
This experimental EEG study was motivated by the need to verify our simulation studies. The expected brain activation regions in SEP experiments are generally well known from human brain anatomy and can be further confirmed by an independent fMRI study (ROI in Figure 7). The dEEG data was processed using Net Station Version 4.5.5 software (Electrical Geodesics, Inc, Eugene, United States). Each subject’s data was filtered using a 60 Hz high-pass FIR filter prior to visual bad channel replacement. Manually marked bad channels were replaced using spherical spline interpolation. Data was segmented into 300 ms stimulus-locked epochs from 100 ms prestimulus to 200 ms poststimulus. The ERPs were then averaged and corrected to a 100 ms baseline. Channels contaminated with eye or movement artifacts were identified by a computerized algorithm and were eliminated. Following computerized bad channel replacement, data were mean corrected and referenced to vertex (Cz). ESI using the sLORETA technique was performed on the ~10 ms time window just before the peak of P50 SEP component. Figure 7 shows the ESI solutions for subject A1 and A2 (sLORETA regularization constant of 0.1). In both subject specific models, clear congruency can be seen in source localization relevance to their predefined anatomical ROI. For subject A2 specifically, the S1 thumb region appears to be functionally defined along the posterior and anterior banks of the postcentral gyrus. In order to demonstrate the importance of head geometry on ESI solutions, we generated a new head model, A2’. This model was applied to the SEP data used for the A2 solution. Figure 7, top right corner shows the results. Notice that the bulk of electrical activity has shifted from the posterior and anterior banks of the postcentral gyrus (S1) to the center of the postcentral gyrus and posterior bank of the precentral gyrus (M1) even though the physical contours of the brain have been unchanged.
Figure 7. Effects of model mismatch on SEP localization. Top row left to right: subject A2 highlighted anatomical ROI, A2 model specific ESI solution, A2’ ESI solution for A2 SEP data (mismatch). Bottom row left to right: A1 highlighted anatomical ROI, A1 model specific ESI solution, A1 ESI solution for A2 SEP data (mismatch).
Finally, we aimed to show what would happen when EEG data is localized to another subject’s head model. As can be seen in Figure 7, bottom right corner, EEG data from subject A2 was localized in the individual head model of A1, using the same time point and activity as above. As in the previous mismatch, the bulk of electrical activity has shifted away from the ROI defined for A2, only this time the activity has shifted ventrally (more toward the functional location of subject A1’s thumb).
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DISCUSSION AND CONCLUSION
The present study demonstrates the importance of accurate physical measurement of head geometry and conductivity for accurate electrical source localization of dense array EEG. Particularly for infants and young children, using rescaled adult electrical head models produces inaccurate results. On the other hand, if the geometry of the child’s head is approximated, such as through warping an older child’s model to the child’s head shape (Figure 4), the source results are a reasonable approximation to what can be gained from using the individual’s MRI and CT. Anatomical data for constructing electrical head models, based on MRI and CT images for a range of age, gender, and ethnicity groups are becoming more readily available [24- 26]. Using these data to create head model atlases with appropriate conductivity specifications is an important near term goal. Given appropriate conductivities, electrical head atlases can be constructed for a look-up repository across the developmental range (from infancy to old age) and across gender and racial groups. To adjust these atlases to a specific subject, a warping procedure to the subject’s own head shape (measured noninvasively such as with photogrammetry [36]) can be used and give reasonably accurate results, as suggested by the analyses above. One approach for gaining accurate head conductivity for each age, sex, and racial group is to use electrical impedance tomography (EIT) for head impedance scanning (impedance is the reciprocal of conductivity). In this approach, harmless currents are injected into the head, and the potential field (“impressed EEG”) created by volume conduction of this current through head tissues is measured [1, 14, 27, 28, 34, 35]. From the impressed EEG and the known position of the injected current on the scalp, properties of the head tissue can be inferred through Ohm’s law. Ideally, subject specific electrical models based on native MRIs and CTs structural information and informed with tissue conductivity specifications are the best choice for the most accurate ESI. However, MRIs and CTs are not usually available for many adult subjects and the majority of infants and young children. In such cases, as we have shown on example of pediatric models, one can use a reasonably close by age atlas model and warp it to the subject specific EEG sensor positions cloud (obtained noninvasively with photogrammetry). Adult models rescaled to the infant size are not a good choice due to the far distant morphology (which makes conductivity uncertainties’ impact amplified as well), producing as a result localization errors up to 3 cm. We have shown previously [28] that conductivity fitting to experimental impressed EEG is feasible. The actual conductivity values for infant skull are not well known presently, but unlikely to be in the adult range of low values. Therefore further studies are needed for practical noninvasive estimation of head impedance for regional tissue conductivity estimates in infants. In addition to EEG, there are several other applications for which accurate (preferably subject specific) models of head-shape, tissue boundaries and tissue properties are required. These range from biomechanical models of cranial injury to imaging techniques such as MEG and EIT [1,8,16,28]. With the addition of optical diffusion equations and tissue parameters to the FDM framework, the child head model database can be extended to diffuse optical tomography (DOT) and Near Infrared Spectroscopy (NIRS) [39]. Finally, accurate electrical head models are needed for more accurate interventions, such as with Transcranial Electrical Stimulation (TES) and Transcranial Magnetic Stimulation (TMS) in neurorehabilitation for stroke and TBI patients, treatment of depression and other neurological disorders [17]. Although the specific issues vary in each of these applications, an accurate database of electrical head models could allow neuroimaging and neurointerventional technologies to be extended more accurately to work with children.
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ACKNOWLEDGMENTS
This project was supported by the National Institute of Neurological Disorders and Stroke (Grants 5R43NS067726-02 and 5R44NS056758-04).
REFERENCES
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[16] van Uitert R, Weinstein D, Johnson C. Volume Currents in Forward and Inverse Magnetoencephalographic Simulations Using Realistic Head Models. Ann. Biomed Eng. 2003;31(1):21-31. [17] Wagner T, Valero-Cabre A, Pascual-Leone A. Noninvasive Human Brain Stimulation. Annu Rev Biomed Eng. 2007;9:19.1–19.39. doi: 10.1146/annurev.bioeng.9.061206.133100. [18] Awada KA, Jackson DR, Baumann SB, Williams JT, Wilton DR, Fink PW, Prasky BR. Effect of conductivity uncertainties and modeling errors on EEG source localization using a 2-D model. IEEE Trans Biomed Eng. 1998;45(9):1135-1145. [19] Vanrumste B, Van Hoey G, Van de Walle R, D'Havé M, Lemahieu I, Boon P. Dipole location errors in electroencephalogram source analysis due to volume conductor model errors. Med. Biol Eng Comput. 2000;38(5):528-534. [20] Pohlmeier R, Buchner H, Knoll G, Rienäcker A, Beckmann R, Pesch J. The influence of skull- conductivity misspecification on inverse source localization in realistically shaped finite element head models. Brain Topogr. 1997;9(3):157-162. [21] Huiskamp G, Vroeijenstijn M, van Dijk R, Wieneke G, van Huffelen AC. The need for correct realistic geometry in the inverse EEG problem. IEEE Trans Biomed Eng. 1999;46(11):1281- 1287. [22] Acar ZA, Makeig S. Effects of forward model errors on EEG source localization. Brain Topogr. 2013;26(3):378-396. [23] Roche-Labarbe N, Aarabi A, Kongolo G, Gondry-Jouet C, Dümpelmann M, Grebe R, Wallois F. High-resolution Electroencephalography and source localization in Neonates. Hum. Brain Mapp. 2008;29:167-176. [24] MNI pediatric and adult template head models. Available from: http://www.bic.mni.mcgill.ca/ ServicesAtlases/ [25] Fonov V, Evans AC, Botteron K, Almli CR, McKinstry RC, Collins DL; Brain Development Cooperative Group. Unbiased average age-appropriate atlases for pediatric studies. Neuroimage. 2011;54:313-327. [26] Shi F, Yap PT, Wu G, Jia H, Gilmore JH, Lin W, Shen D. Infant brain atlases from neonates to 1- and 2-year-olds. PLoS ONE. 2011;6(4);e18746. doi: 10.1371/journal.pone.0018746. [27] Salman A, Turovets S, Malony A, Volkov V. Multi-cluster, mix-mode computational modeling of human head conductivity. IWOMP 2005/2006. LNCS. 2008;4315:119-130. [28] Turovets S, Poolman P, Salman A, Malony A, Tucker D. Conductivity analysis for high- resolution EEG. In: Proceedings of 2008 International Conference on Biomedical Engineering and Informatics. IEEE Computer Society. 2008;386-393. [29] Durston S, Casey BJ. What have we learned about cognitive development from neuroimaging? Neuropsychologia. 2006;44:2149-2157. [30] Luna B, Garver KE, Urban TA, Lazar NA, Sweeney JA. Maturation of cognitive processes from late childhood to adulthood. Child Dev. 2004;75(5):1357-1372. [31] Murias M, Swanson JM, Srinivasan R. Functional connectivity of frontal cortex in healthy and ADHD children reflected in EEG coherence. Cerebral Cortex. 2007;17:1788-1799. [32] Li K, Malony A, Tucker DM. Automatic brain MR image segmentation by relative thresholding and morphological image analysis in The First International Conference on Computer Vision Theory and Applications-VISAPP; 2006; Setubal, Portugal. [33] Li K. BrainK: Structural Image Processing for Electrical Models of the Human Head. Neuroinformatics. Forthcoming 2013. [34] Oostendorp TF, Delbeke J, Stegeman DF. The conductivity of the human skull: Results of in vivo and in vitro measurements. IEEE Trans Biomed Eng. 2000;47:1487–1493.
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[35] Goncalves SI, de Munck JC, Verbunt JP, Bijma F, Heethaar RM, Lopes da Silva F. In vivo measurement of the brain and skull resistivities using an EIT-based method and realistic models for the head. IEEE Trans Biomed Eng. 2003;50(6):754-767. [36] Russell GS, Eriksen KJ, Poolman P, Luu P, Tucker DM. Geodesic photogrammetry for localizing sensor positions in dense-array EEG. Clin. Neurophysiol. 2005;116:1130–1140. [37] Smith K, Politte D, Reiker G, Nolan TS, Hildebolt C, Mattson C, Tucker D, Prior F, Turovets S, Larson-Prior LJ. Automated measurement of pediatric cranial bone thickness and density from clinical computed tomography. Conf Proc IEEE Eng Med Biol Soc. 2012;2012:4462-5. doi: 10.1109/EMBC.2012.6346957. [38] Walters C. Influence of tissue conductivity and anisotropy on EEG/MEG based source localization in the human brain. PhD Thesis, University of Leipzig, Germany; 2003. [39] Gibson AP, Hebden JC, Arridge SR. Recent advances in diffuse optical imaging. Phys Med Biol. 2005;50(4):R1-R43. [40] Malony AD, Salman A, Turovets S, Tucker D, Volkov V, Li K, Song JE, Biersdorff S, Davey C, Hoge C, Hammond D. Computational modeling of human head electromagnetics for source localization of milliscale brain dynamics. Stud. Health Technol Inform. 2011;163:329-35.
Received: June 17 2013 Revised: June 24 2013 Accepted: June 28 2013
Funct Neurol Rehabil Ergon 2013;3(2-3):295-317 ISSN: 2156-941X © Nova Science Publishers, Inc.
A NOVEL ERP PATTERN ANALYSIS METHOD FOR REVEALING INVARIANT REFERENCE BRAIN NETWORK MODELS
Amit Reches1, Dan Kerem1, Noga Gal1, Ilan Laufer1, Revital Shani-Hershkovitch1, Dalia Dickman1, and Amir B. Geva1,2 1ElMindA Ltd., Herzliya, Israel 2Electrical and Computer Engineering, Ben Gurion University of the Negev, Beersheba, Israel
ABSTRACT
Background: Objective and reliable neuro-electrophysiological methods for the longitudinal monitoring of a patient’s cognitive state are scarce. Since baseline neuro-electrophysiological measurements are generally not performed as standard practice, this type of longitudinal monitoring requires an invariant normal reference to which the individual brain activity may be scored, with sufficiently high within-subject repeatability. Methods: Group-common functionally connected Reference Brain Network Models (RBNMs) were extracted with the Brain Network Activation (BNA) Technology from multi- channel ERPs of 120 young healthy subjects (Reference Group) who underwent the three-stimulus Auditory Oddball Task. The test-retest repeatability of an age-matched group of 116 subjects (Database Group), whose individual brain activity on the oddball task was scored on the RBNMs, was determined and the Standard Error of Measurement (SEM) computed as a measure of Minimal Important Clinical Difference. The general applicability was cross-validated on 36 healthy patients of a wider and marginally overlapping age-range (Validation Group). Results: Intraclass correlation values of scores on repeated tests in the Database Group ranged between 0.58-0.81. SEM values ranged from 14.1-17.9, on a score scale of 0-100. Scoring, repeatability and SEM applicability were all successfully validated on subjects from the Validation Group, yielding values that were similar to or higher than those of the Database Group. Conclusions: The BNA generated brain network models are largely invariant and repeatable and as such may be useful for diagnosis and follow-up of disease progression and treatment management. To further test the algorithm’s utility, additional research should be conducted on diseased populations.
Keywords: Functional networks; Brain Network Activation (BNA); ERP; Auditory oddball Task; Normative database; Repeatability; Personalized medicine
Correspondence: Dr. Amit Reches, ElMindA Haminhara 16 st., Herzliya, Israel 46586 Email: [email protected].
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1. INTRODUCTION
Following neurophysiological changes over time relative to a baseline or to a normal reference is important in individual patient management, for the monitoring of both disease progression and response to treatment. Today, managing of CNS pathology is mostly achieved through questionnaires and neuro-psychological tests, which often are subjective and qualitative. It has been proposed that quantitative analysis of EEG (qEEG) as well as components of evoked response potentials (ERPs) may be more informative, objective and appropriate clinical tools for longitudinal monitoring of neuro-cognitive diseases [1-3]. They also hold an advantage over other imaging methods in providing dynamical (at a millisecond timescale) parameters of brain function. In order to assess deviation from the norm, qEEG uses metrics such as frequency band spectral power ratios, coherence and other ERP features that are evaluated by statistical comparisons to normative databases. To capture the full representation of network dynamics, essential for the description of normal and pathological brain function [4], emphasis has been put on spatio-temporal relations reflecting functional connectivity between neuronal assemblages and networks, which underlie continuous EEG as well as ERPs. Such relationships, obtained through various imaging methods, are being promoted as additional potential candidates for detecting various CNS pathologies [5,6]. In this study, in accordance with the network dysfunction perspective, rather than the use of discrete parameters of brain activation, we propose using global parameters that describe network dynamics by utilizing a novel EEG network analysis method, reliant on the Brain Network Activation (BNA) algorithm. BNA is a newly developed ERP-based, network-oriented analysis that produces a spectro-spatio- temporal activity template of scalp potentials in subjects performing a neuro-cognitive task [7]. Unlike other EEG/ERP-based analytical methods, BNA does not evaluate the individual in terms of discrete values such as latency, amplitude, frequency power content, coherence or complexity. Rather, it quantifies/scores the overall resemblance of the individual’s electrical activity in response to a cognitive task to an invariant model response that serves as a reference characterizing the majority of the normal population: the Reference Brain Network Model (RBNM). To do so, BNA utilizes a graph as the formal representation of a group-common network in which the nodes represent time, location, frequency-band and amplitude of an electrical event and the edges representing the level of coordinated activity among nodes. Therefore, the individual neurophysiological measure (the BNA Score) is not based on a discrete observed value of EEG activity such as relative or absolute power, but is derived at the level of entire network dynamics. In addition to the isolation of task-based RBNMs, the BNA algorithm is also used to establish a normative database of individual quantitative scores that could aid in diagnosis as well as in patient treatment management. There are two main goals for using a normative EEG/ERP database: a) quantifying individual differences and between-subject variability in normative brain function and b) establishing a robust normative framework for clinical diagnosis. Such a diagnosis is obtained by comparing the individual participant’s EEG patterns to the patterns of a reference population of healthy individuals. This is done to identify atypical features and to evaluate the magnitudes of deviations [8]. In essence, there are three standards that a normative database must follow in order to be clinically utilized towards these goals. First and foremost, the database must be reliable [1]. Reliability may be approximated from the test-retest repeatability of a large enough group of healthy subjects, all attending two identical sessions of an ERP-generating task. From such a dataset one may also derive the Standard Error of Measurement (SEM) which could be used to construct confidence intervals for mean scores and to determine the Minimal Clinically Important Difference that is surpassed when a non-random change in the response has occurred. The second requirement a database must adhere to is the ability to account for between subject variability. This variance is often considered a problem in normative
ERP Pattern Analysis Reveals Invariant Networks 297 databases due to group heterogeneity [9]. Finally, the third standard requirement that a normative database has to meet is cross-validation [2]. Due to cost considerations, most cross-validations were computed using the leave-one-out, a statistically weaker form of cross validation. The current study introduces several innovations relative to previous studies that constructed normative databases based on EEG data. First, individuals comprising the normative database were compared and scored against RBNMs identified by the BNA algorithm. As described above, this approach permits a more holistic presentation of the network dynamics of both the normative database and the individual subject. Second, although the BNA Score could be used as a single measure and viewed as the dependent variable, in this study, the difference between BNA Scores from two repeated visits (ΔBNA Scores) was not merely used to quantify repeatability but was also used to generate a normative database. Using difference scores greatly reduces the between-subject variance discussed above. Obtaining data through repeated scoring of the same person against the RBNM over time could enable monitoring of disease progression and treatment efficacy. Third, as opposed to previous attempts to construct an EEG based normative database, in the current study we employed a completely independent population of healthy subjects to cross-validate the normative database. In line with the three innovations presented above, the general structure of the manuscript comprises the following three-tiered stages:
A. RBNM Construction Stage: The extraction of task-specific RBNMs from a large group of young healthy subjects (Reference Group). The task chosen for this purpose is the auditory oddball task, a classic EEG paradigm that has been extensively used in neuro-cognitive studies and in many neurologically compromised patient populations [10]. B. RBNM Evaluation and Normative Database Assemblage Stage: For this stage another independent large group of healthy participants (Database Group), age-matched to the Reference Group was recruited. All participants underwent two sessions of the oddball task and were scored twice against the RBNMs. The resulting scores were used to construct both the BNA Score and the 2-visit ΔBNA Scores distributions of the normative database. They also served to evaluate the reliability (within-subject repeatability) of the BNA Scores. In addition, the SEM was determined from the ΔBNA scores and was used as a measure of the likelihood of a given test-retest score difference being due to natural daily variation. C. Validation Stage: validating the general applicability of the RBNMs and normative database, BNA score repeatability and SEM.
2. METHODS
2.1. Subjects
Reference Group: 120 healthy female (N=38) and male high school and college students, with an age range of 14 to 25 years (mean=18.6, median=18.3, SD=2.7) from York University (York) and University of Pittsburg Medical Center (UPMC). Database Group: 116 healthy female (N=67) and male high school and college students with an age range of 14 to 24 years (mean=19.3, median=19.2, SD=2.7), from Clinilabs Clinical Research Organization, New York (Clinilabs), University of Michigan (UMICH) and Vince & Associates Clinical Research, Kansas, USA (V&A). Validation Group: 36 healthy male (N=18) and female volunteers, with an age range of 23 to 64 years (mean=36.6, median=33, SD=12.2), tested at the Lowenstein Hospital Ra’anana, Israel.
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All subjects were right-handed and reported to have normal hearing, normal or corrected-to- normal vision, no history of special education, of neurological or psychiatric disease or of severe head injuries and not to consume any CNS-affecting medications. The study protocols for the three groups were approved by the Ethics Committee Boards for experiments involving human subjects of the respective research centers. All participants signed an informed consent before joining the study.
2.2. Task and Procedure
We utilized a sensory-gating version of the three-stimulus auditory oddball task in which three different types of auditory stimuli were pseudo-randomly presented, at an average rate of 1 each 1.5 sec, each lasting 120 ms, with a sound pressure level of 70 dB re 20 microPascals. A total of 80% of the stimuli ('standard'/'frequent') were pure tones of 2000 Hz. A total of 10% of the stimuli ('deviant/target') were pure tones of 1000 Hz. The remaining 10% of stimuli ('novel') were environmental sounds (e.g., telephone ring, dog bark), different for each stimulus presentation (Figure 1). Subjects heard the sounds binaurally, via earphones, and were instructed to press a button with their right index finger in response to 'target' stimuli only. The total number of stimuli in a session was 600, presented continuously in one ~16 min block. Only correct press/no press responses underwent ERPs analysis. Each session commenced with 10 practice trials (8 frequent and 2 target tones) in order to be familiarized with the experimental paradigm and the recording system. Reference Group subjects attended one visit, Database Group subjects attended two visits and the Validation Group attended three visits (henceforth: V1, V2 and V3), 7±3 days apart, at which time they performed the auditory oddball task. A subset (N=25) of the Database Group subjects repeated the task 6 weeks after attending V1.
Figure 1. Auditory Oddball Paradigm. Frequencies of occurrence for Frequent, Target and Novel stimuli were 80%, 10% and 10%, respectively.
2.3. Electrophysiological Data Acquisition
EEG of members of all groups was recorded with 64 Ag-AgCl active electrodes positioned according to the 10-20 international system. In the Reference and Database groups, HydroCel Geodesic Sensor Net of 256-channels (UMICH) and 128-channels (all other centers) net amps 300 amplifier of EGI (Eugene, Oregon) were used. In the Validation Group, A Biosemi Active Two EEG system (BioSemi Inc., Amsterdam, Netherlands) was used. Four electrodes, above and below the right
ERP Pattern Analysis Reveals Invariant Networks 299 eye, and on the outer canthus of each eye served to record eye movements via the electrooculogram. Subjects were instructed to avoid eye movements, blinking and body movements as much as possible, and to fix their gaze on some point in front of them during task performance. Epochs with the time range from -200ms to 1200ms (zero being stimulus onset), sampled at a rate of 256 Hz, were band- passed filtered (0.1-100 Hz) and stored for off-line analysis.
2.4. General Principles of the BNA Algorithm
BNA is based on identifying patterns of phase-locked evoked activity and it relates network dynamics to several network parameters. Specifically, the BNA algorithm exploits the inter- participant sequential temporal co-occurrence of pairs of ERP peaks (event-pairs) extracted from signals that were band-pass filtered into different frequency ranges and that emerged in different spatial locations. Thus, BNA captures the dynamic integration of group-common event-pairs of specific temporal relations, spatial locations frequencies and amplitudes into a unified functional network. As mentioned above, the information regarding the temporal co-occurring event-pairs, which form into patterns, is extracted from the group. That is, only if a specific sequential activation pattern of co-occurring ERP peaks is common across participants included in the group, it will be considered as the characteristic group’s network. Therefore, the coordinated activity in time, location and frequency depicted in the BNA group’s network implies that the spatiotemporal functional dependencies of regional neuronal activities in different frequency bands represent functional links common to and characteristic of a specific population (e.g., healthy controls, Alzheimer disease patients). Individual brain activation patterns may then be compared against the group’s network to determine the degree of similarity between the two in terms of network dynamics. The degree of similarity is measured by the BNA Score as detailed in “Single participant level process and the BNA Score” below. The BNA method allows an encompassing description of brain activation using a graph as the formal representation of a network in which the nodes represent events defined in time, location and frequency-band and amplitude, and the edges represent consistent temporal association among nodes. This is a suitable and convenient formal representation of the sequence of time-dependent activations that occur in different frequency-bands and scalp-locations. This formal representation allows a comparison between entire networks representing different groups or conditions as well as the comparison of the single participant to a group by comparing between different multidimensional graphs. This approach is in accordance with the view that cognition results from dynamic interactions of distributed brain areas operating in large-scale networks [11].
2.5. Detailed Description of the BNA Algorithm: Two Main Processes
The essence of BNA analysis is the extraction of spectro-spatio-temporal brain activation patterns common to a group of subjects, to which the brain activation of individual subjects may be compared (Figure 2A-H). Accordingly, the analysis involves two independent three-staged processes, a group level pattern recognition process (blue arrows in Figure 2) and a single subject level similarity evaluation process (red arrows in Figure2). At the group level, group-common activation patterns/templates are extracted from the ERP records of N members of a group of subjects, all of whom have undergone the same cognitive task. In the single subject level process, ERP data from a single subject external to the group, who underwent the same task, is evaluated against a reference database of extracted group templates. The subject is then assigned a set of ‘BNA Scores’, reflecting
300 Amit Reches, Dan Kerem, Noga Gal et al. the degree of congruity between their pattern of activation and that of the group's. The two processes will now be described in more detail.
Figure 2. Outline of steps in the BNA functional network analysis. The BNA analysis involves two independent processes – group pattern analysis (blue arrows) and individual participant evaluation (red arrows). For the group analysis, the raw EEG of each participant undergoes three separate processing stages: (1) preprocessing (artifact removal, band-passing); (2) salient event extraction (discretization, normalization) and (3) network analysis (unitary events extraction, pair-pattern extraction) on all salient events gathered from all of the participants. The single participant level process involves three stages – the first two are identical to the first two stages of the group level process. In the third stage, the single participant activity is compared to the set of patterns collected during the group analysis stage. See text for further details. The multiple arrows stemming from the normalization stage represent the pooling of each participant’s salient events to form the database on which the pattern analysis stage was performed (Modified from Figure 1 in Shahaf et al., 2012).
2.5.1. Group Analysis Process The first stage in the group’s pattern recognition process involves data preprocessing (Fig. 2A-C). At this stage individual single trial epochs, beginning 200 ms before and ending 1200 ms after
ERP Pattern Analysis Reveals Invariant Networks 301 stimulus onset, are sorted according to stimulus type. Only epochs corresponding to correct motor responses and free of excessive electrical activity (>100µV) are included in the analysis. Chosen single trial records for each of the three stimuli (Frequent, Target, Novel) undergo band-pass filtering (0.5-30 Hz) and artifact rejection. Next, the data for each electrode undergoes band-passing to conventional frequency bands, with partial overlap to reduce loss of information: delta band (0.5-4 Hz), theta band (3-8 Hz), alpha band (7-13 Hz) and beta band (12-30 Hz). Single trial data at each location are then averaged within each separate frequency band. The end result of this stage are 64 (electrodes) x 4 (frequency bands) = 256 averaged traces per subject. In the second stage, salient event extraction is performed (Figure 2D, E). At this stage, each of the individual's averaged traces is reduced into a set of discrete events designating all maxima and minima of the signal. Due to the near-symmetry of the waveforms, each activity peak may be defined by a pair of numbers denoting its timing (latency) and its amplitude (Figure 2D). The major ERP components (e.g., N100, P200, N200 and P300) will be included among other peaks and troughs in their respective frequency bands. Following discretization, in order to allow for differing conductivities of different electrodes, the amplitudes of the positive and negative activity peaks in each trace are normalized (z-scored) (Figure 2E). For each participant, all peaks that surpassed a specific threshold are selected for further analysis as follows. Initially, the average frequency band is calculated based on the high and low boundaries of the given frequency band. Next, the percentage threshold, which is the inverse of the average frequency, is computed per frequency band. Finally, the number of peaks selected for analysis is determined by the percentage threshold of the highest normalized peaks (see Appendix A1, “Normalization procedure”). This procedure ensures that signals are adequately represented across frequency bands. The selected peaks are considered salient events, each with a defined latency, amplitude, frequency band and location on the scalp (Figure 2D, E). Following the salient-event extraction stage described above, in the third stage, network analysis is performed (Figure 2F, G). In this stage, all salient events of the entire group are projected as points in a four dimensional space of timing, frequency, scalp location (i.e., electrode) and amplitude. It becomes immediately apparent that the point cloud is not homogenous but rather contains collections of tightly spaced points, implying residence within narrow limits in one or more dimensions (Figure 2F, with amplitude omitted due to graphical limitations). The BNA algorithm then performs continuous group clustering in the temporal dimension at each discrete combination of frequency- band and scalp location, in quest of salient-events clusters. Salient-events clusters ensemble a group of salient-events with the same scalp location and frequency-band and within a constrained temporal window, as detailed in Appendix A2 – “The clustering procedure”.
2.5.2. Single Subject-Level Process The single subject level process also involves three stages of which the first two (preprocessing and salient event extraction) are identical to the first two stages of the group level process (Figure 2A- E). In the third stage (Figure 2H) the electrode activity of the single subject is compared to that of the group and is scored according to the degree of similarity between the two (further details in Appendix A3 – “Single-subject BNA similarity score computation”). The BNA Score is a measure of the level of similarity of the single participant’s activation to that of the group’s in terms of the stimulus- evoked consistent activity in location, time and frequency, in the context of goal directed behavior. More specifically, the BNA Score is the measure of the 'functional similarity' between the activation pattern of a single participant and the group’s network in terms of the sequence of the temporal co- occurrence of event-pairs. The timing parameters that define co-occurrence are associated with event pairs of specific spatial locations, frequencies and amplitudes. The BNA algorithm produces a similarity score of the individual to the reference brain network. This score reflects the percentage of similarity to a healthy reference brain activation using all four BNA score parameters: time, location, frequency and amplitude.
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The scoring process yields four BNA Score types per subject, ranging between 0-100 percent, which are generated separately for each of the three response-evoking stimuli in the three-stimulus auditory oddball task:
Amplitude BNA Score – a measure of the similarity of the amplitudes of the events; Absolute Time BNA Score – a measure of the similarity of the latencies of the events; Relative Time BNA Score– a measure of the similarity of latency differences between the two events in the event pairs; Overall BNA Score – the global average of the former three scores.
For the exact calculation of the 4 BNA Scores see Appendix A3.
2.6. Statistical Methods
2.6.1. Poolability of Datasets from Different Research Centers ANOVA was performed to assess poolability with ‘center’ as the independent variable (model: BNA Score/ΔBNA Score=center).
2.6.2. Test-Retest Repeatability For each subject at each session, the 4 BNA scores and the ΔBNA scores between the two sessions were computed. In order to assess the repeatability of two BNA scores obtained in two different task sessions, intra-class correlation (ICC) analysis was performed [12]. ICC was calculated using the two-way random intra-class model, for each of the three stimulus types (Frequent, Target, Novel) and for the four BNA Scores (Amplitude, Absolute Time, Relative Time, Overall) yielding 12 repeatability estimates. In the case of the Validation Group, three-score ICC testing (V1, V2 and V3) was performed. Bland-Altman Plots [13], in which the difference between each subject's two measurements is plotted against their average values, were constructed for each pair of repeated BNA scores. The plots point to outliers as regards repeatability, usually defined as values that lie outside the limits of agreement, being ±1.96 SD around of the mean difference line. Also, one may infer from the plot whether or not repeatability is dependent on the magnitude of the measurement value (BNA scores in this case) and whether or not there is a bias/trend of one measurement giving consistently higher results, e.g., in case of a possible training effect.
2.6.3. Estimating Normal within-Subject Variability of ΔBNA Scores Kolmogorov-Smirnov normality tests and QQ-plots were used to assess the normal distribution of the 12 test-retest ΔBNA Scores. Given a normal distribution, the Standard Error of Measurement (SEM) is employed to estimate the within-subject repeated measure variability. Specifically for the case in question, SEM was defined as the standard deviation of the BNA Score that would have been obtained from a single subject exposed to multiple identical task sessions with consecutive BNA analysis and scoring. The following model was fitted to estimate SEM from the data, for each of the 12 BNA Scores:
BNA Score = Intercept + subject
The Mean Square Error (MSE) of the above model estimates the pooled within-subject variance, with SEM estimated as the square root of the MSE. SEM may be interpreted in terms of the Minimal Important Clinical Difference (MICD) which refers to the smallest difference across two scores considered to be important in that it indicates a true
ERP Pattern Analysis Reveals Invariant Networks 303 change in subject performance; i.e., a change that is unlikely to occur due solely to random variation in subject scores over time. MICD is determined using a distribution-based approach following [14] and uses SEM. This approach assumes that when no change occurs, the distribution of relevant variable is normal with mean = 0 and standard deviation = SEM. Thus, for example, given the characteristics of the normal distribution, we expect about 67% of ΔBNA Scores to reside within ± 1SEM around 0. Alternatively, any ΔBNA Score >1SEM has a 67% likelihood of being the result of a true change rather than the expected, random variation.
2.6.4. Stability over Time of the SEM A subset of subjects (N=25) from the UMICH dataset underwent an additional task session, 6 weeks after V1. ANOVA with random subject effect was performed to assess whether differences between ΔBNA Scores from repeated visits, 1 and 6 weeks apart, were significant.
3. RESULTS
3.1. RBNM Construction Stage (Reference Group)
3.1.1. Group RBNMs As a first step, reference brain network models (RBNMs) were extracted for each of the three- stimuli of the auditory oddball task. These patterns formed the basis for the BNA scores that will be addressed in all following sections.
Figure 3. Reference group RBNMs. Shade of the grey line that connects two nodes forming an event pair is proportional to the corresponding pair’s preponderance as quantified by the weight index (see Appendix A3).
Figure 3 depicts the chosen group activity patterns, namely, the RBNMs. These patterns are composed of interconnected individual nodes (colored circles), each representing a unitary event. Each unitary event in the pattern is connected (grey lines) to at least one other participating event, as part of an event pair, triplet, etc. All connected (co-occurring) nodes that were active throughout the
304 Amit Reches, Dan Kerem, Noga Gal et al. entire epoch are superimposed in a single image. The shade of the connecting lines is proportional to the weight index of the corresponding event pairs (see Appendix A3). Observing Figure 3, it may be seen that the ‘Target’ RBNM has an alpha frequency (yellow coded) fronto-central presentation, mainly issuing from the early ERP components (from 100 ms to about 200 ms). The ‘Frequent’ RBNM shows theta frequency (green coded) central presentation, also related to the ~ 100-200 ms latency interval, while centrally presented delta frequency (red coded), mainly emanating from the P3 peak (~ 300 ms), dominates the Novel RBNM.
3.2. RBNM Evaluation and ND Assemblage Stage (Database Group)
We now describe the next stage in which subjects age-matched to the Reference Group and forming the Database Group are scored to the above RBNMs on two different visits. Scores and score differences are assessed in order to evaluate the performance of the RBNMs in a normal population, in terms of between-subject variability and within-subject variability (repeatability).
3.2.1. BNA Scores on RBNMs The distributions of the 4 BNA Scores on a given visit for the Novel stimulus were rather even, with similar representation of low, moderate and high scores. For the Target stimulus, the distributions were quasi-normal, with the mean at 50 points (Figure 4A). For the Frequent stimulus, distributions were as variant but markedly skewed, with roughly 2/3 of the subjects scoring higher than 60 (Figure 4B).
Figure 4. Histograms of Database Group scores on the RBNMs – two visits pooled. A – Stimulus = Target; BNA Score = Overall; B – Stimulus = Frequent; BNA Score = Absolute Time.
Means of the 12 BNA Scores (averages of two visits) ranged between 45.8 and 69.0, with ‘Frequent’ scores being significantly higher than ‘Novel’ and ‘Target’ scores (Friedman’s two-way analysis of variance by ranks, adjusted p value of pair-wise comparisons = 0.001).
3.2.2. Intraclass Correlation (ICC) of BNA Scores Table I lists V1-V2 ICC values for the four BNA Scores, for each of the three stimuli.
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Table I. ICCs of BNA Scores obtained at two visits of the Database Group
Stimulus Parameter ICC value P-Value Target Amplitude 0.66 <.0001 Absolute Time 0.70 <.0001 Relative Time 0.58 <.0001 Overall 0.69 <.0001 Novel Amplitude 0.81 <.0001 Absolute Time 0.74 <.0001 Relative Time 0.72 <.0001 Overall 0.80 <.0001 Frequent Amplitude 0.67 <.0001 Absolute Time 0.71 <.0001 Relative Time 0.75 <.0001 Overall 0.73 <.0001 Average 0.713
An example of a Bland-Altman plot for the Novel stimulus’ BNA Overall Score is shown in Figure 5. Dotted blue lines are ± 1.96 SD from the mean difference line. This combination had the highest number [8] of outliers. The rhomboid shape of the point cloud stems from the fact that very low and very high averages can only result from very similar single scores, while intermediate averages could arise from widely different scores (e.g., 0 and 100). The mean difference for this combination was significantly higher than 0, at about 5 points.
Figure 5. Bland-Altman Plot: Stimulus = Novel, BNA Score = Overall. Each point in the scattergram represents a single subject, defined by the average of and the difference between his two scores. Green line is the mean difference and dotted blue lines are ± 1.96 SD from the mean.
Inspection of all 12 plots revealed that the number of outliers varies between 4 and 8. This is in accordance with ~6 out of 116 (~ 95%) expected to be outside the range of ± 1.96 SD in a normal
306 Amit Reches, Dan Kerem, Noga Gal et al. distribution. Differences were generally evenly distributed above and below the mean and did not show any bias as regards to the magnitude of the single scores.
3.2.3. Testing the Normality of ΔBNA Scores Distributions We now move from single scores to 2-visit score differences of the database, with the general aim of quantitative delimitation of the expected random within-subject variability. All 12 ΔBNA Score distributions were normal or near normal, with P values of Kolmogorov-Smirnov normality tests ranging between 0.010 and 0.15. High (>0.05) P values resulted from leptokurtic distributions (values being more closely packed around the mean than in a Gaussian distribution), therefore the assumption that these distributions are normal is conservative in the sense that less values being outside the ±1SEM or the ±2SEM range are expected. Figure 6 shows the histogram and the QQ plot of the Target stimulus-BNA Overall score combination, the one having the highest p-value.
Figure 6. Test for normality of Database Group’s 2-visit ΔBNA Scores. Shown for the combination: BNA Score = Overall; Stimulus = Target; A – Histogram; B – QQ Plot. Kolmogorov-Smirnov P-Value=0.1500.
Table II. Standard Error of Measurement (SEM) by Stimulus and BNA Score
Stimulus Parameter SEM 2 SEM Target Amplitude 16.1 32.2 Absolute Time 16.7 33.5 Relative Time 15.9 31.8 Overall 14.1 28.3 Novel Amplitude 16.6 33.1 Absolute Time 19.2 38.5 Relative Time 17.0 34.1 Overall 13.9 27.9 Frequent Amplitude 17.9 35.7 Absolute Time 17.2 34.4 Relative Time 14.1 28.3 Overall 13.3 26.5 Average 16.0 32.0
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3.2.4. Computation of Standard Error of Measurement (SEM). The SEM and 2 SEMs values were calculated for each BNA Score of each stimulus and are presented in Table II. Since the SEM values are actually SD units (see Methods), this metric could be used with any choice of threshold value as signifying a clinically meaningful change or MICD. For example, based on the table there is on the average ~ 95% likelihood that a BNA Score change of more than 30 points between tests is non-random.
3.2.5. Comparison of ΔBNA Scores from Two Different Intervals between 2 Visits The differences between V2-V1 ΔBNA Scores at 1 and at 6 week intervals for all 12 combinations were not significant. P-values from the ANOVA model ranged between 0.092-0.912.
3.3. Validation Stage (Validation Group)
The final step confronts the RBNMs extracted from young subjects with a healthy population sample with an extended and only partly overlapping age range, tested on 3 different visits, in order to validate measures obtained from the Database Group.
3.3.1. BNA Similarity Scores The distribution of the BNA scores of the Validation Group roughly paralleled that of the Database Group, with both ‘Novel’ and ‘Frequent’ curves being skewed towards high scores, especially those of the Relative Time score (Figure 7).
Figure 7. Histogram of Validation Group scores on the RBNM – three visits pooled. Stimulus = Frequent; BNA Score = Relative Time.
Mean BNA scores of the Validation Group matched or were even higher than those of the Database Group and, judging by the SD values, showed lower inter-subject variability. Pooling the BNA Overall Scores for the Database Group’s visits and for the Validation Group’s visits, the respective group means (±SD) for the Target stimulus were 47.1±20.1 and 43.6±16.2 (NS), for the Novel stimulus: 54.1±23.4 and 68.2±17.5 (p<0.001, Mann Whitney U test) and for the Frequent stimulus: 64.5±20.0 and 69.0±12.6 (NS).
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3.3.2. Intraclass correlation (ICC) of BNA Scores Table III lists ICC values for the 3-visit comparison. The ‘Frequent’ scores are the most repeatable, followed by ‘Novel’ and ‘Target’ scores. Here too, values match or are higher than those of the Database Group, overall averages being 0.787 and 0.713, respectively.
Table III. Validation Group’s 3-visit (V1 vs. V2 vs. V3) ICC values
Stimulus Parameter ICC value P-Value Target Amplitude 0.561 0001 Absolute Time 0.726 <.0001 Relative Time 0.687 <.0001 Overall 0.645 <.0001 Novel Amplitude 0.802 <.0001 Absolute Time 0.903 <.0001 Relative Time 0.738 <.0001 Overall 0.792 <.0001 Frequent Amplitude 0.934 <.0001 Absolute Time 0.910 <.0001 Relative Time 0.826 <.0001 Overall 0.914 <.0001 Average 0.787
3.4. SEM Applicability In order to test whether the SEM values derived from the Database Group are validated by the Validation Group, the number and % of the Validation Group’s subjects for whom the test-retest ΔBNA score surpassed 2SEM are listed in Table IV. The V1-V2 combination, being the ‘worst case’ by having the largest average ΔBNA score variance, was picked out for this comparison.
Table IV. Number and % of Validation Group subjects with ΔBNA Score > 2SEM (derived from the Database Group)
BNA Score 2SEM V1 vs V3 # %
Target Amplitude 32.2 7 19.4* Target Absolute Time 33.5 5 13.9* Target Relative Time 31.8 4 11.1 Target Overall 28.3 4 11.1
Novel Amplitude 33.1 10 27.8* Novel Absolute Time 38.5 4 11.1 Novel Relative Time 34.1 1 2.8 Novel Overall 27.9 3 8.3
Frequent Amp 35.7 3 8.3 Frequent Absolute Time 34.4 2 5.6 Frequent Relative Time 28. 0 0 Frequent Overall 26.5 0 0 *Proportion significantly different from the expected 5% (z score test statistic).
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Results from the other two 2-visit combinations (V1-V3 and V2-V3) were not significantly different, such that for the Novel and Frequent stimuli the proportion of outliers conformed to the ΔBNA Score distributions of the Database Group.
4. DISCUSSION
4.1. Rationale and Scope
The overarching goal of the study was the characterization of an invariant and repeatable network that will serve as a reference brain network model (RBNM) against which individuals can be compared and scored. The ultimate utility of such an RBNM would be in both diagnostics and treatment monitoring over multiple time points. The BNA algorithm that was applied in this study on data recorded during the performance of an auditory oddball task provides the evaluator with 12 scaled scores (4 BNA parameters × 3 different RBNMs) which quantify the resemblance of the individual to an RBNM extracted at the group level. Dependent on the type of cognitive malfunction, some or all of these scores may in the future prove to be an objective tool by which the movement towards or away from the normative cognitive state could be longitudinally monitored. The BNA method allows an encompassing description of brain activation using a graph as the formal representation of a network in which the nodes represent events defined in time, location and frequency-band, and the edges represent consistent temporal association among nodes. This is a suitable and convenient formal representation of the sequence of time-dependent activations that occur in different frequency-bands and scalp-locations. This formal representation allows a three- dimensional representation of different subject groups or stimuli as well as the comparison of the single participant to the group by comparing between different multidimensional graphs. In addition, the BNA algorithm consists of a two-stage process, and is performed at both the individual and the group level. The group level process does not involve averaging across participants, which masks variability within the group, but is rather based on identifying the largest common denominator of activation across participants while still preserving the inter-subject variability of individual participants (for more details see Methods). This feature of the BNA algorithm allows the identification of invariant networks. In the current study we focused on examining the utility of the RBNM in longitudinal monitoring. For that aim we utilized a three-stage procedure as follows. In the first stage, RBNM-extraction, RBNMs were extracted for each of the stimuli of the three-auditory oddball task (Novel, Target, Frequent). In this stage the BNA methodology was applied on a large group of young healthy subjects (Reference Group). In the second stage, RBNM Evaluation and normative database assemblage, a second large group of healthy subjects (the Database Group), age-matched to the Reference Group served as the normative database. In this stage the RBNMs were assessed by examining the BNA and the ΔBNA Score distributions as well as their repeatability. In addition, confidence levels for the individual ΔBNA Scores and the Minimal Clinically Important Difference (MCID) were determined to detect non-random changes in the response across visits. Finally, in the third stage, Validation, the same assessments performed for the Database group were also carried out on an external group of subjects with an extended age range, the Validation Group. Overall, the results of this study showed that individual scores on the RBNMs demonstrated good repeatability and that the database ΔBNA Scores was characterized by normal or quasi-normal distributions enabling the determination of MCIDs.
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4.2. RBNMs for Diagnostics and Longitudinal Monitoring
The practical utility of invariant RBNMs could be ascribed to two main purposes: diagnostics, i.e., assessing the degree of deviation of a single subject from the norm based on a single test; and monitoring, i.e., longitudinal follow-up of the clinical state with or without treatment. The utility of the RBNM for the first purpose should be based on the distribution of scores that were computed against that RBNM. Specifically, when the distribution of the BNA Scores of the normative database associated with the RBNM is characterized by a high mean and a small variance, the directionality of an individual BNA Score could be assessed and the RBNM could serve for diagnostic purposes. In this case, for example, a low BNA score relative to the mean implies that the patient deviates from the norm and that his brain functioning is impaired in certain cognitive aspects relative to the normative population. If the repeatability of the BNA scores computed against a specific RBNM over two visits is high, the specific RBNM could be suitable to be used for longitudinal observations. An RBNM could be used for either one or both of these clinical purposes. In our study, the RBNM for the ‘Novel’ stimulus could only be used for patient monitoring, while the RBNM for the ‘Frequent’ stimulus could be utilized for both purposes (diagnostics and longitudinal monitoring). This is because the distribution of scores associated with the frequent stimulus was skewed such that for the Database Group, the % of subjects with ‘Frequent’ BNA Score values >45 ranged from 74-83 and for the Validation Group, all ‘Frequent’ scores were >45. Although the BNA Score associated with the Target RBNM was characterized with a normal distribution, the mean BNA Score was quite low at around 50 points, and is therefore not as optimal as the Frequent RBNM for diagnostics. The repeatability of the Target was high and could be used for longitudinal follow-up.
4.3. A Possible Confounding Floor Effect
The results of this study demonstrated that for a 95% confidence level, the critical threshold of the ΔBNA Score which is clinically meaningful, that is defined here as the MCID, should roughly exceed 30 score points. For a healthy subject, this would have to set a practical lower limit for the absolute (single) baseline score, in order to accommodate this degree of change in the direction of score deterioration. A subsequent increase over time by more than 30 score points could then be construed as significant improvement. If, however, a low score remains stable over time it clouds the interpretation of the results since it may mean that a patient either continues to exemplify their baseline state or that a deterioration has occurred in their condition but due to the floor effect it could not have been detected [15].
4.4. Repeatability
Within-subject repeatability is a prerequisite of any tool which professes to detect clinically meaningful longitudinal changes. Individual BNA similarity scores on the RBNMs demonstrated good repeatability, as evident from the ICC values of the Database Group ranging between 0.58-0.81. The ‘Target’ stimulus response was found to be the least repeatable. Repeatability was as good when tests were separated by 1 or by 6 weeks. Noteworthy is the even higher repeatability (0.56-0.93) demonstrated by the Validation Group. Quite a lot of effort has been invested into proving the test-retest reliability of quantitative EEG (qEEG) measures, including inter-channel coherence (see Thatcher, 2010 for a review). The neurocognitive and neurophysiological test battery ‘Neuromarker’ [16], tested and retested 4 weeks
ERP Pattern Analysis Reveals Invariant Networks 311 apart on 21 healthy subjects (aged 12-59 years), produced high repeatability for qEEG spectral power (Pearson Point Product correlation r values ranging from 0.71–0.95), particularly for theta and delta frequency bands (r>0.85). Similar results were reported by Gudmansson et al., [17] on 15 elderly healthy subjects (mean age – 71 years), tested 10 times over a period of 2 months. ICC values ranged from 0.27–0.91, with the reliability of the qEEG features being highest for power spectral parameters, followed by regularity measures based on entropy and complexity, coherence being least reliable. Three recent studies addressed repeatability of graph metrics that describe small world properties of functional neuronal networks. The test–retest reliability of graph metrics of functional networks derived from magnetoencephalography data was studied by Deuker et al. [18]. ICC values ranged from 0.02 to 0.89, with a mean of 0.62±0.20 (SD). Values were much lower in the resting state compared to the task-performance state. Functional magnetic resonance imaging data collected from 45 elderly healthy subjects (aged 65-75 years) was examined during two consecutive ~5 min scans performed one after the other on the same scanning session [19]. Participants performed a visual executive function task presented using a rapid event-related design. ICC scores ranged from 0.29 to 0.86. Finally, reproducibility of graph metrics obtained by performing tractography on diffusion tensor imaging data was studied by Vaessen et al. [20]. Six normal subjects were scanned twice after a mean lag of 14 days. ICC scores ranged from 0.23 to 0.77. Thus, the ICC values of the BNA method compare well to those reported for other EEG/ERP-based methodologies advanced for the detection and longitudinal follow-up of brain function.
4.5. Age Effects
Since the normative database is supposed to represent invariant features of the healthy population, to truly do so, stratified sampling should be employed (Thatcher and Lubar, 2008) [2]. Since age contributes to a large portion of inter-subject variability observed in normative databases [1,8,21], age stratification or age regression should be implemented [8,2], otherwise, the database should be considered “reference” rather than “normative”. In this study we used three groups of subjects. The Reference Group and the Database group were of almost identical age ranges (14-25 and 14-24 years, respectively) while the Validation Group was with an extended and only partly overlapping age range (23-64 years). The availability of the Validation Group, members of which were tested with the exact same protocol as the other two groups allowed us to test the generality of the models in relation to age. Judged by the results of the Validation Group, the RBNMs, score distributions and repeatabilities as well as MCIDs obtained for the Database Group were validated and may therefore indicate that they are age invariant over the tested age range. Nevertheless, it is important to emphasize that these results regarding age should be further tested and validated both by BNA and by more conventional ERP analyses such as peak identification.
4.6. Summary and Concluding Remarks
In this study we presented a novel EEG-based analysis method, Brain network Activation (BNA) that extracts invariant and repeatable brain networks, the Reference Brain Network Models (RBNMs). The RBNMs were extracted during the performance of a cognitive task, the three-auditory oddball, and RBNMs were identified for each of the three oddball stimuli. The BNA Scores computed against the RBNMs were repeatable; the ΔBNA Scores computed over two visits against each of the RBNMs approximated a normal distribution and were validated by an independent external group of participants. Importantly, the results imply that in some instances, depending on the database distributions of the single scores, the RBNM could be used for diagnostics, i.e., evaluation of the
312 Amit Reches, Dan Kerem, Noga Gal et al. current cognitive state of the individual, but that in all instances it could be used for monitoring, i.e., assessing whether the condition of the individual improves or deteriorates at follow-up. The future utility of the RBNM should be determined based on the distribution of the single BNA Scores as well as on the basis of BNA score repeatability across visits. The distributions of the single BNA scores indicated that the latter should be thoroughly inspected to identify floor effects disabling the detection of deterioration at follow-up. The Database Group’s distributions of all difference scores in the current study allowed the determination of a MCID between scores to ascertain a true trend in a patient’s cognitive state. The results of the current study indicate that BNA could potentially be used as a screening and monitoring tool of cognitive integrity. It characterizes the normal functional activation elicited by a cognitive task by extracting RBNMs that represent fixed templates reflecting the cognitive processing of an ‘archetypical normal brain’. It must be emphasized that although the RBNMs enable diagnostics in certain conditions in a manner dependent on the distribution of the single BNA Scores, in this study the emphasis was on ΔBNA scores acquired at two different visits, which could aid the clinician in following the evolution of suspected cognitive malfunction in longitudinal studies. The results show that individual activity is sufficiently stable to allow difference scores to be a suitable measure to detect the clinically meaningful changes during disease progression or following treatment. This utility should still be validated on a specific pathology, since in this study only healthy participants were involved in both database construction and validation stages.
APPENDIX A
1. The Normalization Procedure
The normalization process was carried out separately for each participant. All minimal and maximal peaks were extracted from the ERPs, for each frequency band and for each electrode. Next, the amplitude of the peaks of each frequency band and electrode was z-score normalized using the standard deviation of the corresponding ERP waveform. Finally, all electrodes were pooled together within each frequency band and the highest normalized peaks were selected in the following manner. In the first step, the average frequency band was calculated based on the high and low boundaries of the frequency band:
ℎ ℎ + = 2 (A1.1)
In the second step, the percentage threshold was computed per frequency band as follows:
1 ℎ ℎ = × 100 (A1.2)
The number of peaks selected for analysis was determined by the percentage threshold of the highest normalized peaks which were defined as salient events. The percentage of selected peaks using the above formulas is higher for the lower frequencies and lower for the higher ones. This procedure ensured that signals were adequately represented across frequency bands.
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2. The Clustering Procedure
In order to maintain the temporal constraints on pairs of salient events across subjects, a pattern extraction algorithm was implemented which relates to density-based clustering methods [22]. For each possible combination of two regions/electrodes at two specific frequency bands (or the same band), a temporal plane was constructed into which all subjects having two salient events at the same specific combination of regions and frequency bands were pooled (Figure A1). Event-pairs identification may be conceptually grasped as a searchlight scanning the space of salient events across individual participants. Each point in this plane represents a pair of salient events which occurred in the activity of an individual subject. The X axis coordinate denotes the latency of the event which occurred at the first region and the Y-axis coordinate, the time difference (ΔT) between that event and the one that occurred at the second region (Relative Time). The algorithm then sought clusters containing an above-subject-threshold number of points which met both the Absolute and the Relative Time windows’ constraints, by scanning the plane with a sliding and adjustable rectangular search window (Figure A1). Upon finding such a cluster, the rectangle was further reduced in size to the minimum not incurring ‘loss’ of subjects. The selected cluster was considered an event pair mutual to all subjects fulfilling the two temporal constraints. This defined collection of event-pairs across individual participants is represented in the group network that preserves inter-subject variability and therefore allows the comparison of the individual activation to the group’s pattern. Each discovered event pair is assigned a weight index, reliant on its preponderance (see Appendix A3 for details). The weight index is an important component of the single subject scoring. Patterns with three clusters and above were then formed by concatenating event pairs sharing a common salient event cluster. The number of subjects sharing the extended pattern was determined by the cross-section between the two groups of subjects who participated in the two appended patterns. Patterns with more than three unitary events were constructed in a similar fashion, until the subject threshold was violated, thereby terminating the concatenation. Final patterns comprised a group- common set containing the maximum number of salient event clusters that survived the appending process with their temporal interrelations. The final result of the group analysis stage is a suite of brain activity patterns/templates which characterize the group that underwent analysis. These defined patterns actually constitute brain networks which may be viewed as an array of nodes connected by a set of links, in which each node is functionally connected to at least one other node.
Figure A1. Application of the BNA algorithm in the time domain.
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In the case of the oddball paradigm, each of the three stimulus types, e.g. 'Frequent', 'Target' and 'Novel', produces its own set of patterns. Within the set, templates are ranked (Rankx (x=1…n)) based on the number of subjects sharing them and on their complexity, i.e. the number of interconnected nodes. The highest ranking or sometimes two closely matching highest ranking templates are then chosen as the set’s RBNM. The combined chosen templates form the RBNM Database, which is locked into the algorithm and to which single subjects may be compared and scored on.
3. Single-Subject BNA Similarity Score Computation
For the scoring procedure, all N event pairs (EP) contained in each of the group’s RBNMs are evaluated in turn. The evaluation is based on z-score distributions of the absolute times, relative times and amplitudes of the two events in the EP and the subject is assigned four similarity indices (SIs) to each one of them: SIAbsolute Time, SIRelative Time, SIAmplitude, SIOverall the computation of which will be detailed below. In order for a subject to receive >0 SIs for a given EP, the following two conditions need be satisfied:
1. The subject should have two salient events at the same scalp locations and frequency-bands as those of the two salient event clusters in the EP. In case there is more than one per cluster, the one with the latency nearest to that of the mean latency of the cluster is chosen. 2. The latency of the two salient events and the latency difference between them (Relative Time) should fall within ±3SD around the respective group means.
If these conditions are not met, the subject scores 0 on all four SIs for that EP. BNA SIs, ranging between 0-1, of EPs for which the above conditions were met are then computed by referencing the subject’s salient event parameters to the normal (Gaussian) z-scored probability density function (GPDF) of those parameters in the corresponding salient event clusters of the RBNM (equations A3.1, A3.2 and A3.3). The GPDF describes the relative likelihood for a continuous random variable, x, to take on a given value and the z-scoring assures that the GPDF value for the mean will equal 1 and that 0≤ GPDFx ≤1. The single subject Absolute Time SI of the ith EP is arrived at by comparing the subject’s latencies of the two salient events to the distribution of the corresponding latencies in the two salient- events clusters of the pair, as follows:
( 1 ( 1 ), ( 1 ) ) + ( 2 ( 2 ), ( 2 ) ) = 2 (A3.1) where: T1i, T2i are the latencies of all members of the two salient-events clusters of the first and second events, respectively. t1i, t2i are the latencies of the closest events of the single subject to the means of T1i and T2i respectively. The Relative Time SI of the ith EP was calculated by comparing the latency difference of the two single events to the distribution of the Relative Times in the two salient-event clusters, as follows:
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= (( 2 − 1 ), ( 1 − 2 ), ( 1 − 2 ) ) (A3.2)
The single subject Amplitude SI corresponding to the ith EP is valued according to the distribution of the corresponding amplitudes in the two salient-event clusters as follows:
( 1 ( 1 ), ( 1 ) ) + ( 2 ( 2 ), ( 2 ) ) = 2 (A3.3) where:
Amp1i, Amp2i are the amplitudes of all members of the two salient-events clusters of the first and second events, respectively.
amp1i, amp2i are the amplitudes of the closest events of the single subject to the means of T1i and T2i respectively. Averaging the above three BNA SIs leads to the final BNA Overall SI of the ith EP:
+ + = 3 (A3.4)
Weights of pairs in the Reference Brain Network Model (RBNM):
The weights represent the relative number of subject that shares the EP in RBNM that may be perceived as the strength of the connection between the two salient-events clusters of the ith EP in the RBNM, representing two temporally synchronized functional activities, each in a specific scalp location and frequency-band:
N W = N (A3.5) where: th Ni is the number of subjects sharing the i event-pair pattern in the RBNM N is the overall number of subjects used to create the RBNM
The final 4 BNA Scores of a single subject are then calculated by weight-averaging the SIs of each of the N functional pairs in the RBNM, including zero scores:
∑ ( ∗ ) = ∑ ( ) (A3.6) ∑ ( ∗ ) = ∑ ( ) (A3.7) ∑ ( ∗ ) = ∑ ( ) (A3.8)
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∑ ( ∗ ) = ∑ ( ) (A3.9)
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[1] Thatcher RW. Validity and reliability of quantitative electroencephalography (qEEG). J. Neurotherapy. 2010;14:122-52. [2] Thatcher RW, Lubar JF. History of the scientific standards of qEEG normative databases. In: Budzinsky T, Budzinski H, Evans J, Abarbanel A, editors. Introduction to QEEG and Neurofeedback: Advanced Theory and Applications. San Diego, CA: Academic Press; 2008. p. 29-59. [3] Gordon E, Cooper N, Rennie C, Hermens D, Williams LM. Integrative Neuroscience: The role of a standardized database. Clin. EEG Neurosci. 2005;36:64-75. [4] Rish I, Cecchi G, Thyreau B, Thirion B, Plaze M, Paillere-Martinot ML, Martelli C, Martinot JL, Poline JB. Schizophrenia as a network disease: disruption of emergent brain function in patients with auditory hallucinations. PLoS One. 2013;8:e50625. [5] Ahmadlou M, Adeli H. Functional community analysis of brain: a new approach for EEG-based investigation of the brain pathology. Neuroimage. 2011;58:401-8. [6] Michel CM, Murray MM. Towards the utilization of EEG as a brain imaging tool. Neuroimage. 2012;61:371-85. [7] Shahaf G, Reches A, Pinchuk N, Fisher T, Ben Bashat G, Kanter A, Tauber, Kerem D, Laufer I, Aharon-Peretz J, Pratt H, Geva AB. Introducing a novel approach of network oriented analysis of ERPs, demonstrated on adult attention deficit hyperactivity disorder. Clin. Neurophysiol. 2011;123:1568-80. [8] Aguilar M, Congedo M, Minguez J. A data-driven process for the development of an eyes- closed EEG normative database. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:7306-9. [9] Fotenos AF, Snyder AZ, Girton LE, Morris JC, Buckner RL. Normative estimates of cross- sectional and longitudinal brain volume decline in aging and AD. Neurology. 2005;64:1032-9. [10] Polich J. P300 in clinical applications. In: Niedermeyer E, de Silva FL, editors. Electroencephalography, basic principles, clinical applications, and related fields. Baltimore, MD: Urban and Schwarzenberg; 1999. p. 1073-91. [11] Bressler SL, Menon V. Large-scale brain networks in cognition: emerging methods and principles. Trends Cogn Sci. 2010;14:277-90. [12] Shrout PE, Fleiss JL. Intraclass Correlations: Uses in assessing rater reliability. Psychol Bull. 1979;86:420-28. [13] Bland JM, Altman DG. Statistical methods for assessing agreement between 2 methods of clinical measurement. Lancet. 1986;i:307-10. [14] Wyrwich KW, Tierney WM, Wolinsky FD. Further evidence supporting an SEM-based criterion for identifying meaningful intra-individual changes in health related quality of life. J. Clin. Epidemiol. 1999;52:861-73. [15] Bindman AB, Keane D, Lurie N. Measuring health changes among severely ill patients. The floor phenomenon. Med Care. 1990;28:1142-52. [16] Williams LM, Simms E, Clark CR, Paul RH, Rowe D, Gordon E. The test-retest reliability of a standardized neurocognitive and neurophysiological test battery: “Neuromarker”. Int. J. Neurosci. 2005;115:1605-30.
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[17] Gudmundsson S, Runarsson TP, Sigurdsson S, Eiriksdottir G, Johnsen K.. Reliability of quantitative EEG features. Clin. Neurophysiol. 2007;118:2162-71. [18] Deuker L, Bullmore ET, Smith M, Christensen S, Nathan PJ, Rockstroh B, Bassett DS. Reproducibility of graph metrics of human brain functional networks. Neuroimage. 2009;47:1460-8. [19] Telesford QK, Morgan AR, Hayasaka S, Simpson SL, Barret W, Kraft RA, Mozolic JL, Laurienti PJ. Reproducibility of graph metrics in fMRI networks. Front Neuroinform. 2010. doi: 10.3389/fninf.2010.00117. [20] Vaessen MJ, Hofman PA, Tijssen HN, Aldenkamp AP, Jansen JF, Backes WH. The effect and reproducibility of different clinical DTI gradient sets on small world brain connectivity measures. Neuroimage. 2010;51:1106-16. [21] Thatcher RW. Normative EEG databases and EEG biofeedback, J. Neurotherapy. 1998;2:8-39. [22] Cao F, Ester M, Qian W, Zhou A. Density-based clustering over an evolving data stream with noise. In: Proceedings of the 6th SIAM international conference on data mining. Gosh J, Lambert D, Skillicorn D, Srivastava J Bethesda, editors. Bethesda, MD; 2006. p. 328-39.
Received: July 6 2013 Revised: July 10 2013 Accepted: July 14 2013
Funct Neurol Rehabil Ergon 2013;3(2-3):319-328 ISSN: 2156-941X © Nova Science Publishers, Inc.
DISRUPTED AXONAL FIBER CONNECTIVITY AS A MARKER OF IMPAIRED CONSCIOUSNESS STATES
Rafael Rodriguez-Rojas1,2, Karla Batista1, Yasser Iturria3, Calixto Machado4, Gerry Leisman5,6,7,8, Robert Melillo5,6, Mauricio Chinchilla9, Philip DeFina8, Maylen Carballo1, and Juan M. Morales1 1Brain Imaging Group, International Center for Neurological Restoration, Havana, Cuba 2The Abdus Salam International Centre for Theoretical Physics, Trieste, Italy 3Neuroimaging Department, Cuban Neuroscience Center, La Habana, Cuba 4Institute of Neurology and Neurosurgery, Department of Clinical Neurophysiology, Havana, Cuba 5F.R. Carrick Institute for Clinical Ergonomics, Rehabilitation and Applied Neuroscience, Garden City, NY USA 6The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel 7Biomedical Engineering, ORT-Braude College of Engineering, Karmiel, Israel 8Neuroscience, University of the Medical Sciences of Havana, Faculty Manuel Fajardo 9Neurology Department, Hermanos Ameijeiras Hospital, Havana, Cuba, 10International Brain Research Foundation, New York, USA
ABSTRACT
Background: Persistent vegetative states (PVS) and locked-in syndrome (LIS) are well- differentiated disorders of consciousness that can be reached after a localized brain injury in the brainstem. The relations of the lesion topography with the impairment in the whole-brain architecture and functional disconnections are poorly understood. Methods: Two patients (PVS and LIS) and 20 age-matched healthy volunteers were evaluated using diffusion tensor imaging (DTI). Anatomical network was modeled as a graph whose nodes are represented by 71 brain regions. Inter-region connections were quantified through Anatomical Connection Strength (ACS) and Density (ACD). Complex networks properties such as local and global efficiency and vulnerability were studied. Mass univariate testing was performed at every connection using network based statistic approach. Results: LIS patients’ network showed significant differences from controls in the brainstem- thalamus-frontal cortex circuitry, while PVS patients showed a widespread disruption of anatomical connectivity in both hemispheres. Both patients showed a reorganization of network attributes, with decreased global and local efficiency, significantly more pronounced in PVS.
Correspondence: Dr. Rafael Rodriguez-Rojas, International Center for Neurological Restoration, Ave 25 # 15805, CP 11300, Havana, Cuba. E-mail: [email protected]
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Conclusions: Our results suggest that DTI-based network connectivity combined with graph theory is useful to study the long-range effect of confined injuries and the relationship to the degree of consciousness impairment, underlying PVS and LIS.
Keywords: Persistent vegetative state, locked-in syndrome, consciousness, functional disconnection, diffusion tensor imaging, graph theory
INTRODUCTION
The brainstem plays a key role in cerebral cortex activation as the origin of the ascending reticular activating system. Severe conditions can arise as a consequence of a traumatic or a non-traumatic injury in this area. Characteristic clinical symptomatology includes well-differentiated disorders of consciousness (DOC) such as “vegetative states” (VS) and “locked-in syndrome” (LIS). The VS encompasses a spectrum of patients who have emerged from coma to exhibit basic orienting response but show no indication of awareness [1,2]. By contrast, LIS is marked by tetraplegia and anarthria but consciousness and somatosensory perception are preserved [3,4]. Because patients with LIS show paralysis of all voluntary motor function except eye movements, they may be mistakenly thought to be in VS. Behavioral deficits in these patients can be as severe as those produced by diffuse damage to the cortical areas underlying high-level processing, indicative of awareness. The specific contribution of individual regions to the clinical performance is determined by their topological integration into brain networks [2,5]. This highlights the need to delineate the connectivity pattern in specific patients in order to elucidate how each connection and sub-network is anatomically related to the injured area and makes specific contribution to the level of consciousness. Advancements in neuroimaging techniques, such as diffusion tensor imaging (DTI), offer the potential to probe anatomical connectivity between remote neuronal populations. Recent studies have suggested that structural networks of the human brain can be characterized by using graph theoretical approaches [for review, see Bullmore and Sporns [6] and He and Evans [7]. Even though DTI has provided unique insights on the underlying brain circuitry accounting for the presence of consciousness and its alterations [5], the relationship of the network topology and efficiency metrics with specific clinical states such as VS and LIS remains unclear. On the other hand, recent studies in patients with DOC using functional MRI (fMRI) have shown impaired connectivity in the thalamo-cortical and fronto-parietal networks, possibly reflecting interruptions of higher-order processes [8,9]. However, these studies do not provide information about neuroanatomic connectivity between different network nodes. Furthermore, the complexities of the association between brain structure and function are not well understood. To our knowledge, this work introduces for the first time, the use of graph theoretical approaches and DTI to differentiate the topological organization of white matter network in patients in VS and with LIS. In order to identify the characteristics properties of injured networks in comparison with healthy architectures we used network-based statistics. In this study, we therefore sought to suggest essential differences in reduced global network efficiency and altered nodal efficiency between these DOC.
METHODS
The Ethics Committee of the Institute of Neurology and Neurosurgery, Havana approved this study. Informed written consent was obtained from the patient’s legal representative and from all healthy volunteers.
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Participants
Patient in VS: We studied a 24-year-old female patient who suffered a meningoencephalitis when she was 3 years old, and developed a hydrocephalus requiring several ventricular derivations to peritoneum, pleura and gallbladder. Four years ago, she suffered an acute hydrocephalus due an obstruction of the ventricular derivation, causing a central and uncal herniation with a compression of the brainstem. After being in coma during 4 weeks she was diagnosed as been in a persistent vegetative state (PVS). Magnetic resonance imaging showed destruction of the rostral part of the pons, the mesencephalon, and both thalami.
Patient with LIS
We studied a 47-year-old male patient who developed an acute stroke of the basilar artery territory with sudden loss of consciousness. The patient remained in coma for 3 weeks, but afterwards opened his eyes and showed sleep-wakefulness cycles. He was diagnosed as having been in a PVS state. Nonetheless, when our group clinically examined him we noted that we were able to establish communication with him using through coded messages by blinking or vertical eye movements, indicating answers of YES or NO. We diagnosed him as being in a Locked-in syndrome (LIS). The patient demonstrated quadriplegia and the inability to speak, but he was undoubtedly conscious and aware, with no loss of cognitive function. He only preserved vertical eye movements and the blink responses. MRI showed ischemic lesions of the pons, corresponding to the basilar artery territory.
Controls Twenty healthy subjects (13 male, 11 female, age: 35.0 ± 12.1) were selected from the Cuban Human Brain Mapping Project database [10]. Volunteers reported no history of psychiatric or neurological disorders. Those studies were selected so as to coincide with the average age of the patients and the age of these were within the standard deviation of the controls database.
Image Acquisition and Preprocessing All images were acquired using a MRI scanner Siemens Symphony 1.5 T (Erlangen, Germany). Using a standard diffusion gradient direction scheme (twelve diffusion-weighted images and a b=0 image), DW-MRI data were acquired using a single shot EPI sequence. To each subject, two interleaved sets of 25 slices of 6 mm thickness with a distance factor of 100% were acquired with the following parameters: b=1200 s/mm2; FOV=256×256 mm2; acquisition matrix=128×128; corresponding to an ‘in plane’ spatial resolution of 2×2 mm2; TE/TR=160 ms/7000 ms. Two interleaved sets were necessary because it was impossible to cover the whole head with a good spatial resolution using a single set due to a pulse sequence limitation (max: 35 slices). Both sets were joined to form a volume of 50 contiguous slices of 3 mm thickness covering the whole brain for each subject. The aforementioned acquisition was repeated 5 times to improve signal to noise ratio (SNR). In order to improve EPI quality, magnitude and phase difference images of a T2 gradient echo field mapping sequence were acquired with TE=7.71 ms and 12.47 ms. Also, a 3D high-resolution T1-weighted MPRAGE pulse sequence covering the whole brain was acquired with the following parameters: 160 contiguous slices of 1-mm thickness in sagittal orientation; in plane FOV=256×256 mm2, and matrix size 256×256 yielding an spatial resolution of 1×1×1 mm3. The echo time, repetition time, and inversion time were set to TE/TR/TI=3.93 ms/3000 ms/1100 ms with a flip angle FA=15°. Lesion areas were manually segmented on the MPRAGE images using MRIcron software (http://www.sph.sc.edu/comd/rorden/mricron/) to create binary masks in native space.
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Network Definition The graph framework used here has been widely described in Iturria-Medina et al. [11]. In brief, the cerebral volume is represented as a non-directed weighted graph G in which nodes N correspond to anatomically defined regions and arcs to the connections joining them. In DTI-based graphs, between-regions connectivity can be reasonably restricted to white matter tracts connecting voxels of the surfaces of the corresponding anatomical areas. This approach significantly reduces the computational cost of the procedure. While definition of the network nodes is consubstantial with graph theory, standard image- matching algorithms to map atlas to brains are challenged in patients with brain injury. To overcome this inconvenience, MPRAGE volumes were spatially normalized to the T1-MNI template using the ‘unified segmentation’ approach, available in SPM8 (http://fil.ion.ulc.ac.uk/spm) [12]. This procedure combines segmentation, bias correction and spatial normalization in the non-linear deformation model. Lesioned area was excluded from the calculation using a cost function masking to improve normalization results. Lesion masks for each patient were created using rough drawings of lesion boundaries. Atlas was registered with the gray matter volume maps in native space and segmented into 71 regions, using the anatomically labeled template corresponding to the Jacob Atlas developed by the Montreal Neurological Institute (http://www.mni.mcgill.ca/) and the IBASPM toolbox (available at http://www.fil.ion.ucl.ac.uk/spm/ext/#IBASPM) [13]. Thus, the topological properties of the brain anatomical networks were defined on the basis of the 71x71 binary graph G.
Fiber Tracking and Node-Node Connectivity Figure 1 shows an overview of the methodology used in this study to identify impaired connections and compromised sub-networks in patients. An iterative streamline fiber tractography algorithm is employed for finding the most probable trajectory between each pair of gray matter regions [11]. Streamlines exceeding 20 mm and below 500 mm in length and a curvature threshold of ±90o were used to generate the connectivity matrix for each subject. The connectivity between a pair of nodes was quantified by two different anatomical connectivity measures: Anatomical Connection Strength (ACS) and Anatomical Connection Density (ACD) [11]. ACS is related to the amount of nervous fibers shared by regions Ai and Aj by counting the nodes on the surfaces involved in the connection:
( , )=∑ ( ) (1) where ( ) quantifies the conditional weight of the arc . On the other hand, ACD is a measure of the fraction of the surface involved in the connection with respect to the total surface of both areas.
Thus, it can be estimated as the ratio between ACS and the number of nodes Ni and Nj belonging to the surfaces of Ai and Aj, respectively:
( , ) ( , )= (2) | |
Z transformation was used to provide probability statements about the deviation of the connectivity measures from the normal values. Z scores of ACD and ACS were calculated by means of Z = (x – µ)/, where x represents the value of ACD or ACS in each patient, while µ and are respectively the mean value and the standard deviation of x in the population of normal subjects.
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States 323
Figure 1. I. Streamline fiber tractography; II. Nodes definition using non-linear transformations and IBASPM toolbox; III. Anatomical network construction; IV. Calculation of network efficiency using graph theory; and V. Identification of impaired connections using network based statistic.
Graph Analysis To characterize the effect of the lesions over the efficiency in information exchange in brain connectional architecture, we estimated the global and local efficiency of network as organizational attributes of integration and segregation, respectively. For a graph G with N nodes, the global efficiency can be computed as
= ∑( )∈ (3) ( ) where dij is the shortest geodesic lengths between pair of nodes i and j. On the other hand, the local efficiency Eloc is measured as:
= ∑ ( ) (4) ∈
where Eglob(Gi) is the global efficiency of the local subgraphs, neighbors of node i. In order to identify disconnected subnetworks in the patients, mass univariate testing was performed at every connection using network based statistic (NBS) approach [14]. Primary t statistic threshold for each link was set to 3.1 and 5000 permutations test were used to determine the statistical significance of differences in network parameters.
RESULTS
Fiber tractography localized connectivity disruption at different levels in the brainstem in patients in VS and with LIS, showing high consistency with lesion’s topology (Figure 2). In VS patients, lesion in mesencephalon and rostral pons caused a disruption of cortico-spinal tract and cerebral peduncle, causing a widespread alteration of thalamus-subcortical and cortico-cortical connectivity.
324 Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria et al.
On the other hand, brain injury in LIS is confined to the ventral pons disrupting the cortico-spinal and spino-thalamic tracts, while cortical connectivity is preserved. As shown in figure 3, for Cluster, E_glob and E_loc the values of ACD and ACS in VS subject were lower than the corresponding mean values of control subjects, as expected. On the contrary, a trend toward increased clustering and local efficiency accompanied by reduced global efficiency was found for ACD in patients with LIS, but these differences were not significant.
Figure 2. From left to right: anatomical damage, streamline fiber tractography and spatial correlation of impairments in patients. Upper: Patient in VS showing a widespread disruption in cortical and subcortical connectivity. Lower: Patient with LIS showing an injury in pontine crossing tracts and preserved cortical networking.
Figure 3. Differences in area under the global network properties curves: clustering index, global efficiency and local efficiency. The clustering and efficiency index differences between normal controls and patients for Anatomical Connection Density (ACD) and Anatomical Connection Strength (ACS) descriptors are depicted. Bars represent the mean of each network property and black lines represent standard deviations in control database.
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States 325
Table 1. Z scores of anatomical connectivity measures for both patients. Note that the patient with LIS shows a (non-significant) tendency to higher local properties than healthy controls
ACD ACS Cluster E_glob E_loc Cluster E_glob E_loc % Z % Z % Z % Z % Z % Z PVS -19.2 2.79* -55.2 8.84* -15.1 2.13* -55.5 1.44 -75.4 2.06* -53.8 1.20 LIS 3.5 -0.51 -5.3 0.85 4.4 -0.62 -3.7 0.09 -2.5 0.07 11.4 -0.26 *statistically significant (Z > 2)
The Z score test showed significantly lower (Z > 2) global and local efficiency, as well as clustering index in ACD network in patient in VS, while ACS network showed significant reduction only for global efficiency. On the other hand, anatomical connectivity measures showed no differences in patients with LIS compared to controls (Table 1). Seeing together, these results suggest that balance between local specialization, provided by Cluster and E_loc, and global integration indicated by E-glob, has been spoiled in VS while remains essentially intact in LIS.
Figure 4. Nodes and streamline representation of impaired connections in VS (A), and LIS (B). Each node is depicted as a black circle positioned at its node’s center of gravity. Gray circle is positioned in brainstem where structural injury is located. Significance of differences was calculated using network-based statistics.
A network based statistical analysis was used to identify particular node pairs that were abnormally connected in patients. NBS reveals that the architectural network presents anomalous organization in both patients compared with the corresponding healthy values, but is suggestively different between them. Streamlines interconnecting each of these node pairs are visualized in Figure 4. A widespread network was found to be significantly impaired in VS patient (p<0.05, corrected) interconnecting several nodes comprising all cerebral lobes. Only two sub-networks were found to be significantly impaired in the patient with LIS (p<0.05, corrected), corresponding to the basal ganglia- thalamus-frontal cortex circuitry.
326 Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria et al.
DISCUSSION
An accurate and reliable assessment of the level and content of consciousness in DOC is critical for the subsequent management and rehabilitation, as well as legal and ethical decision-making. To date, the gold standard for diagnosis of the level of consciousness is behavioral. However, the scope and reliability of available scales, examiner experience and overlapping of impairments in consciousness limit clinical diagnosis. These concerns may lead to misdiagnosis in patients with LIS, where cortical functions are preserved but the inability of production of voluntary motor behavior may resemble patients in VS. This study provides supports that DTI is a potent tool for dissecting the complex neuroanatomic substrate of different DOC. Although the result of brain fiber tracking was not necessarily parallel to the clinical symptoms, essential differences between patients in VS and LIS are evidenced in Figure 4. Viewed as a network disorder, vegetative state has been found widespread impairment in cortico- cortical connectivity in addition to the brainstem connections. This result suggests that the loss of awareness in patients with lesions in the brainstem might be associated with aberrant neuronal connectivity among widely distributed brain regions, and provide structural evidence for the notion of VS as a disconnection syndrome. Significant reduction of all structural network attributes in this pathological condition might be interpreted as a considerable decline in the amount of possible nervous information that can be exchanged over the brain, and how deficiently it can be managed at local and global levels. On the contrary, patient with LIS showed a cortical connectivity pattern that was comparable with that observed in healthy controls. This is in agreement with previous studies showing a near-to-normal functional connectivity in LIS [15,16]. Disruption of connections between brainstem, basal ganglia and frontal motor regions is consistent with quadriplegia, aphonia and quadriplegia and paralysis of the cranial nerves, while cortical networks supporting consciousness remain intact. Those results are highly consistent with remarkable functional and cognitive differences between these pathological states, extensively reported in previous studies [1,3,16-20]. Curiously, ACD shows a higher sensitivity to differentiate network properties of pathological states, especially VS, from healthy connectivity patterns. This is an unexpected result, considering that differences in ACS exceed 50% for all the network parameters. More likely, this apparent contradiction could be a result of the comparison of single subject against a normalized database. The relatively large range of age in a small population of healthy subjects induces an overstated standard deviation, which decreases the predictive ability of the Z score. A seminal study made by Iturria et al. [11] found significant correlations among these connectivity matrixes. However this high correlation was obtained between gray matter structures of healthy subjects, which may support our conclusion. By definition, ACD is searched as a measure of the fraction of the surface involved in the connection with respect to the total surface of both areas, while ACS give an estimate of the amount of nervous fibers shared by these areas [11]. Thus, ACD normalize for the differences in surface area and volume of brain regions (network nodes) related with normal inter-subject variability and/or aging [21]. Our MRI configuration allows for acquisition in 12 isotropically distributed diffusion-encoding directions. This limitation determines the capacity of a tensor to model properly multiple fiber tracts in one voxel. For that reason we applied the fiber assignment by continuous tracking (FACT) streamline tracking algorithm [22]. This algorithm is computationally inexpensive and has been demonstrated to be able to robustly reproduce brain circuitry. Figure 2 illustrate the performance of the tractography method and the high topological association between damaged tissue and fiber disruption in both patients. Application of advanced tractographic algorithms with high angular resolution can avoid limitations inherent to streamline tracking. However, they might not be computationally feasible as diagnostic tools in a clinical environment.
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States 327
The main limitation to our study is that our findings are limited to two patients. However, large scale trials from patients with severe brain damage present challenging complexities related with acquisition, analysis and interpretation of neuroimaging data and inhomogeneities in lesion topology, which are unique for each patient. Our results suggest that DTI-based network connectivity combined with graph theory is useful to study the long range effect of confined injuries and the relationship with the degree of consciousness impairment, underlying PVS and LIS. The feasibility and reliability in the application of these techniques to characterize single cases have encouraging implications for use them as diagnostic and prognostic techniques in DOC. Our results suggest that DTI-based network connectivity combined with graph theory is useful to study the long range effect of confined injuries and the relationship with the degree of consciousness impairment, underlying PVS and LIS. This is the first approach to characterize the dissimilarities in branching configuration underlying the clinical and behavioral differences between vegetative states and locked-in syndrome. More detailed comparisons between normal and pathological ACS and ACD maps combined with graphic theoretical tools could become a potential procedure to diagnose and distinguish different disorders of consciousness related to white matter injury in the pathways from brainstem to cerebral cortex.
ACKNOWLEDGMENTS
RRR was partially supported by the “Abdus Salam” International Center for Theoretical Physics, Trieste, Italy. Authors would like to thank Andy Stanert for the revision of the manuscript.
REFERENCES
[1] Monti MM, Laureys S, Owen AM. The vegetative state. BMJ. 2010;341:c3765. [2] Querol-Pascual MR. Clinical Approach to Brainstem Lesions. Semin Ultrasound CT MRI. 2010;31:220-9. [3] Cardwell MS. Locked-in syndrome. Tex Med. 2013;109(2):e1. [4] Patterson J, Grabois M. Locked-in syndrome: a review of 139 cases. Stroke. 1986;17(4):758-64. [5] Edlow BL, Takahashi E, Wu O, Benner T, Dai G, Bu L, et al. Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J. Neuropathol Exp Neurol. 2012 Jun;71(6):531-546. [6] Bullmore E, Sporns O. Complex brain networks: graph theoretical analysis of structural and functional systems. Nat. Rev. Neurosci. 2009 Mar;10(3):186-198. [7] He Y, Evans A. Graph theoretical modeling of brain connectivity. Curr. Opin Neurol. 2010 Aug;23(4):341-350. [8] Crone JS, Ladurner G, Holler Y, Golaszewski S, Trinka E, Kronbichler M. Deactivation of the default mode network as a marker of impaired consciousness: an fMRI study. PLoS One. 2011;6(10):e26373. [9] Noirhomme Q, Soddu A, Lehembre R, Vanhaudenhuyse A, Boveroux P, Boly M, et al. Brain connectivity in pathological and pharmacological coma. Front Syst Neurosci. 2010;4:160. [10] Hernandez-Gonzalez G, Bringas-Vega ML, Galan-Garcia L, Bosch-Bayard J, Lorenzo-Ceballos Y, Melie-Garcia L, et al. Multimodal quantitative neuroimaging databases and methods: the Cuban Human Brain Mapping Project. Clin. EEG Neurosci. 2011 Jul;42(3):149-159. [11] Iturria-Medina Y, Canales-Rodriguez EJ, Melie-Garcia L, Valdes HP, Martinez E, Aleman- Gomez Y, et al. Characterizing brain anatomical connections using diffusion weighted MRI and graph theory. Neuroimage. 2007;36:645-660.
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[12] Ashburner J, Friston KJ. Unified segmentation. Neuroimage. 2005;26(3):839-851. [13] Alemán-Gómez Y, Melie-García L, Valdes-Hernández P. IBASPM: toolbox for automatic parcellation of brain structures. Proceeding of 12th Annual Meeting of the Organization for Human Brain Mapping. Available on CD-Rom in NeuroImage. 2006;27(1). [14] Zalesky A, Fornito A, Bullmore E. Network-based statistic: Identifying differences in brain networks. Neuroimage. 2010;53:1197-1207. [15] Soddu A, Vanhaudenhuyse A, Bahri M, Bruno M, Boly M, Demertzi A, et al. Identifying the Default-Mode Component in Spatial IC Analyses of Patients with Disorders of Consciousness. Hum. Brain Mapp. 2012;33:778-796. [16] Vanhaudenhuyse A, Noirhomme Q, Tshibanda LJ, Bruno MA, Boveroux P, Schnakers C, et al. Default network connectivity reflects the level of consciousness in non-communicative brain- damaged patients. Brain. 2010 Jan;133(Pt 1):161-171. [17] Guldenmund P, Vanhaudenhuyse A, Boly M, Laureys S, Soddu A. A default mode of brain function in altered states of consciousness. Arch Ital Biol. 2012 Jun;150(2-3):107-121. [18] de Jong BM. "Complete motor locked-in" and consequences for the concept of minimally conscious state. J. Head Trauma Rehabil. 2013 Mar;28(2):141-143. [19] Bardin JC, Schiff ND, Voss HU. Pattern classification of volitional functional magnetic resonance imaging responses in patients with severe brain injury. Arch Neurol. 2012 Feb;69(2):176-181. [20] Bruno MA, Vanhaudenhuyse A, Thibaut A, Moonen G, Laureys S. From unresponsive wakefulness to minimally conscious PLUS and functional locked-in syndromes: recent advances in our understanding of disorders of consciousness. J. Neurol. 2011 Jul;258(7):1373- 1384. [21] Hedman AM, van Haren N, Schnack H, Kahn R, Hulshoff Pol HE. Human brain changes across the life span: a review of 56 longitudinal magnetic resonance imaging studies. Hum. Brain Mapp. 2012;33(8):1987-2002. [22] Mori S, Crain BJ, Chacko V, Van Zijl PC. Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging. Ann. Neurol. 1999;45:265-269.
Received: June 13 2013 Revised: June 18 2013 Accepted: June 23 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):329-340 ISSN: 2156-941X © Nova Science Publishers, Inc.
IF IT IS LOCALIZATION THEN THERE IS NO DEVELOPMENT, EDUCATION, AND REHABILITATION: NEUROEDUCATION NEEDS TO BE ABOUT BUILDING NETWORKS
Gerry Leisman1,2,3,4, 1The F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation and applied Neurosciences, Garden City, NY USA 2The National Institute for Brain and Rehabilitation Sciences, Israel 3O.R.T.-Braude College of Engineering 4Universidad de Ciencias Médicas de la Habana Facultad Manuel Fajardo, Havana, Cuba
ABSTRACT
Little of the 150 years of research in Cognitive Neurosciences, Human Factors, and the mathematics of Production Management have found their way into educational policy and certainly not into the classroom or in the production of educational materials in any meaningful or practical fashion. While more mundane concepts of timing, sequencing, spatial organization, and Gestalt principles of perception are well known and applied, as well as the maintenance of simplistic notions of developmental brain organization and hemisphericity for language rather than the neurophysiology of embodied language, these concepts still inform pre-K-3 curriculum and clinical neurological practice in both the diagnostic and therapeutic modalities. The paper overviews the science of human physiologic efficiencies to develop a fundamental understanding that the concept of localization of function in the brain is a just reflection of plasticity and required for optimized function, but understanding brain function by that alone would obscure the understanding of the education and rehabilitation process from early childhood through the older years. Diagnostic and therapeutic systems need to address pathways in the brain and their changes as a result of intervention rather than examine more static notions of localized function.
Keywords: Localization of Function, Connectography, Plasticity, EEG, Networks
The paper is based on a presentation at the Oxford Roundtable Session on Childhood Education 11-15 March 2012 at Harris Manchester College, Oxford University. This work is supported in part by the Ministry of Absorption, Kamea Dor-Bet, State of Israel, Apex Laboratories, and by the Children’s Autism hope Project. Address for correspondence: Dr. Gerry Leisman, National Institute for Brain and Rehabilitation Sciences, O.R.T. College of Engineering, 51 Snunit POB 78, Karmiel Israel 2161002 E-mail: [email protected].
330 Gerry Leisman
INTRODUCTION
Recent spectacular advances in neurosciences have stimulated the hope that the application of our understanding that it is no longer about cerebral asymmetries and simplistic left-right differences but more complex applications of networks, and communication system principles that have led to newly developed concepts and findings that have not, as yet, found there way into clinical thinking in an significant way. We are at the cusp of developing breakthrough concepts in the understanding of educational and rehabilitation processes, notably learning, memory, motivation and of course evaluation methods that examine these functions. Gradually it is being appreciated that there is considerable overlap between the problems of educational, sociological, and psychological processes and those of neurobiology, biochemistry and neurophysiology, and there is every possibility of reciprocal assistance. Researchers in these fields are willing to approach complex functions such as memory and learning on a physiological basis. We believe that the techniques and knowledge of neuroscience as well as Human Factors and Industrial Engineering notions of efficiency and production management can provide a service for treatment and educational interventions at all stages throughout life. There are findings of relevance for educators and rehabilitationists from those in the most diverse biological fields. Although the human brain - the most crucial part of the anatomy - is the most complex mechanism known to man, it is now being analyzed in ways that are clearly significant for education and rehabilitation. Recent research on the human brain has provided data relevant to understanding the processes of human learning and therefore to improving teaching and increasing the likelihood of recovery of function after brain damage. This author sees no fundamental difference between the task of education and the mission of the educational system, rehabilitation after neurological insult or developmental disabilities, the task of parenting, the effects of social interaction, the effects on the nervous system of sport, or even the ability to intervene in the natural consequences of cognitive aging. The term education can then be used interchangeably with rehabilitation as all directly relate to measurable dynamic plastic changes in neural connectivities. Education has been grabbing at straws for a long time. Often when a preliminary finding is reported in the neuroscience literature or presented at a conference, it is grabbed and expounded upon with little consideration of the fundamental nature of biological processes that underlie those changes. For better or worse, over the last 10 years, education has been actively and aggressively looking to the biological sciences in order to inform education policy and practice. A good example is that of the 1998 decision in Georgia to fund an expensive program, to provide CDs of Mozart’s music to all new mothers. In establishing this policy, the governor of Georgia drew heavily on work in cognitive neuroscience conducted at the University of California, Irvine. The actions were taken in the hope of “harnessing the ‘Mozart effect’ for Georgia’s newborns—that is, playing classical music to spur brain development.” Despite what the program implied, Mozart effect research, upon close examination, had little to offer education. One study, reported in Nature [1], found that listening to Mozart raised the IQs of college students for a brief period of time. Another study found that keyboard music lessons boosted the spatial skills of three-year-olds [2]. Cognitive neuroscientists responsible for this work were baffled by Georgia’s program and actions based on their work. Since this debacle, major figures in the sciences have published articles emphasizing caution and care as scientists, educators, and practitioners proceed down this exciting, but pitfall-laden road. These cautionary articles have laid the groundwork for relationships between neuroscience and education. However, there is a paucity of publications that systematically examine an area of research where conservative but confident claims can be made of the benefits of interdisciplinarity. Most currently prevailing patterns of education are heavily biased towards left cerebral functioning and are antithetical to right cerebral functioning. Reading, writing and arithmetic are all
If It Is Localization then There Is No Development … 331 logical linear processes, and for most of us are fed into the brain through our right hand. Most educational policies have tended to aggravate and prolong this one-sidedness. There is a kind of damping down of fantasy, imagination, clever guessing, and visualization in the interests of rote learning, reading, writing, and arithmetic. Great emphasis is placed upon being able to say what one has on one's mind clearly and precisely the first time. The atmosphere emphasizes intra-verbal skills, “Using words to talk about words that refer to still other words" [3]. If there is any truth in the assertion that our culture stresses left hemisphere skills and discriminates against the right hemisphere, this is especially true of school systems. Our society's overemphasis on "propositionality" at the cost of "appositionality" does not only result in adjustment difficulties but also in a lopsided education for the entire student body. Our students are not being offered the education they require to understand the complex nature of the world and themselves, an education for the whole brain. Sperry wrote: Our education system and modern society generally (with its very heavy emphasis on communication and on early training in the three R’s) discriminates against one whole half of the brain. I refer, of course, to the nonverbal, non-mathematical, minor hemisphere, which we find has its own perceptual, mechanical and spatial mode of apprehension and reasoning. In our present school system, the attention given to the minor hemisphere of the brain is minimal compared with training lavished on the left, or major hemisphere [4]. Educational institutions have placed a great premium on the verbal/numerical categories and have systematically eliminated those experiences that would assist young children's development of visualization, imagination and/or sensory/perceptual abilities. The over-analytic models so often presented to children in their textbooks emphasize linear thought processes and discourage intuitivity, analogical and metaphorical thinking. These factors of neural functioning among children have been left to modification by random environmental, rather than systematic, institutional means. Education, which is predominantly abstract, verbal and bookish, does not have room for raw, concrete, esthetic experience, especially of the subjective happenings inside oneself. Education imposes a structure of didactic instruction, right-wrong criteria and dominance of the logical-objective over the intuitive- subjective on the learning child so early in the course of emergent awareness of his world and of himself that, except in rare cases, creative potential is inhibited, or at least diminished. [cf. 5]. This leads us to affirm that our system of education is one which leads to the underdevelopment of the right hemisphere. As a result of excessive emphasis on intellectualizing, verbalizing, analyzing and conceptualizing processes, 'curriculum' has become equated with mere 'understanding'. This imposes 'neurotogenic limitation' and binds mental processes so tightly that they impede the perception of new data. In the words of Gazzaniga [6] a long time ago, curriculum is "inordinately skewed to reward only one part of the human brain leaving half an individual's potential unschooled.” The traditional preoccupation with formal intellectual education effectively blocks the possibility for the students to recognize and cultivate creativity and transcendence. It has been the adaptation by educators of applications of brain sciences into the classroom and the culture of dichotomies of the Behavioral Sciences over the past 150 years that have placed undo reliance by our educational systems on functional brain models that may be irrelevant at best and damaging at worst to children’s classroom performance and its evaluation. What emerges as the central proposition of this paper is that (A) the examination and study of regional cerebral differences in brain function as a way of explaining and evaluating the learning process within the educational system is a non-starter. (B) The evaluation of students by standardized aptitude and achievement tests is not sufficient although probably still necessary and (C) the educational systems would be better to examine student performance and teach towards “cognitive efficiency” rather than simply mastery v. non-mastery with methods that employ both psychophysics that examine person-environment interaction and mathematical means of examining optimization and the strategy used to get there as well as how far or close a student is functioning from a
332 Gerry Leisman mathematically derived optimization regression line or, in fact, how quickly the learner is progressing in that direction. Educators, although perhaps not palatable to conceive of early childhood education as such, are producing product and production management techniques that should be useful for evaluating not just the product but the process or “manufacture” of that product as well.
BRAIN ANATOMY IS IRRELEVANT TO EDUCATIONAL PRACTICE AND LIKELY TO REHABILITATION AS WELL
We possess, especially as adults, but with children as well, a high degree of localization of function, but that is not enough to explain the capacity for plasticity, regeneration, spontaneous recovery, and optimization in neurological terms and certainly not in its translation into educational practice. On the other hand, educational gains are measured largely by achievement and also by aptitude testing. Achievement testing deals with educational gains and not necessarily with the concept of optimization, and aptitude testing again largely deals with the probability of success but does not give a comprehensive view of the tools skills, both physiological and cognitive, that would directly relate to that educational success that would be better measured psychophysically and through the tool skills of project management, in the same way that cognitive optimization of pilots or air traffic controllers might be measured or evaluated and that product evaluation might be achieved. In attempting to understand why neuroanatomic conceptualization is a non-starter for educational practice it is important to understand that what we are really attempting to achieve both in educational practice as well as in understanding the neurological basis of cognitive development is not what brain area controls a given cognitive function, but how efficiently it is operating. Whilst not the scope of this paper to provide a detailed overview of this principle, the reader is invited to review these concepts more comprehensively elsewhere [5]. To illustrate how it is that localization has less relevance to our point, Figure 1(A) below presents a CT-Scan of the brain of Terry Schiavo while in a persistent vegetative state and 1(B) of a young lady of normal intelligence born with hydrocephalus where no significant anatomic difference is evidenced between the PVS patient and the normally functioning young lady, but clear functional differences are noted during language processing.
Figure 1. (A) CT of normal (l.) and that of the brain of Terry Shiavo (r.) when the latter was in Persistent Vegetative State. (B) CT of normally functioning teenager with congenital hydrocephalus and a CT similar to that of the patient. (C) Regional Cerebral Blood Flow image of individual in (B) while performing language- based cognitive tasks.
The concept of ‘‘cortical efficiency’’ that we have earlier described [7-11] that higher ability in a cognitive task is associated with more efficient neural processing and not necessarily a particular brain region that is involved in that processing. Whereas intuitively, we would expect higher performance to correlate with more activity, for the cerebral cortex the contrary is the case. Higher performance in several tasks, including verbal [12], numeric, figural, and spatial reasoning [13,14] is consistent with the reduced consumption of energy in several cortical areas. This phenomenon has also been studied
If It Is Localization then There Is No Development … 333 with EEG techniques in different frequency bands. The amount of a background power (7.5–12.5 Hz) decreases during cognitive activity compared with a resting state. This decrease has been observed to correlate with higher performance in subjects with higher IQ scores [9] or with higher performance after training, indicating a more efficient processing strategy for a cognitive task [15]. Most of these studies come from the psychological literature, focusing mainly on the domain of intelligence but drawing relatively little attention to the investigation of task performance in second language learners or bilinguals. In an EEG coherence study on second language (L2) processing/bilingualism, an extension of the ‘‘cortical efficiency’’ paradigm was examined. Coherence, the amount of shared activity between any two electrode pairs and taken over the entire scalp surface, gives an index of inter-regional communication effectiveness. The acquisition of an L2 is equivalent to the training of a cognitive– behavioral skill, and some individuals respond to this training more efficiently than others. If an L2 is acquired before a certain age or critical period, even native speaker proficiency is achieved easily (early bilingualism). If training starts later in life, the proficiency level achieved depends on the amount of training, exposure, and on some kind of ‘‘predisposition’’ or aptitude of the individual. Whereas, in general, L2 processing involves the same language-specific cortical areas (with left hemisphere preference) as native language (L1) processing (cf. review 16], neuroimaging studies have repeatedly shown that lower L2 proficiency is correlated with more widespread cortical activity. Perani et al., [17] was tacitly in line with the ‘‘cortical efficiency’’ concept, but not explicitly investigating it. Reiterer and colleagues [18] (2005) applied this concept in studying late bilinguals/second language learners, comparing, with EEG recording techniques, the recruitment of cortical areas during L2 processing in two groups of individuals differing profoundly in L2 proficiency (although both had started to learn L2 at the same age) In using coherence analysis or the amount of sharing between any two wave trains and thus reflective of brain integration of functioning and efficiency, the coherence brain maps (exemplified in Figure 2) revealed more pronounced and widespread increases in coherences in the α1-band (8–10 Hz) in low-proficiency than in the high-proficiency L2 speakers. Surprisingly, this difference was obtained also during L1 processing and corroborated for both languages by multivariate permutation tests. These tests revealed additional differences between the low- and the high-proficiency group also for coherences within the β1- (13–18 Hz) and the β2-band (18.5–31.5 Hz). The point is that greater activity is demonstrated with less proficiency and vice versa. The function of childhood neurological development is precisely to facilitate the creation of localized function and it is dynamic. It can be changed and is therefore plastic. This localization of function is not the explanation of a process, but rather the end-result of training. The efficiency of cognitive function is directly a consequence of the effectiveness of networks that now can be measured. Fewer brain regions necessary to accomplish a single task in one individual compared to another for the same task is a measure of efficiency. These networks, active during learning and problem solving of all kinds, are plastic and can be changed as a direct consequence of experience and training. In attempting to apply graph theory concepts to child and adolescent neurocognitive performance to create a fundamental change in the educational training and evaluation paradigm, we can characterize the organization & development of large-scale brain networks using graph-theoretical metrics as represented in Figure 3 below.
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Figure 2. Coherence, or the amount of shared activity between EEG electrode sites, demonstrates significant coherence differences in high-proficiency versus low-proficiency bilinguals relative to the default condition (silence, noisy screen) in the δ frequency band (0.5–3.5 Hz) during processing of visual and acoustic signals (A), and in the θ-band (4.0– 7.5 Hz), during processing of visual and acoustic signals (B), and of visual signals only (C). The text was either in British English (1st row), American English (2nd row), or in Austrian German (3rd row). (cf. Reiterer et al., 2005).
Figure 3. Functional connectivity along the posterior-anterior and ventral-dorsal axes showing increased subcortical connectivity (●), decreased paralimbic connectivity (●) in children, compared to young-adults. Brain regions plotted using y and z coordinates of centroids (in mm), 430 pairs of regions show increased correlations in children & 321 pairs showed significantly increased correlations in young-adults.
What we can learn from the characterization, organization and development of large-scale brain networks in children using graph-theoretical metrics is that small-world networks are characterized by an increased clustering coefficient or an average node-to-node distance (also known as average shortest path length) and a decreased characteristic path length (and represented in Figures 4). Functional brain networks in children and young-adults show small-world properties. In mathematics, physics and sociology, a small-world network is a type of mathematical graph in which most nodes are not neighbors of one another, but most nodes can be reached from every other node by a small number of steps. Specifically, a small-world network is defined to be a network where the typical
If It Is Localization then There Is No Development … 335 distance L between two randomly chosen nodes (the number of steps required) grows proportionally to the logarithm of the number of nodes N in the network that is [19]:
L α log N
In the context of a social network, this results in the small world phenomenon of strangers being linked by a mutual acquaintance. Many empirical graphs are well modeled by small-world networks. Social networks, the connectivity of the Internet, Wikipedia, and gene networks all exhibit small- world network characteristics [20] These findings suggest sub-networks of densely connected nodes, connected by a short-path. Functional connectivity networks of brain from EEG [21] as well and MEG [22] have also been shown to possess small-world architecture. Large-scale brain networks in 7-9-year-old children show similar small-world, functional organization. Functional brain networks in children show lower levels of hierarchical organization compared to young-adults. Children and young-adults possess different interregional connectivity patterns, stronger subcortical-cortical connectivities in young adults and weaker cortico-cortical connectivities in children. Large-scale brain connectivity involves functional segregation and integration, stronger short-range connections in children, and stronger long-range connections in young-adults. In taking this concept further, we note that represented in Figure 4(a) and (b) below is a representation of functional connectivity along the posterior-anterior and ventral-dorsal axes showing elevated subcortical connectivity and decreased paralimbic connectivity in children, compared to young-adults. This clearly demonstrates that the wiring and connectivities of young children are significantly different than teenagers and beyond and the change in organization of these connectivities directly speaks to the issue of optimization of pathways and is a direct consequence of training and therefore of education. In attempting to apply graph theory to an understanding of language acquisition, Figure 4(b) below shows the responses of both typically developing (TD) and of at-risk, late-talkers (LT). There is exists a significant and apparent visual difference in the networks with the TD's network showing higher clustering coefficient and higher median in-degree, but lower geodesic distance, than the LT. These differences are consistent at both the individual and population level.
Figure 4. Continued on next page.
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Figure 4. (a) Characterization, Organization & Development of Large-Scale Brain Networks in Children Using Graph-Theoretical Metrics. (b) The graph on the left is a typically developing (TD) child (17 mo., 40%) and the graph on the right is of an at-risk, late-talker (LT) (24 mo., 10%). The network of the TD child includes the 60 words in the child's productive vocabulary and the network of the at-risk LT child includes the 61 words in the child's productive vocabulary. The apparent visual differences in the networks are supported by the differences in the corresponding table, with the typical talker's network showing higher clustering coefficient and higher median in-degree, but lower geodesic distance, than the LT. These differences are consistent at both the individual and population level.
Figure 5. Demonstration of computational modulations in connectivity resulting from lesions in the (a) frontal cortex and (b) sensorimotor cortex. Red lines indicate strength in connectivity. Note the widespread disruption caused by lesion in prefrontal cortex compared with relatively constrained, intrahemispheric changes resulting from a lesion of the sensorimotor cortex.
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Figure 5 demonstrates clearly the computational modulations in connectivity resulting from lesions in the (a) frontal cortex responsible for executive function, decisions, and therefore associations and (b) the sensorimotor cortex. Red lines indicate strength in connectivity. Note the widespread disruption caused by lesions in the prefrontal cortex compared with relatively constrained, intrahemispheric changes resulting from a lesion of the sensorimotor cortex. It has been thought since the time of both Broca and Wernicke that there exists a high decree of localization of function with an area anterior to the Sylvian fissure of the temporal lobes being responsible for expressive language and Wernicke’s area responsible for comprehension. Today we better understand that there no longer exists the localization of receptive functions in one area (cf. Figure 6(a)). Multiple stream models are more likely. Receptive language functions are organized into multiple self-organizing simultaneously active networks. It appears also as represented in Figure 6 (b) that the meaning of words and sentences has been grounded indicating that there is an “embodiment” of meaning in brain networks as previously described.
Figures 6. (a) Bye to the good old days: No more receptive functions in one (Wernicke's) area. Multiple stream models are more likely. Receptive language functions are organized into multiple self-organizing simultaneously active networks. (b) Grounded meaning indicates that the meaning of words and sentences have been claimed to be "embodied".
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Figures 7. (A) and (B) represent the effect of brain on early as opposed to late exposure to a second language. The figures clearly indicate the nature of the optimization and efficiency of brain function connections when notions that related to early training and critical periods are applied.
DISCUSSION
The paper has attempted to give an overview of the nature of neurologic processing efficiencies in engineering terms in an attempt to develop novel approaches and thinking to classroom-based practice and subsequently leadership and policy informed by current neuro-scientific realities and by production management and optimization principles now applied to schools, and their consumers. We have known that small-world networks are characterized by an increased clustering coefficient and a decreased characteristic path length. Applying this notion to brain networks in children, we note that functional brain networks in children and young-adults show small-world properties. This suggests sub-networks of densely connected nodes, connected by short path. The functional connectivity networks of the brain from EEG-based systems demonstrate they possess small-world architecture. Large-scale brain networks in 7-9-year-old children show similar small- world, functional organization. Functional brain networks in children show lower levels of hierarchical organization compared to young-adults and children and young-adults have different interregional connectivity patterns, stronger subcortical-cortical connectivities in young adults and weaker cortico-cortical connectivity in children. Large-scale brain connectivity involves functional segregation and integration. Children possess stronger short-range connections as opposed to younger adults who demonstrate stronger long-range connections.
If It Is Localization then There Is No Development … 339
We have seen that brain connectivities are variously organized efficiently or inefficiently in systems that can be relatively easily measured. It is possible to evaluate optimized changes in brain connectivities after training and learning with applications ranging from progress in early child development, classroom instruction, and bilingualism. These brain connectivities are different and delayed in some as a direct consequence of experience. The measurement of skill and function based on grade level or binary considerations such as a child possesses or does not possess certain skills “medicalizes” the learning paradigm. The focus should be less on binary thinking and more on strategy and optimized performance most easily measured by processing speeds, and strategic solutions. For example, individuals learning a second language late possess brain activity in regions that are not optimally coordinated and synchronized. As the brain continues to develop, more distant but simultaneously active areas require synchronization. It is the developmental lack of effective synchrony that we hypothesize speaks to the connections between motor and cognitive function and to the very nature of learning itself.
REFERENCES
[1] Rauscher FH, Shaw, Gordon L, Ky KN. Music and spatial task performance. Nature. 1993;365:611. [2] Schlaug, G, Norton, A, Overy, K, Winner, E. 2005. Effects of Music Training on the Child’s Brain and Cognitive Development. Ann NY Acad Sci. 1060:219–230. [3] Bruner, J. The Relevance of Education. London: Allen and Unwin; 1971. p. 89. [4] Sperry, RW. Right Brain-Left Brain. Sat Rev. 1975 Aug 9;30-33. [5] Melillo, R, Leisman G. Neurobiological disorders of childhood: an evolutionary approach. New York: Springer; 2009. [6] Gazzaniga, MS. Editorial: Review of the split brain. J. Neurol. 1975:209(2);75-79. [7] Ertl JP, Schafer EWP. Brain response correlates of psychometric intelligence. Nature. 1969:223(5204);421-422. [8] Grabner, RH, Stern E, Neubauer, AC. When intelligence loses its impact: neural efficiency during reasoning in a familiar area, Intern J. Psychophysiol. 2003;49(2):89–98. [9] Grabner RH, Fink A, Stipacek A, Neuper C, Neubauer, AC. Intelligence and working memory systems: evidence of neural efficiency in alpha band ERD, Cog Brain Res. 2004:20(2);212–225. [10] Gilchriest J. A method for quantifying visual search scanpath efficiency. Funct Neurol, Rehabil Ergon. 2011;1(2):181-196. [11] Leisman G, Machado C, Melillo R, Mualem R. Intentionality and “free-will” from a neurodevelopmental perspective. Front Integrat Neurosci. 2012;6:36. doi: 10.3389/ fnint.2012.00036. [12] Parks RW, Loewenstein DA, Dodrill KL, Barker WW, Joshii F, Chang, JY, Emran A, Apicella A, Sheramata, WA, Duara, R. Cerebral metabolic effects of a verbal fluency test: a PET scan study. J. Clin. Exp Neuropsychol. 1988;10:565– 575. [13] Lamm C, Bauer H, Vitouch O, Gstattner R. Differences in the ability to process a visuo-spatial task are reflected in event-related slow cortical potentials of human subjects, Neurosci. Lett. 1999;269(3):137–140. [14] Vitouch O, Bauer H, Gittler G, Leodolter M, Leodolter U. Cortical activity of good and poor spatial test performers during spatial and verbal processing studied with slow potential topography, Intern J. Psychophysiol. 1997;27(3):183–199. [15] Neubauer, AC, Grabner, RH, Freudenthaler H, Beckmann H, Jens F, Guthke J. Intelligence and individual differences in becoming neurally efficient. Acta Psycholgica (Amsterdam). 2004;116(1):55– 74.
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[16] Perani D, Abutalebi J. The neural basis of first and second language processing, Curr. Opin. Neurobiol. 2005;15:202–206. [17] Perani D, Abutalebi J, Paulesu E, Brambati S, Scifo P, Cappa SF, Fazio F. The role of age of acquisition and language usage in early, high-proficient bilinguals: an fMRI study during verbal fluency. Hum. Brain Map. 2003;19(3):170-182. [18] Reiterer S, Hemmelmann C, Rappelsberger P, Berger ML. Characteristic functional networks in high- versus low-proficiency second language speakers detected also during native language processing: an explorative EEG coherence study in 6 frequency bands. Brain Res. Cogn. Brain Res. 2005;25(2):566-78. [19] Watts, Duncan J, Strogatz SH. Collective dynamics of 'small-world' networks. Nature. 1998;393:440-442. [20] Howard N, Leisman G. DIME (Diplomatic, information, military and economic power) effects modeling system: Applications for the modeling of the brain. Funct Neurol Rehab Ergon. 2013:3(2-3), [21] Leisman G. Brain networks, plasticity, and functional connectivities inform current directions in functional neurology and rehabilitation. Funct. Neurol Rehab Ergon. 2011;1(2), 315-356. [22] Stam CJ. Functional connectivity patterns of human magnetoencephalographic recordings: a 'small-world' network? Neurosci Lett. 2004;355(1-2):25-28.
Received: May 11 2013 Revised: June 15 2013 Accepted: June 23 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):341-360 ISSN: 2156-941X © Nova Science Publishers, Inc.
THE EFFECT OF OFF VERTICAL AXIS AND MULTIPLANAR VESTIBULAR ROTATIONAL STIMULATION ON BALANCE STABILITY AND LIMITS OF STABILITY
Frederick R. Carrick1,2,3 ,Guido Pagnacco,1,2,3, Elena Oggero1,2,3, Susan E. Esposito2,3, James L. Duffy2,3, Derek Barton2,3, Matthew Antonucci2,3, Jacob Shores2,3, and Diana M. Stephens2,3 1FR Carrick Institute for Clinical Ergonomics, Rehabilitation and Applied Neuroscience, Garden City, NY USA 2Carrick Institute for Graduate Studies, Cape Canaveral, Fl USA 3Carrick Brain Center, Marietta, GA USA
ABSTRACT
Background: Off vertical axis and multiplane whole body vestibular rotational therapy has received great attention by major network television and press subsequent to its utilization in the treatment of sports concussions and other traumatic brain injuries that result in neurological challenges to balance and gait. We desired to test the therapy in isolation from other therapies customarily used in a brain and vestibular rehabilitation center. Methods: Volunteer human subjects underwent postural evaluations to ascertain the characteristics of maintained head position/posture in the yaw and pitch planes. Based on this evaluation, normal human subjects were randomized to one of four groups based on head pitch and yaw. Each subject was then randomly assigned to a vestibular whole body rotational montage specific stimulation group. Immediate and time referenced pre and post-computerized dynamic posturographic measurements were compared. Conclusion: Vestibular activation in a multiplane whole body rotational devise has a modest but significant beneficial effect on the stability of the subjects as measured by the Stability Score and the Normalized 95% Confidence Ellipse Area. However, this beneficial effect appears to be temporary and disappears within one day. Neither the evaluation nor the stimulation had a significant effect on the limit of stability suggesting that the evaluation methodology adopted in this study was not sufficient to properly decide the direction and type of rotational stimulation and that this therapy is not a stand alone treatment. We recommend that this type of therapy not be utilized in isolation of other rehabilitation strategies.
Keywords: Posturography, Functional Neurology, Balance, Gait, Whole Body Rotation
Correspondence: Prof Frederick Carrick, 203-8941 Lake Drive, Cape Canaveral, Fl32920 USA. E-Mail: [email protected]
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INTRODUCTION
We desired to study the effects of vestibular activation in a multiplane whole body computerized rotational chair. Specifically, we wanted to see if such stimulation would affect static balance and stance as well as the limit of postural stability. We have used off vertical axis rotation and multiplanar whole body stimulation combined with individualized brain and vestibular rehabilitation strategies in several hundred cases of traumatic brain injury with impressive outcomes of posture, balance and gait. Abnormalities of posture, balance and gait are commonly associated with traumatic brain injuries and other neurological syndromes that we see frequently. We wanted to test this modality of treatment in isolation from the other integrated treatment regimes we utilize to ascertain the consequences of the therapy. The evaluation of postural stability using computerized dynamic posturography (CDP) is an established functional diagnostic and treatment outcome-monitoring tool [1]. Because we have found that clinical applications of rotational multiplane therapy in concert with an intense multimodal brain and vestibular rehabilitation program have demonstrated posturographic changes, we elected to use CDP as a baseline and an outcomes measure in this study. Body sway increases with age and many neurological disorders and diseases are associated with pathology of balance and gait. Balance is an ability to maintain the line of gravity (vertical line from center of gravity) of a body within the base of support with minimal postural sway [2]. Sway is the horizontal movement of the center of gravity even when a person is standing still. A certain amount of sway is essential and inevitable due to small perturbations within the body (e.g., breathing, shifting body weight for one foot to the other or from forefoot to rearfoot) or from external sources (e.g., air currents, floor vibration). Vestibular information is critical for the control of balance, posture, and eye movements and we desired to obtain baseline data and the characteristics of balance performance before and after whole body multiaxis rotational vestibular stimulation in a randomized controlled study of healthy human subjects. Elderly subjects demonstrate a higher degree of postural imbalance and use a hip strategy to maintain their balance while requiring a longer reaction time and a lower directional control in balance performance [3]. Our experimental model has been designed in concert with an understanding of a variety of strategies utilized in role activities. We have observed many different strategies that patients utilize to maintain balance in a variety of clinical scenarios. Almost all measures of balance are worse in elderly subjects compared with young controls [4], most likely as a result of biomechanical or central processing changes as opposed to diminished sensory or vestibular input. It appears that clinically significant balance impairment in the elderly may be the result of age-related disease rather than an inevitable consequence of aging and is therefore potentially treatable. Treatment of balance related pathology has a societal benefit of decreasing falls and increasing function and autonomy that is not limited to the elderly. Athletic performance and activities of daily living are in a large part associated with integrity of the systems that we desire to measure. The contribution of sensory inputs to balance control differs considerably per individual and may be due to differences in the vestibular function related to the specific pathology or to differences in motor learning strategies in relation to daily life requirements [5]. These individual differences have resulted in specific rehabilitation strategies and treatments that are not similar between individual neurologically compromised patients. It is difficult for us to understand the value of the different contributing therapeutic applications we use as we have never used them in isolation of other therapies. We do know that it is important to evaluate both vestibulo-oculomotor and vestibulospinal pathways in patients with balance disorders. There is a significant correlation (p < 0.005) with a sensitivity and specificity of 95 percent and 90 percent, respectively, between the clinical assessment using CDP and the results of moving-platform posturography [6]. We use CDP regularly in clinical
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 343 applications and find that it has an ease of application with a richness of data for interpretation. Signals from vestibular receptors (semicircular canals and otoliths) are carried by the eighth nerve and distributed to the four nuclei of the vestibular nuclear complex (VNC). Otolith stimulation engages brainstem structures both within and outside of the vestibular nuclear complex, many of which project to the cerebellum [7]. While otoliths act as gravito-inertial force sensors and contribute to the perception of spatial orientation, patients with chronic utricular dysfunction can be identified with the use of difference angles (on-axis SVV - off-axis SVV) [8]. Functional canal and otolith vestibular impairment can be evaluated with vertical and off vertical axis rotation (OVAR) tests. We expect graviceptive moments of receptor activation coupled with angular and translator activation of the head and body when the subject is rotated in a multiplanar scenario. Deficits of vestibular function are involved in the delay of posturo-motor development as well as visual deficit and neurological impairment [9]. We desired to utilize diagnostic procedures in a therapeutic application to ascertain whether we could affect postural motor changes as measured with computerized dynamic posturography (CDP). Otolith-ocular responses can be investigated during off-vertical axis rotation. This stimulus induces nystagmus consisting of an exponentially decaying canalicular response, and an eye-velocity modulation and offset which arise from the excitation of the otoliths by the gravity vector, which lasts as long as the rotation continues [10]. We expected that the gravity vector might be changed after a rotation ceases and desired to test this vector with CDP. Constant velocity off-vertical axis rotation (OVAR) provides dynamic linear acceleration stimuli that can be used to assess otolith function [11]. Neurons with two-dimensional spatio-temporal properties to linear acceleration behave like one- dimensional rate sensors in that they encode the component of angular velocity (associated with a rotating linear acceleration vector) that is normal to their response plane. During off-vertical axis rotation (OVAR) otolith-sensitive neurons are activated by the gravity vector as it rotates relative to the head [12]. During passive whole-body motion in the dark, the motion perceived by subjects may or may not be veridical. We expect reflexive eye movements to be compensatory for the perceived motion, however for certain motions, the perceived motion and eye movements are incompatible [13]. This incompatibility has not been explained by basic differences in gain or time constants of decay but suggest that perceived motions are more compatible with eye movements in three dimensions than one-dimensional components indicate. We therefore decided to utilize CDP as an outcome measure rather than measurements of eye movements and perceived eye position and movements. Vestibular functional impairment leads to delayed posturomotor development if the impairment occurs before independent walking in children [14]. The interrelationship between vestibular functionality and posturomotor development led us to suggest that stimulation of the vestibular system might have a consequence in posturomotor expression. The caudal aspect of the parabrachial nucleus (PBN) contains neurons responsive to whole body, periodic rotational stimulation in alert monkeys while vestibulo-recipient caudal PBN units may detect potentially dangerous anomalies in control of postural stability during locomotion [15]. We desired to test whether whole body rotational stimulation might result in changes of postural stability in human subjects. The integration of neck proprioceptive and vestibular inputs underlies the generation of accurate postural and motor control, however the central mechanisms underlying the integration of these sensory inputs differs across species [16] with multimodal neuronal pools sensitive to neck proprioceptive and vestibular stimulation during passive body-under-head and whole-body rotation, respectively. We cannot rely on animal studies when dealing with human subjects who have compromise of postural and motor control. Reticular neurons take part in the neck tuning of vestibulospinal reflexes by transforming a head-driven sensory input into a body-centered postural response [17]. Vestibulospinal reflexes are elicited by head displacement and contribute to body stabilization owing to the integration of neck input by the cerebellar anterior vermis.
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Due to this integration, the preferred direction of spinal motoneurons' responses to a tilt rotates by the same angle and by the same direction as the head over the body, which makes it dependent on the direction of body displacement rather than on head displacement. The responses of vestibulospinal neurons to whole body rotations in three dimensional space reflect a complex combination of static and dynamic vestibular inputs that may be required by postural reflexes that vary depending on head, trunk, and limb orientation, or on the frequency of stimulation [18]. Somatosensory reafferent inputs to the cerebellar vermis are activated in whole animal rotation and used to plastically modify the gain of the vestibulospinal reflex (VSR) when external forces produce changes in the final posture of the foot during animal tilt [19]. We expected modification of the VSR gain in our subjects and further expected that they might have Posturographic changes as a consequence of the gain change. We understand that sensory vestibular signals are transformed from head-in-space coordinates to trunk-in- space coordinates on many secondary vestibular neurons in the vestibular nuclei by the addition of inputs related to head rotation on the trunk. This coordinate transformation is presumably important for controlling postural reflexes and constructing a central percept of body orientation and movement in space [20]. The vestibulospinal (VS) reflexes elicited by animal rotation modify the activity of limb musculature, thus preserving balance and postural stability [21]. Periodic changes in the phase difference and gain ratio of the neck to the vestibular response may occur during dynamic displacement of the head over the body, depending on the stimulus direction resulting in prominent responses of P cells of the cerebellar vermis that may affect spatially organized postural responses by utilizing vestibular and reticular targets [22]. The conscious perception of passive horizontal rotations of the trunk, the head, or both depends on the interaction of canal and neck afferents such that the sensation of passive head rotation appears to be contaminated by an illusionary contribution from neck afferents that have parallels in postural reflexes as well as in neuronal responses that are known in the cat [23]. We desired to stimulate the vestibular system with multiplanar rotation to see if we would be able to change balance. The motor system that controls the neck musculature stabilizes the head to external perturbations or body movements, and generates both voluntary and orientating head movements. These movements are mediated by complex pathways involving the cerebral cortex and superior colliculus while stabilization is thought to be mediated by simple short-loop pathways that generate vestibulocollic (VCR) and cervicocollic (CCR) reflexes [24]. The VCR and CCR attempt to stabilize head position in space during whole body movements and are subserved by relatively direct, as well as indirect pathways linking vestibular nerve activity to cervical motor neurons [25,26]. Head stability is important during human balance corrections and the VCR modulates the amplitude of functionally stabilizing responses and damps mechanically induced instability of the head and neck [27]. Patients often time complain of stability problems when moving the head. The short-latency VCR is not suppressed by active head turns and its amplitude is not consistently modulated by the direction of head turns [28]. When the head rotates, VCR counteracts the rotation by causing contraction of the neck muscles that pull against the imposed motion [29]. We know that transient passive head rotations in PD (Parkinson's disease) patients are followed by an initial rapid rise in resistive torque representing reflexive head stabilization that normal subjects are able to suppress [30]. PD patients have gait instability and often have absent VCR [31], prompting us to investigate its stimulation in this investigation. Elderly subjects rely upon a combination of active trunk mechanics and vestibular integration in order to coordinate their head and trunk motion [32]. Rotation of the body and head in vertical planes of the VCR and of activation of vestibular neurons projecting to the neck tend to be antagonistic with the vector orientations usually opposite, and the response gains and phases similar in decerebrate cats [33]. We anticipated similar activities in humans, knowing that the CCR and VCR behave approximately linearly, both individually and in combination. Acting together, the two reflexes assist
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 345 each other in preventing oscillation of the head on a stationary body [34]. We postulated that multiplane rotational stimulation would have a definitive vestibular stimulation that would simulate natural activation by head and body rotations. Yaw head-movement kinematics are unaffected by changes in the head's inertia when the whole body is rotated. The VCR and CCR accommodate for changes in the head's inertia that produces forces on the neck when the body moves and stabilizing the head with respect to the trunk during whole body movements. Stiffness and VCR gain appear to be the primary contributors to the control of head stabilization in space. When angular velocities of the head and trunk in yaw and pitch are induced, the behavior of the head in yaw is found to change relatively little with added inertia while in pitch, increasing inertia accentuates phase shifts at higher frequencies [35]. We expected that whole body rotations in multiple planes at the same time might result in increasing balance performance. Incremental rotation axes for both pitch and yaw oscillations are functions of the pitch but not the yaw head positions, perhaps because of the head interface with the dens and occipital condyles during head oscillation with a contribution of the lower spine to pitch during locomotion [36]. Anteflexion and retroflexion of the head are among the main movements of the atlanto-occipital joint and head movements produce neck proprioceptive stimulation in the vestibular system [37] which we thought might be beneficial. Stabilization of the head is required for adequate motor performance, including maintaining balance while standing or walking, and for the adequate reception of sensory inputs such as visual and auditory information. The vestibular organs (semicircular canals, utriculus, sacculus), provide the most important input for the detection of head movement and their activation evokes the VCR which stabilizes head position in space [38]. Otolith and canal inputs are superposed when animals are rotated about roll and pitch axes from an upright position, insuring that these neurons respond over a broad frequency range from very low to high frequencies [39] and allow detection of linear acceleration generated by two different head conditions, dynamic linear translation and static tilt relative to gravity [40]. Otoliths also contribute to the perception of head rotation whole-body constant-velocity pitch rotations about an earth-horizontal, interaural axis because they sense the changes in direction of the gravity vector [41]. The convergence of canal and otolith inputs contribute mainly to vestibulospinal (VSP) reflexes by sending inputs to the neck and other muscles during head inclination [42] but also activate brain structures involved in movement disorders. For instance, activation of the sacculus evokes VCR activation of a multisensory cortical vestibular network within both hemispheres, including the posterior insular cortex, the middle and superior temporal gyri, and the inferior parietal cortex [43]. There are differences between responses to vertical and horizontal rotations [44] suggesting that we would need to rotate subjects in combined planes. The sensory signal from the semicircular canals in constant-velocity chair rotations undergoes neural processing to compute the percept of self-motion [45] an important contribution to human stabilization. We were interested to measure the consequences of this sensory signal specific to stabilization of balance and the limit of stability in our subjects. Sensory vestibular signals are transformed from head-in-space coordinates to trunk-in-space coordinates on many secondary vestibular neurons in the vestibular nuclei by the addition of inputs related to head rotation on the trunk [20]. Stability is dependent upon adaptation to body motions and adaptation to head movements performed during fast rotation during supine head-on-axis rotation is specific to the particular plane of the head movement [46]. Postural compensatory head pitch movements may be produced predominantly by the angular vestibulocollic reflex (aVCR) at low walking speeds and by the linear vestibulocollic reflex (1VCR) at the higher speeds [47]. During mixed angular head accelerations, the VCR may be partly accomplished by VSP and vestibulo-oculospinal (VOS) convergent neurons. For instance, stimulation of the anterior semicircular and/or posterior semicircular canal nerves in decerebrate cats evoke four types of collateral projections to the oculomotor complex and spinal cord; vestibulo-ocular, vestibulospinal, vestibulo-oculospinal, and vestibular neurons [48]. We wanted to see if such
346 Frederick R. Carrick, Guido Pagnacco, Elena Oggero et al. stimulation in human subjects would evoke similar postural responses when they are accelerated in a variety of planes. Low acceleration anteroposterior movement in the standing position induces a body sway in proportion to the acceleration, pivoting on the ankle joint, while high acceleration increases body sway with the head-neck joint remaining locked upright [49]. The postural responses of the neck muscles suggest that the VCR might tonically activate them. Banovetz et al recorded electromyographic activity of dorsal neck muscles and neck torques to study VCR, CCR, and combined reflexes in cats during rotations about many axes. They characterized neck muscles by maximal activation direction vectors and found that all muscles were excited by the nose down phase of pitch rotation and by yaw and roll away from the side on which the muscle lay. All muscles responded as though they received convergent input from all three semicircular canals [50]. The spatial response properties of medial (MVST) and lateral (LVST) vestibulospinal tract neurons during whole body sinusoidal angular rotations of cats in various planes demonstrate a maximum activation direction vector (MAD) that maximally excites the neuron [51]. We wanted to stimulate human subjects in a combination of planes to attempt a similar maximized response. It is likely that activation of reticulospinal fibers, with their resultant motor consequences, are an important part of the neural substrate of the VCR [52]. Reticulospinal fibers make an important contribution to the horizontal VCR and in response to stimuli in vertical planes, the pontomedullary reticulospinal fibers depend on convergence of inputs within the neck with otolith reflexes [53]. Natural stimulation of the labyrinth of decerebrate cats in vertical planes evokes responses of pontomedullary reticulospinal neurons, the largest fraction of which project to the lumbar cord, playing a role in gravity-dependent postural reflexes of neck and limbs [54]. The effectiveness of vestibulospinal and reticulospinal fibers can be modified by spontaneous activity of neurons in the C3 ventral horn subsequent to sinusoidal vestibular stimulation of decerebrate paralyzed cats in multiple vertical planes [55]. Many neurological disorders that are associated with balance pathology involve the cerebellum. All cerebellar patients demonstrate impaired otolith-ocular responses and may demonstrate severe vestibular deficits [56]. Impairment of the corresponding otolith-spinal reflexes may contribute substantially to falls which pose an important problem to neurologists caring for patients with cerebellar disorders [57]. Cerebellar disease results in a higher sensitivity of anterior than posterior semicircular canal pathways, perhaps through loss of inhibition from the flocculus/paraflocculus complex on anterior canal secondary neurons in the vestibular nuclei [58]. We know that sustained centrifugation decreases gravitational modulation, reflecting a shift towards a more body centered frame of reference [59] and this is what we desired to explore.
Research Questions:
1. Does multiplanar whole body rotational stimulation affect static balance in the subjects considered?
If so: How long does the effect last? Is it dependent on the pitch/yaw evaluation of the subject? Is it dependent on the pitch/yaw stimulation?
2. Does the multiplanar whole body rotational stimulation affect the limit of stability in the subjects considered?
If so: How long does the effect last?
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 347
Is it dependent on the pitch/yaw evaluation of the subject? Is it dependent on the pitch/yaw stimulation?
Methods: 1 Static Balance
This study was approved by our IRB and conducted in accordance with the Helsinki Declaration. 52 volunteer subjects without a history of neurological disease, vertigo, balance problems or head injuries were included in this study. The subject population was composed of 31 male and 21 females, aged 20 to 60 years old (age equals 29.9 ± 9.3 years; height equals 1.71 ± .08 m; weight equals 8.16 ± 15.5 kg). Participants were recruited from advertisements for research subjects and volunteered without reimbursement. All subjects underwent postural evaluations by a team of neurology residents skilled in postural observations and classification, to ascertain the characteristics of maintained head position/posture in the yaw and pitch planes. Based on this evaluation, the subject was assigned to one of four groups based on head pitch (positive if extended, negative if flexed) and yaw (positive to the right, negative to the left). Each subject was then randomly assigned to a stimulation group; the rotational stimulation could match both head rotations ( pitch and yaw), only one of them, or could be the opposite. Table 1 summarizes for each evaluation/stimulation, the number of subjects assigned to each group.
Table 1. Number of subjects assigned to each group, based on evaluation and stimulation
Evaluations Total - Pitch – + Pitch – - Pitch + + Pitch + Yaw (1) Yaw (2) Yaw (3) Yaw (4)
Both matched 3 5 2 3 13 (1)
Pitch opposite Yaw matched 3 2 3 6 14 (2) Stimulation Pitch matched Yaw opposite 1 5 0 8 14 (3)
Both opposite 1 2 1 7 11 (4)
Total 8 14 6 24 52
Subjects underwent computer-controlled multi-axis vestibular chair (Gyrostim, UltraThera Technologies, Colorado Springs CO, USA) whole body rotations in randomized combinations Pitch and Yaw simultaneously over a 40 second profile at 90 deg/sec (15 RPM). The acceleration rates to 90 degrees per second as well as deceleration rates were linear and occurred in 1 second. We designed rotations that would represent all combinations of pitch and yaw as indicated in Table 1. To evaluate the effects over time the rotational stimulation could have on the balance of the subjects, each subject was tested using a dynamic computerized posturography system (CAPS™ Professional system (force platform and BalanceTRAK® software) – Vestibular Technologies, LLC – Cheyenne WY, U.S.A.).
348 Frederick R. Carrick, Guido Pagnacco, Elena Oggero et al.
The posturographic test battery included a standard modified Clinical Test of Sensory Integration in Balance (mCTSIB – Tests #1-4) [60-62] augmented with 4 additional static balance tests. These 4 additional tests were performed, similarly to the last of the mCTSIB test conditions, with the subjects standing on the perturbing foam cushion with their eyes closed, but instead of the head in a neutral position, the tests were performed with the head rotated volitionally and maximally to the patient’s comfort to the right (Right Yaw – Test #5), to the left (Left Yaw – Test #6) and with the head flexed (Test #7) and extended (Test #8). Each test lasted 20 seconds and was acquired with a sampling frequency of 64 Hz and a resolution of 20 bits. The entire test battery lasted approximately 5 minutes. Each subject performed the posturographic testing protocol four times: first just before the rotational stimulation to obtain a baseline reading (Time 1), then immediately afterward (Time 2), 1 day (Time 3) and finally one week (Time 4) later. Height-normalized posturographic measures provided by the BalanceTRAK® software for each test were used as outcomes. As the BalanceTRAK® software provides almost a hundred different measures, a choice had to be made as to which one to include in the analysis. It was decided to include a subset of posturographic measures of stability we believe are representative of those more commonly found in clinical and research applications. The following were therefore considered:
Stability Score (indicating in percentage the subject's ability to maintain balance during the test, with 0 being unable to maintain balance and 100 being perfectly still)
Directionality (indicating in percentage how the envelope of the Center of Pressure (CoP) path can be approximated by a circle, with 0 being a perfect circle and 100 being a line)
Fatigue/Adaptation Ratio (the percentage of change in the Stability Score between the first and second half of the test, indicating if the subject is getting worse (negative value indicating fatigue) or better (positive value indicating adaptation) during the test)
Normalized Sway Area (the area covered by the subject's CoP during the test normalized by dividing it by the square of the subject's height)
Normalized Drift Velocity Vx (the average velocity at which the CoP drifts in the mediolateral direction during the test, positive when drifting to the right and negative when drifting to the left, normalized by dividing it by the subject's height)
Normalized Drift Velocity Vy (the average velocity at which the CoP drifts in the antero- posterior direction during the test, positive when drifting forward and negative when drifting backward, normalized by dividing it by the subject's height)
Normalized Average Velocity (the average velocity at which the subject CoP moves during the test, normalized by dividing it by the subject's height; since the duration of the test is constant among all cases, it is equivalent to the normalized CoP path length)
Normalized 95% Confidence Ellipse Area (the area of the standard posturographic measure of the 95% CoP ellipse normalized by dividing it by the square of the subject's height).
The statistical data analysis was performed using the software IBM® SPSS® Statistics release 20.0.0. For all the statistical analyses a significance level of p<0.05 was considered. The normality was assessed visually, using the Q-Q plots, as well as numerically using the Kolmogorov-Smirnov
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 349
(with the Lilliefors Significance Correction) and the Shapiro-Wilk tests before further proceeding with the analysis. Data found to be not normally distributed were made normally distributed by taking the natural logarithm of each value. Since for each subject the eight posturographic measures considered were obtained for every one of the eight types of test and the four times considered, the resulting experimental design consisted in a 2 factors (test and time), within subject repeated measures and 2 4 levels factors (evaluation and stimulation groups) unbalanced (the groups did not have the same number of subjects) between subject design. Therefore, given the type of experimental design, General Linear Model (GLM) analysis with repeated measures and Type III sum of squares was used. The Mauchly's Test of Sphericity was used to evaluate the sphericity of each measure and the Greenhouse-Geisser and the Huynh-Feldt correction factors of the degrees of freedom were used in estimating the significance of the effects of the factors. When considering the repeated-measure time factor, simple contrast tests were performed to compare the posturographic measures of Time 2, 3 and 4 with those of Time 1 (baseline). When an effect due to either of the between subject factors (evaluation and stimulation) was found, a post-hoc analysis was conducted adjusting the significance to account for the multiple comparisons (Sidak and Tukey HSD). To evaluate if the Rotational Whole Body stimulation had an effect on the posturographic results in general, or if there was an effect specific to the evaluation and stimulation groups, three analyses were performed: one investigating only the effect of time, one investigating if the effects of time were dependent on the examination groups the subjects belong to, and one investigating if the effects of time were dependent on the stimulation groups the subjects belong to. Given the uneven distribution of subjects among the evaluation and stimulation groups (Table 1), it was not possible to perform a single analysis with time, evaluation and stimulation as main factors.
RESULTS
The Kolmogorov-Smirnov (with the Lilliefors Significance Correction) and the Shapiro-Wilk Tests of Normality both identified the Fatigue/Adaptation Ratio, Normalized Sway Area, Normalized Average Velocity and the Normalized 95% Confidence Ellipse Area as having a non normal distribution. The distributions were made normal by taking the natural logarithm of each value (in the case of the Fatigue/Adaptation Ratio, as some of the original values were negative, a constant value of 1 was added before transforming the data with the logarithm). Both Tests of Normality were then repeated to verify that the transformed variables were in fact distributed normally. The multivariate tests of the between subject factors for the two General Linear Model analyses failed to show a significant effect of either the evaluation (lowest p=0.116 (Hotelling's Trace) with an observed power at α=0.95 of 0.918) or stimulation (lowest p=0.385 (Pillai's Trace) with an observed power at α=0.95 of 0.801). After compensating for the lack of sphericity, the multivariate tests of the within subject time factor as well of the time*evaluation and time*stimulation effect showed a significant effect of time (highest p=0.019 (Pillai's Trace) with an observed power at α=0.95 of 0.983) and no significant effects of time*evaluation (lowest p=0.082 (Hotelling's Trace) with an observed power at α=0.95 of 1.000) and time*stimulation (lowest p=0.130 (Hotelling's Trace) with an observed power at α=0.95 of 0.999). The univariate tests of the within subject effect of time showed an effect of time on the Stability Score (highest p=0.003 (Greenhouse-Geisser correction) with an observed power at α=0.95 of 0.894), and the Normalized 95% Confidence Ellipse Area (highest p=0.014 (Greenhouse-Geisser correction) with an observed power at α=0.95 of 0.772) and no significant effects of time*evaluation and time*stimulation. Contrast tests found a statistically significant difference between Time 1 (baseline pre Rotational stimulation) and Time 2 (immediately post Rotational stimulation) for the Stability Score (p=0.000 with an observed power at α=0.95 of 0.989) and the Normalized 95% Confidence
350 Frederick R. Carrick, Guido Pagnacco, Elena Oggero et al.
Ellipse Area (p=0.000 with an observed power at α=0.95 of 0.964). A difference between Time 1 and Time 2 was also found for the Normalized Sway Area (p=0.011 with an observed power at α=0.95 of 0.731) and Normalized Average Velocity (p=0.011with an observed power at α=0.95 of 0.735), as well as between Time 1 and Time 4 (one week post Rotational stimulation) for the Stability Score (p=0.015 with an observed power at α=0.95 of 0.695) and the Normalized Drift Velocity Vx (p=0.040 with an observed power at α=0.95 of 0.542). However, these differences failed to have an observed power greater than the conventionally accepted level of 0.80 [4] and therefore their significance is questionable. Table 2 reports the estimates of the mean and its 95% confidence interval for the Stability Score, Normalized Sway Area, Normalized Average Velocity and the Normalized 95% Confidence Ellipse Area across all tests for the 4 times considered, and Figure 1-2 graphically illustrate the same values for the Stability Score and the Normalized 95% Confidence Ellipse Area respectively. Further pairwise comparisons adjusting the significance to account for the multiple comparisons (Sidak), found a statistically significant difference (p=0.021) between Time 1 (pre Rotational stimulation) and Time 2 (immediately post Rotational stimulation) only for Test #8 (Perturbed Stability Eyes Closed with Head Extended) for the Stability Score.
Table 2. Estimates of the mean and its 95% confidence interval for the measures found to have a statistically significant difference between Time 1 and Time 2
Estimates 95% Confidence Interval of Measure Time Mean Std. Error the mean Lower Bound Upper Bound 1 80.3% 0.5% 79.3% 81.3% 2 81.5% 0.5% 80.6% 82.5% Stability Score 3 80.6% 0.6% 79.4% 81.8% 4 81.3% 0.5% 80.3% 82.2% 1 520.4 24.2 474.2 571.2
Normalized Sway Area 2 485.3 25.0 437.8 538.1 (mm²/m²) 3 519.1 28.3 465.4 578.9 4 515.8 25.8 466.5 570.3 1 16.7 0.5 15.7 17.7
Normalized Average 2 16.1 0.5 15.0 17.2 Velocity (mm/s*m) 3 16.4 0.6 15.3 17.5 4 16.3 0.5 15.3 17.4 1 185.8 7.9 170.6 202.4 Normalized 95% 2 170.1 8.3 154.2 187.6 Confidence Ellipse Area (mm²/m²) 3 184.8 9.7 166.4 205.3 4 180.2 8.9 163.3 198.9
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 351
Stability Score
83.0% 82.5% 82.0% 81.5% 81.0% 80.5% 80.0% 79.5% 79.0% 1234
Time (1 = Pre, 2 = Immediately Post, 3 = 1 day Post, 4 = 1 week Post)
Figure 1. Estimates of the mean and its 95% confidence interval for the Stability Score across all tests for the 4 times considered.
Normalized 95% Confidence Ellipse Area
210 200 190 180 170 160 150 140 Area (m m ²/m ²) 130 120 110 1234
Time (1 = Pre, 2 = Immediately Post, 3 = 1 day Post, 4 = 1 week Post)
Figure 2. Estimates of the mean and its 95% confidence interval for the Normalized 95% Confidence Ellipse Area across all tests for the 4 times considered.
Methods: 2 Limit of stability
56 healthy (no history of neurological disease, vertigo or postural compromise) subjects, 33 males and 23 females, age 20 to 61 years old (age = 30.23±9.97 years; height = 1.72±0.08m; weight = 81.6±15.5kg) participated in the study. Participants were recruited from advertisements for research subjects and volunteered without reimbursement.
352 Frederick R. Carrick, Guido Pagnacco, Elena Oggero et al.
All subjects underwent postural evaluations by a team of neurology residents skilled in postural observations and classification, to ascertain the characteristics of maintained head position/posture in the yaw and pitch planes. Based on this evaluation, the subject was assigned to one of four groups based on head pitch (positive if extended, negative if flexed) and yaw (positive to the right, negative to the left). Each subject was then randomly assigned to a stimulation group; the rotational stimulation could match both head rotations (pitch and yaw), only one of them, or could be the opposite. Table 3 summarizes for each evaluation/stimulation, the number of subjects assigned to each group.
Table 3. Number of subjects assigned to each group, based on evaluation and stimulation
Evaluations Total - Pitch – + Pitch – - Pitch + + Pitch + Yaw (1) Yaw (2) Yaw (3) Yaw (4)
Both matched 4 5 2 3 14 (1)
Pitch opposite 3 3 3 6 15 Yaw matched (2) Stimulation Pitch matched 1 5 0 8 14 Yaw opposite (3)
Both opposite 1 2 1 9 13 (4)
Total 9 15 6 26 56
Subjects underwent computer-controlled multi-axis vestibular chair (Gyrostim, UltraThera Technologies, Colorado Springs CO, USA) whole body rotations in randomized combinations Pitch and Yaw simultaneously over a 40 second profile at 90 deg/sec (15 RPM). The acceleration rates to 90 degrees per second as well as deceleration rates were linear and occurred in 1 second. We designed rotations that would represent all combinations of pitch and yaw as indicated in Table 3. To evaluate the effects over time the rotational stimulation could have on the balance of the subjects, each subject was tested using a dynamic computerized posturography system (CAPS™ Professional system (force platform and BalanceTRAK® software) – Vestibular Technologies, LLC – Cheyenne WY, U.S.A.). The posturographic test battery included a standard modified Clinical Test of Sensory Integration in Balance (mCTSIB – Tests #1-4) [60-62] augmented with 4 additional static balance tests. These 4 additional tests were performed, similarly to the last of the mCTSIB test conditions, with the subjects standing on the perturbing foam cushion with their eyes closed, but instead of the head in a neutral position, the tests were performed with the head rotated volitionally and maximally to the patient’s comfort to the right (Right Yaw – Test #5), to the left (Left Yaw – Test #6) and with the head flexed (Test #7) and extended (Test #8). Each test lasted 20 seconds and was acquired with a sampling frequency of 64 Hz and a resolution of 20 bits. The entire test battery lasted approximately 5 minutes. Each subject performed the posturographic testing protocol four times: first just before the rotational
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 353 stimulation to obtain a baseline reading (Time 1), then immediately afterward (Time 2), 1 day (Time 3) and finally one week (Time 4) later. Theoretical Limit of Stability normalized Limit of Stability measures provided by the BalanceTRAK® software for each test were used as outcomes. The following measures of the Limit of Stability were considered (refer to Figure 3 for the descriptive significance of the nomenclature):
Ellipse_Major_Axis (the major axis of the Limit of Stability ellipse)
Ellipse_Minor_Axis (the major; axis of the Limit of stability ellipse)
Ellipse_Angle (the direction of the major axis of the ellipse - the angle is measured positive counterclockwise, with 0 being to the right of the subject and 90° being forward)
LoS_Bias (the coordinates of the center of the Limit of Stability ellipse with respect to a Cartesian coordinate system centered in the starting position of the test (first point acquired during the test): the mediolateral (ML_LoS_Bias) and the antero-posterior (AP_LoS_Bias) coordinates respectively)
LoS (the four intersections of the Limit of Stability ellipse with the Cartesian coordinate system centered in the starting position of the test. They are expressed as percentage of the theoretical limit of stability: left (L_LoS), right (R_LoS), anterior (A_LoS) and posterior (P_LoS) interceptions respectively)
Directionality (the aspect ratio of the Limit of Stability ellipse; with 0% meaning the ellipse was a perfect circle, and 100% meaning the ellipse was a segment).
Limit of Stability Ellipse y is Ax jor Ma
A_LoS Angle ML_LoS_Bias R_LoS L_LoS M in x o r P_LoS A x is
Starting position AP_LoS_Bias of the test
Figure 3. Limit of Stability ellipse nomenclature.
354 Frederick R. Carrick, Guido Pagnacco, Elena Oggero et al.
The statistical data analysis was performed using the software IBM® SPSS® Statistics release 20.0.0. For all the statistical analyses a significance level of p<0.05 was considered. The normality was assessed visually, using the Q-Q plots, as well as numerically using the Kolmogorov-Smirnov (with the Lilliefors Significance Correction) and the Shapiro-Wilk tests before further proceeding with the analysis. Data found to be not normally distributed were made normally distributed by taking the natural logarithm of each value. Since for each subject the ten Limit of Stability measures considered were obtained for the four times considered, the resulting experimental design consisted in a 1-factor (time), within-subject repeated measures and 2-4-levels-factors (evaluation and stimulation groups) unbalanced (the groups did not have the same number of subjects) between-subject design. Therefore, given the type of experimental design, General Linear Model (GLM) analysis with repeated measures and Type III sum of squares was used. The Mauchly's Test of Sphericity was used to evaluate the sphericity of each measure and the Greenhouse-Geisser and the Huynh-Feldt correction factors of the degrees of freedom were used in estimating the significance of the effects of the factors. When considering the repeated-measure time factor, simple contrast tests were performed to compare the LoS measures of Time 2, 3 and 4 with those of Time 1 (baseline). When an effect due to either of the between-subject factors (evaluation and stimulation) was found, a post-hoc analysis was conducted adjusting the significance to account for the multiple comparisons (Sidak and Tukey HSD). To evaluate if the Rotational stimulation had an effect on the LoS results in general, or if there was an effect specific to the evaluation and stimulation groups, three analyses were performed: one investigating only the effect of time, one investigating if the effects of time were dependent on the examination groups the subjects belong to, and one investigating if the effects of time were dependent on the stimulation groups the subjects belong to. Given the uneven distribution of subjects among the evaluation and stimulation groups (Table 1), it was not possible to perform a single analysis with time, evaluation and stimulation as main factors.
RESULTS
The Kolmogorov-Smirnov (with the Lilliefors Significance Correction) and the Shapiro-Wilk Tests of Normality both confirmed all the measures considered were normally distributed. The multivariate tests of the between-subject factors for the two General Linear Model analyses failed to show a significant effect of either the evaluation (lowest p=0.062 ( Pillai's Trace) with an observed power at α=0.95 of 0.968) or stimulation (lowest p=0.411 (Hotelling's Trace) with an observed power at α=0.95 of 0.845). After compensating for the lack of sphericity, the multivariate tests of the within-subject time factor as well of the time*evaluation and time*stimulation effect showed a significant effect of time (p=0.000 (Pillai's Trace, Hotelling's Trace, Wilks' Lambda) with an observed power at α=0.95 of 0.999) and no significant effects of time*evaluation (lowest p=0.707 (Hotelling's Trace) with an observed power at α=0.95 of 0.997) and time*stimulation (lowest p=0.132 (Hotelling's Trace) with an observed power at α=0.95 of 1.000). The univariate tests of the within-subject effect of time showed an effect of time on the Ellipse_Major_Axis (highest p=0.026 (Greenhouse-Geisser correction) with an observed power at α=0.95 of 0.704), the Ellipse_Angle (highest p=0.041 (Greenhouse-Geisser correction) with an observed power at α=0.95 of 0.653),the AP_LoS_Bias (highest p=0.047 ( Greenhouse-Geisser correction) with an observed power at α=0.95 of 0.640),the L_LoS (highest p=0.014 (Greenhouse- Geisser) with an observed power at α=0.95 of 0.774), and the A_LoS (highest p=0.012 (Greenhouse- Geisser) with an observed power at α=0.95 of 0.792). The only significant effect of the time*stimulation interaction was found for the Ellipse_Angle (highest p=0.031 (Greenhouse-Geisser correction) with an observed power at α=0.95 of 0.850). No significant effects of time*evaluation was found. Contrast tests found a statistically significant difference between Time 1 (baseline
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 355 pre-Rotational stimulation) and Time 2 (immediately post-Rotational stimulation) for the Ellipse_Major_Axis (p=0.001 with an observed power at α=0.95 of 0.943), the L_LoS (p=0.000 with an observed power at α=0.95 of 0.983) and the Directionality (p=0.002 with an observed power at α=0.95 of 0.902). A difference between Time 1 and Time 2 was also found for the ML_LoS_Bias (p=0.011 with an observed power at α=0.95 of 0.734), as well as between Time 1 and Time 4 (one week post GyroStim stimulation) for the Ellipse_Angle (p=0.016 with an observed power at α=0.95 of 0.688), the AP_LoS_Bias (p=0.013 with an observed power at α=0.95 of 0.710), A_LoS (p=0.006 with an observed power at α=0.95 of 0.810). However, these differences, with the exception of the A_LoS, failed to have an observed power greater than the conventionally accepted level of 0.80 [2] and therefore their significance is questionable. Post-hoc pairwise comparisons adjusting the significance to account for the multiple comparisons (Sidak) found for the time*stimulation interaction a statistically significant difference only between Time 1 (baseline pre-GyroStim stimulation) and Time 2 (immediately post-GyroStim stimulation) for the Ellipse_Angle (p=0.027) only for the “Both matched” stimulation group. Table 4 and Figure 4-6 report the estimates of the mean and its 95% confidence interval for the Ellipse_Major_Axis, the L_LoS, and the Directionality for the 4 times considered.
Table 4. Estimates of the mean and its 95% confidence interval for the Ellipse Major Axis, the L LoS, and the Directionality for the 4 times considered
Estimates
Measure Time Mean Std. Error 95% Confidence Interval of the mean
Lower Bound Upper Bound
1 108.2% 2.0% 104.2% 112.1%
2 103.2% 2.0% 99.2% 107.1% Ellipse_Major_Axis 3 107.4% 2.1% 103.1% 111.7%
4 106.0% 2.3% 101.4% 110.5%
1 95.6% 2.0% 91.5% 99.7%
2 87.0% 1.9% 83.1% 90.9% L_LoS 3 89.7% 3.0% 83.7% 95.6%
4 90.2% 2.8% 84.6% 95.8%
1 28.7% 1.3% 26.2% 31.3%
2 25.0% 1.1% 22.7% 27.3% Directionality 3 26.5% 1.4% 23.7% 29.2%
4 26.1% 1.4% 23.3% 28.9%
356 Frederick R. Carrick, Guido Pagnacco, Elena Oggero et al.
Ellipse_Major_Axis
115.0% 113.0% 111.0% 109.0% 107.0% 105.0% 103.0% 101.0% 99.0% 97.0% 95.0% 1234 Time (1 = Pre, 2 = Immediately Post, 3 = 1 day Post, 4 = 1 week Post)
Figure 4. Estimates of the mean and its 95% confidence interval for the Ellipse Major Axis for the 4 times considered.
L_LoS
100.0% 98.0% 96.0% 94.0% 92.0% 90.0% 88.0% 86.0% 84.0% 82.0% 80.0% 1234 Time (1 = Pre, 2 = Immediately Post, 3 = 1 day Post, 4 = 1 week Post)
Figure 5. Estimates of the mean and its 95% confidence interval for the LLoS for the 4 times considered. Directionality
32.0%
30.0%
28.0%
26.0%
24.0%
22.0%
20.0% 1234
Time (1 = Pre, 2 = Immediately Post, 3 = 1 day Post, 4 = 1 week Post)
Figure 6. Estimates of the mean and its 95% confidence interval for the Directionality for the 4 times considered.
The Effect of Off Vertical Axis and Multiplanar Vestibular Rotational … 357
DISCUSSION
The results indicate that vestibular activation in a multiplane whole body rotational devise has a modest but significant beneficial effect on the stability of the subjects as measured by the Stability Score (which increases, indicating a reduction in sway) and the Normalized 95% Confidence Ellipse Area (which decreases, consistently again with a reduction in the sway). However, this beneficial effect appears to be temporary and disappears within one day. No effect can be seen for all the other measures of stability. It appears the stimulation has a modest effect on the subjects' Limits of Stability. The main effects appear to be a significant decrease of the Left LoS, a reduction of the largest axis of the LoS Ellipse (i.e. a decrease in the subject's maximum LoS) and a reduction in the directionality. The last two results indicate that the subjects' LoS on average decreases but it becomes more uniform across all directions (the decrease in directionality means the LoS is less elliptical and more circular). This change might be a direct consequence of the decrease in the left LoS.
CONCLUSIONS
We have noted in several hundred cases that clinical applications of this therapy in concert with an intense multimodal brain and vestibular rehabilitation program have demonstrated posturographic changes that have been greater than those seen without inclusion of the multiplanar rotational therapy. The changes demonstrated have only been seen in clinical cases and not subjected to a controlled environmental research investigation. That in any case some small beneficial stability effects of the multiplane whole body vestibular stimulation was detected suggests that the stimulation is useful even when it is non-specific. With a different type of evaluation it might be possible to maximize the beneficial effects of a stimulation such as that provided by the therapy by more appropriately targeting the stimulation parameters. Doing so might also produce significant changes in the other posturographic measures for whose no significant change was found in this study. The fact that neither the evaluation nor the stimulation had a significant effect on the limit of stability suggests that the evaluation methodology adopted in this study was not sufficient to properly decide the direction and type of rotational stimulation and that this therapy is not a stand alone treatment. We were surprised with the outcomes of this study and recommend that this type of therapy not be utilized in isolation of other rehabilitation strategies. Further investigation to compare the consequences of a multimodal rehabilitation program with appropriate randomization of subjects to it will help us to further understand the consequences of such integration.
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Received: May 24 2013, Revised June10 2013, Accepted June 12 2013.
Funct Neurol Rehabil Ergon 2013;3(2-3):361-387 ISSN: 2156-941X © Nova Science Publishers, Inc.
POSTER ABSTRACTS
4TH ANNUAL CONFERENCE OF THE INTERNATIONAL ASSOCIATION OF FUNCTIONAL NEUROLOGY AND REHABILITATION
QUICK RESOLUTION OF BPPV OF TWO YEARS DURATION AFFECTING GAIT AND ADL
Igor Dijkers1 1 Private Practice, Harderwijk, The Netherlands Email: [email protected]
Background and aims: Symptoms of benign paroxysmal positional vertigo (BPPV) are considered to be short lived in most cases as the brain is thought to compensate within weeks for the alteration of vestibular afferentation. A 71-year-old Caucasian female presented to our clinic with complaints of vertigo, loss of balance while walking as she swayed to the left side and inability to cycle. Methods: Symptoms were present for 2 years. She had been diagnosed by the ENT specialist with BPPV and was advised to perform Brandt-Daroff habituation exercises. On functional neurological evaluation she was swaying to the left while walking and showed nystagmus on Dix- Hallpike testing for the left posterior semicircular canal on VNG testing. Gaze stability was poor in the horizontal plane. Treatment included Epley repositioning manoeuver for the left posterior canal followed by standard instructions. Home exercises were no/no gaze stability exercises. Results: After the second treatment her Dix-Hallpike tests were negative and she was able to walk straight without her husband supporting her. After the third treatment she was able to cycle. Three weeks later she was still without symptoms and discharged from care. Conclusion: Although BPPV is benign in nature, when uncompensated or unresolved it can have serious invalidating consequences if unresolved for many aspects of ADL. Even two years after initial onset appropriate repositioning of the otoconia in combination with gaze stability exercises can rapidly resolve symptoms and enhance quality of life.
362 Poster Abstracts
FUNCTIONAL IMPROVEMENTS IN A 27-YEAR-OLD FEMALE WITH LEFT SIDED HEMIDYSTONIA
Igor Dijkers1 1Private Practice, Harderwijk, The Netherlands E-Mail: [email protected]
Background and aims: Standard care for recovery for patients with dystonia involves periodical botox injection with or without a physical conditioning program. Pathophysiology points at the basal ganglia, vestibular system and cerebellum. A 27-year-old Caucasian female suffering from left sided hemidystonia since 2004 (9 years) presented to our clinic; she was wheel chair bound and unable to walk for more than a few minutes without falling over due to dystonic posturing. Methods: On initial consultation she reported cervical dystonia (retrocollis to the left) when sitting or standing up, immediately relieved by lying down. She also reported dystonic posturing (leaning over to the left) when walking for several meters, dystonia over her left arm and accommodative spasm. Functional neurological evaluation revealed severe vestibular and cerebellar dysfunctions, poor ocular motor control, poor right sided basal ganglionic functioning. Treatment included: graded vestibular/cerebellar exercises, Carrick eye exercises (right hemisphere), visualization and TENS applications. Results: After 11 months of care she was able to walk using TENS application for 40 minutes, she could spin around in both directions in any chair, she was able to travel on her own by train and just started to incorporate jogging in her training regime. Even though her functional improvements were life changing she still suffered with cervical dystonia under specific circumstances. Conclusion: A functional neurological approach in which the specific functional lesions are addressed was successful in improving ADL functions and greatly increased her independency.
IMPROVEMENTS IN FINE MOTOR TASKS, SPEED AND BALANCE IN A PATIENT WITH PARKINSON’S DISEASE SUBSEQUENT TO FUNCTIONAL NEUROLOGIC TREATMENT
Susan Esposito1, Linda Mullin1, and Frederick Carrick2 1Life University, Marietta, GA USA 2Carrick Institute of Graduate Studies, Cape Canaveral, FL USA Email: [email protected] Submitted: June 2 2013, Revised: June 13 2013 Accepted: June 15 2013
Background: We describe a case of a 78-year-old female who presented to a functional neurology clinic with a diagnosis of Parkinson’s disease. Classic Parkinsonian findings were present including resting tremor, rigidity, bradykinesia, hypokinesia, hypomemia, and feeling depressed and irritable. Her chief complaint was a decrease in fine motor skills rendering her incapable of performing certain tasks such as tying her shoes and opening her flip cell phone. Methods: Compromised frontal lobe and basil ganglionic function were confirmed by aberrant saccades and optokinetic responses. The patient was unable to stand without falling during computerized dynamic posturography (CDP) on a perturbation cushion with eyes closed giving a score of zero. She underwent a 3 day treatment program of cortical rehabilitation involving gaze holding strategies, frontal eye movement exercises and multi-axis vestibular stimulation.
Poster Abstracts 363
Results: After three days of treatment, the patient was able to complete a CDP evaluation and was measured to have a stability rating of 79.1% with eyes closed on a perturbation cushion. She also showed improved facial tone, fuller range of motion and stamina. She achieved her goal of tying shoe laces and opening her phone. Conclusion: Vestibular rehabilitation strategies utilizing eye movement exercises and multi- axis labyrinthine and otolithic stimulation demonstrated significant improvement in activities of fine motor control as well as improved balance, station, gait. Positive outcomes in this case promote further study with these strategies in cases of motor disorders.
RESOLUTION OF SEVERE LEG PAIN, HEADACHES, DIZZINESS AND IMBALANCE AFTER ONE WEEK OF FUNCTIONAL NEUROLOGICAL AND VESTIBULAR TREATMENT
Susan Esposito1, Linda Mullin1, and Frederick Carrick2 1Life University, Marietta, GA USA 2Carrick Institute of Graduate Studies, Cape Canaveral, FL USA Email: [email protected] Submitted: June 2 2013, Revised: June 13 2013 Accepted: June 15 2013
Background: A 41-year-old female presented to a functional neurology clinic for assessment of somatosensory disturbances characterized by severe right lower limb pain of 9 months duration described as constant deep sharp pain exacerbated by touch or movement. She displayed an antalgic gait with shortened stance phase. Any active or passive movement of the lower extremity created extreme apprehension and pain for this patient. Vascular exam of the lower extremity showed a reduced pedal pulse. The feet were cold and mildly edematous bilaterally. She manages pain with prescribed hydrocodone. Pain was recalcitrant to the chiropractic adjustment treatments previously attempted. Other complaints included right upper extremity pain, imbalance, dizziness, severe head pain, severe insomnolence, and sadness also rated as severe. Methods: A thorough neurological exam including Computerized Dynamic Posturography (CDP) and videonystagmography (VNG) testing confirmed a central vestibulopathy and somatosensory lesions. She underwent a one week long program of functional neurological treatment that included complex passive movements of upper and lower extremities, brain-based therapeutic eye exercises, somatosensory evoked potential stimulations, and whole-body multiaxis vestibular rehabilitation. Results: Full and painless movement was restored in all limbs. Symptoms of dizziness, insomnolence and feelings of sadness were also resolved. CDP scores significantly improved across all parameters. Square wave jerks and other eye movement aberrations were markedly diminished on VNG testing. Conclusion: Functional neurological treatments including vestibular rehabilitation strategies were used with positive outcomes in this case of somatosensory disturbances and imbalance. Further study in of the use of these strategies is suggested.
364 Poster Abstracts
DIMINISHED HEAD PAIN AND FOGGINESS WITH FUNCTIONAL NEUROLOGICAL TREATMENT OF A POST-CONCUSSIVE PATIENT
Susan Esposito1, Linda Mullin1, and Frederick Carrick2 1Life University, Marietta, GA USA 2Carrick Institute of Graduate Studies, Cape Canaveral, FL USA Email: [email protected] Submitted: June 2 2013, Revised: June 13 2013 Accepted: June 15 2013
Background: A 24-year-old male, former professional soccer player presented to a university-based functional neurology clinic for relief of symptoms resulting from his prior three concussions. These symptoms included sharp head and neck pain, cervical hypertonia, fogginess, lightheadedness, anxiety and imbalance. Examination findings included grade two hypomimia, ptosis of the left eyelid, left facial and right palatal paresis, marked decrease in point localization bilaterally, and delays in raising the left shoulder during shoulder shrug. Videonystagmography (VNG) revealed slow and dysmetric eye function during saccadic, pursuit and optokinetic testing. Methods: Diagnostic inventories of brain function revealed traumatic brain injury with a central vestibular axis and a postural instability confirmed by computerized dynamic posturography (CDP). The patient underwent a week long program of vestibular rehabilitation strategies including frontal eye movements, parietal stimulatory exercises, oculomotor/brain therapies including 2x viewing, strategically targeting soccer exercises and multi-axis labyrinthine and otolithic stimulation. Results: Stability of balance was restored and confirmed by computerized dynamic posturogaphy. Hypomimia, facial and palatal pareses, head pain and cervical hypertonia were resolved. Shoulders rose symmetrically. VNG batteries showed significant improvements in all eye movements. Fogginess, anxiety and lightheadedness decreased. Conclusion: This case reports positive outcomes associated with the use of functional neurological treatment strategies including whole body multi-axis vestibular therapies in the treatment of TBI. Positive outcomes in this case promote further study of TBI and post-concussive syndromes using these strategies.
INCREASES IN MOBILITY AND DEXTERITY IN A POST-STROKE PATIENT USING A FUNCTIONAL NEUROLOGICAL APPROACH TO TREATMENT
Susan Esposito1, Linda Mullin1, and Frederick Carrick2 1Life University, Marietta, GA USA 2Carrick Institute of Graduate Studies, Cape Canaveral, FL USA Email: [email protected] Submitted: June 2 2013, Revised: June 13 2013 Accepted: June 15 2013
Background: A 65-year-old female presented to a university based functional neurology clinic with persistent symptoms that began after an ischemic left cerebral stroke two years prior. The patient exhibited flexor posturing of right-sided musculature with weakness. This patient’s chief complaints were right-sided hypokinesia with spasticity and impaired balance. She also experienced episodes of severe anxiety, fatigue and inability to sleep. Finger to thumb tapping test revealed a grade 3 on the left for slowness and inaccuracy and a grade 4 on the right due to the inability to approximate her fingers. Post-stroke cerebral dysfunction was evidenced by an inability to maintain a standing posture on a computerized dynamic posturography (CDP) exam. Methods: The patient received five consecutive days of treatment. Each treatment consisted of brain based eye exercises specifically designed to stimulate the left cerebral cortex and gaze
Poster Abstracts 365 stabilization, passive complex right arm and leg movement therapies, mirror therapy, somatosensory evoked potential stimulation of the right hypoglossal and trigeminal nerves, breathing exercises as well as occasional cervical and rib adjustments. Results: Stability of balance and posture were confirmed by CDP, as she maintained balance and showed improvements in every category. She could now straighten her right arm, utilize fingers of her right hand to open zippers, cut meat and feed herself. Anxiety and fatigue were resolved. She slept through the night for the first time in 2 years. Conclusion: Positive outcomes in this case encourage further study of functional neurological strategies in the treatment of persistent symptoms in patients with ischemic stroke.
HEPATIC ENCEPHALOPATHY: PRESENTATION, DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 40-year-old male who presented to our clinic on 03/14/2012 complaining of upper abdominal pain, stomachache, general body pain, and back pain. The patient reported that he was sweating, had faint feeling and the pain felt like “taking your breath away”. He also complained of weight loss and icy cold feet and hands. The patient reported that his pain was a 7/10, on a scale of 1 to 10, 10 being the worst. He has had a past medical history of fractured bones, gallbladder problems, stiffness, painful/swollen joints, leg cramps, hip/leg pain, and fatigue. The patient was put on several medications for stomach pain. An abdominal ultrasound obtained on February 17, 2012 showed “fatty and infiltrated liver”. Another ultrasound obtained on 04/05/2012 showed “gallstones, gallbladder sludge, and heterogeneous liver echotexture”. Methods: The patient had undergone a comprehensive neurological and physical examination using standard neurological tests and diagnostics including VNG, posturography, tremorscope and blind spot mapping. He had global sensory and motor deficiencies, in addition to incoordination, cerebellar dysmetria, hyperreflexia, allodynia, posterior center of pressure, asterixis, dyskinesia, Myerson’s sign, ocular dysmetria, irregular vertical saccades compared to horizontal ones. Systemic Functional Neurology and Organ-Remapping procedures and applications were implemented using various sensory and motor applications, coupled motion reductions, pre- ganglionic and post-ganglionic applications, visual and auditory stimulation, cerebellar activation, complex therapeutic activities, home instructions, and various specific mitochondrial nutraceuticals and phytonutrients. Various applications were administered on daily basis for 2 weeks. Results: After the first day the patient’s icy cold feet and hands sensation was normalized. By the end of the week his fainting and sweating feeling was resolved. Patient was discharged for one month, and returned for one week. Today the patient’s symptoms have decreased by 95%, he has returned to work and enjoys life with his family.
366 Poster Abstracts
AKATHESIA COUPLED WITH INTENTIONAL TREMORS AND METABOLIC DISORDERS: A FUNCTIONAL NEUROLOGY APPROACH
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 61-year-old female who presented to our clinic on 05/10/2012 complaining of inner restlessness, hand tremors, fatigue, and blood sugar imbalance. The patient reported that she was diagnosed with Chronic Fatigue Syndrome. She has had a past medical history of fractured bones, high blood pressure, balance problems, eye pain, blurred vision, belching and gas, stiffness, headaches, dizziness, tremors, back/neck pain, muscle pain, weight gain and hemochromatosis. The patient was put on acid reflux medications and antibiotics. She reported an overall feeling of ill-being and increase in her symptoms. Methods: The patient had undergone a comprehensive neurological examination using standard neurological tests and diagnostics including VNG, posturography, and tremorscope. She had orthostatic blood pressure concomitance, global sensory and motor deficiencies, in addition to incoordination, cerebellar dysmetria, posterior center of pressure, akathisia, Myerson’s sign, ocular dysmetria, irregular vertical saccades compared to horizontal ones, as well as poor gaze stabilization. Systemic Functional Neurology and Organ-Remapping procedures and applications were implemented using various sensory and motor applications, coupled motion reductions, pre- ganglionic and post-ganglionic applications, visual and auditory stimulation, cerebellar activation, complex therapeutic activities, home instructions, and various specific mitochondrial nutraceuticals and phytonutrients. Various applications were administered on daily basis for 2 weeks. Results: By the end of the first week the patient’s akathetic feeling has resolved, and tremors decreased 85% by the second week. Patient was discharged for three months with prescribed brain activities. The patient returned for one week. Today the patient’s symptoms have resolved. She enjoys life with her family.
HYPERKINETIC/JERKY MOVEMENT DISORDER COMPLICATED BY HYPOCAPNIA: PRESENTATION, DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 36-year-old male who presented to our clinic on 09/15/2011 complaining of severe tics and jerking since 2007. He has had a past medical history of fractured bones, high blood pressure, eye pain, blurred vision, stiffness, headaches, dizziness, tremors, muscle cramps, and strokes. The patient was put on anti-seizure medications. He reported extreme anxiety and an overall increase of symptoms. Methods: The patient had undergone a comprehensive neurological examination using standard neurological tests and diagnostics. He had orthostatic blood pressure concomitance, global motor deficiencies, in addition to incoordination, cerebellar dysmetria, posterior center of pressure, hyperkinesia, frontal release sign, ocular dysmetria, poor gaze stabilization and saccades. Systemic Functional Neurology procedures and applications were implemented using various sensory and motor applications, coupled motion reductions, visual and auditory stimulation,
Poster Abstracts 367
cerebellar activation, complex therapeutic activities, home instructions, and various specific mitochondrial nutraceuticals and phytonutrients. Various applications were administered on daily basis for 2 weeks. Results: By the end of the second week the patient’s hyperkinetic movement disorder has resolved and his respiratory vitals were stabilized. Today the patient lives symptom free.
MULTIPLE SYSTEM ATROPHY/DYSAUTONOMIA COMPLICATED BY VIRAL INFECTIONS, HASHIMOTO’S AND OTHER AUTOIMMUNE DISORDERS: FUNCTIONAL NEUROLOGY APPROACH AND APPLICATIONS
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: A 41-year-old female presented to our clinic complaining of fatigue, anxiety, muscle tension, headaches, brain fog, interrupted sleep, autoimmune sensitivities, digestive issues, bone spurs, and neck and shoulder pain. History of the patient consisted of allergies all her life, Hashimoto’s, light-headedness, migraine headaches, viral infections, in addition to several accidents, falls and surgeries. The patient has seen several allopathic and alternative doctors and was as put on several medications and supplements, but her symptoms kept worsening. The patient feared that her symptoms would make her bedridden and helpless in the next 2 years, and become a burden on her husband and family. Methods: The patient had undergone a comprehensive and extensive neurological examination using standard neurological tests and diagnostics including VNG, computerized dynamic posturography, tremorscopic testing. She had bilateral areflexia, orthostatic concomitance, sensorimotor deficiencies and an anterior center of pressure (ACOP). She also had positive pathological reflexes. The patient had balance and incoordination issues. She also had slow saccadic eye movements in various planes, and aberrant vertical to horizontal optokinetic responses. She also had irregular pursuits, bilateral hippus with loss of gaze. A slow systemic Functional Neurology approach was implemented using various visual, auditory, vestibular, sensory and motor applications, brain based activities, cerebellar activation, complex therapeutic activities, home instructions and dietary changes. Results: During the first 2 days of treatment the patient had slept for 6 hours straight and was able to digest better. By the second week of treatment 80% of her symptoms have resolved. The patient was discharged for one month, followed by one week of treatment. Today the patient is seen three times a year and enjoys life with her family.
FIBROMYALGIA/ALLODYNIA COMPLICATED BY DIABETES AND GENERALIZED OSTEOARTHRITIS: A FUNCTIONAL NEUROLOGY APPROACH
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 74-year-old male who presents with long-standing history of Fibromyalgia, Polymayalgia Rheumatica, joint pain, stiffness, balance problems, high blood pressure, and heart attack. The patient reported that he had been to several Rheumatologists
368 Poster Abstracts
who put him on different medications including Atenelol and Linsinopril with no effect. He also has a history of DJD, low back pain, neck pain, shoulder and arm pain, muscle spasms, leg cramps, and fatigue. Methods: The patient had undergone a comprehensive neurological examination using standard neurological tests and diagnostics including videonystagmography (VNG), computerized dynamic posturography (CDP), tremorscopic testing. He had a grade 3 blinking reflex, 3:1 right V:A ratio, orthostatic concomitance, motor deficiencies, posterior center of pressure (PCOP). The patient had balance and incoordination issues. He also had slow saccadic movements in various planes, and aberrant vertical to horizontal optokinetic. He also had irregular pursuits, with loss of gaze stabilization. A slow systemic Functional Neurology approach was implemented using various visual, auditory, vestibular, sensory and motor applications, brain based activities, cerebellar activation, complex therapeutic activities, home instructions and dietary changes. Results: Functional Neurology addresses different faulty pathways which lead to brain plasticity, remapping and proto oncogene in the nucleotide sequence. It has been diagnostically determined that through specific and gradual applications in Functional Neurology the patient’s fibromyalgia, joint pain, stiffness, and imbalance were contained. Today, the patient is Fibromyalgia free, and symptom free. He enjoys a normal life with his friends, something he has not been able to realize for years.
TRAUMATIC BRAIN INJURY COMPLICATED BY POST TRAUMATIC STRESS DISORDER AND LEAKY GUT: PRESENTATION, DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 16-year-old male who presents with Traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) due to a severe motor vehicle accident 3 years ago. The patient reports being depressed, unmotivated, fatigued, has no appetite and is not able to digest. His mother reports that ever since the accident her son has been foggy, has blurred vision, extremely fatigued and unable to pass any of his tests at school. She reports that they have been to several allopathic physicians that recommended anti-depression medications. He also has had several abdominal surgeries to repair lacerated blood vessels post-accident. Methods: The patient had undergone a comprehensive neurological examination using standard neurological tests and diagnostics including videonystagmography (VNG), computerized dynamic posturography, tremorscopic testing. He had memory and cognitive issues, sensorimotor deficiencies, posterior center of pressure (PCOP), Myerson’s sign, tachycardia, positive dual tasking, Fukuda and Moro tests. The patient had balance and incoordination issues. He also had slow saccadic movements, aberrant vertical to horizontal optokinetic responses. He also had irregular pursuits, with loss of gaze stabilization. A slow systemic Functional Neurology and Organ Remapping approach was implemented using various pre and post ganglionic procedures, visual, auditory, vestibular, sensory and motor applications, brain based activities, cerebellar activation, complex therapeutic activities, home instructions and dietary changes. Results: Faulty pathways lead to misfiring and signal mismatch. Functional Neurology addresses different faulty pathways which lead to brain plasticity, remapping and proto oncogene in the nucleotide sequence. It’s been diagnostically determined that through specific and gradual applications in Functional Neurology the patient’s TBI was contained. Today, the patient is back to a regular school schedule, scores A’s and is symptom free. He enjoys a normal life with his friends, able to eat regular, and is head of the robotics department at school.
Poster Abstracts 369
AUTISM/ASPERGER’S COUPLED WITH DEPRESSION AND DIGESTIVE DISORDERS: DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 14-year-old female who presents with long-standing history of depression, anxiety, lack of focus, anger, seclusion, eating disorder, fatigue, no motivation, and repetitive patterns of behavior. The patient’s parents reported that their daughter can stay in her room for days without any interaction with them or her brother and sister. They said that her family doctor put her on Tylenol since 2011. The parents were extremely concerned and bewildered regarding their daughter’s condition. Methods: A comprehensive neurological examination was done, using standard neurological tests and diagnostics including videonystagmography (VNG), computerized dynamic posturography, tremorscopic testing. The vestibulo-ocular reflex (VOR) was absent, pursuits irregular with saccadic intrusions, positive Moro, Spinal Galant, and ATNR reflexes, positive dual tasking (freezing), poor memory and cognition, very emotional and angry, posterior center of pressure (PCOP). The patient had balance and incoordination issues. She also had slow saccadic movements in various planes, and aberrant vertical to horizontal optokinetic responses. A slow systemic Functional Neurology approach was implemented using various visual, auditory, vestibular, sensory and motor applications, brain based activities, cerebellar activation, complex therapeutic activities, home instructions and dietary changes. Results: The patient’s VOR was restored to normal within the first 2 days of treatment. In two weeks the patient verbal communication and eye contact improved 85% and was able to digest better. Functional Neurology addresses different faulty pathways which lead to brain plasticity. It’s been diagnostically determined that through specific and gradual applications in Functional Neurology the patient’s depression disorder, Autistic/Asperger’s spectrum is resolved. Today, the patient enjoys normal life with her family and friends, is interested in art and has composed and presented our facility with a fine artistic portrait of the brain.
PERIPHERAL NEUROPATHY COMPLICATED BY RETROPULSION AND BILIARY DUCT OBSTRUCTION: DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: A 52-year-old female presents with severe burning and tingling sensations in her lower extremities complicated by a perception of falling backwards. She has been diagnosed with peripheral neuropathy and was put on several medications. The patient reports that her condition has been worsening and is not able to sleep. The patient also reports that she had been to more than 15 doctors of different specialties, over a period of 8 years. Methods: The goal was to diminish the symptoms of neuropathy and eliminate the sensation of falling backwards. A thorough neurological examination was conducted including videonystagmography (VNG), Posturography, Vestibular Examination and optokinetic (OPK) assessment. In a supine position the patient developed severe retropulsion. Vertical saccades were
370 Poster Abstracts
lost. Horizontal saccades preserved with right hypometria and saccadic intrusions. Bilateral lower extremity hyperesthesia was discovered. Motor and short memory deficiencies existed. Balance issues, incoordination and inability to perform dual tasking were all observed. Brain-Based Activities were instructed targeting fronto-cerebellar-mesencephalic pathways. Oxygen therapy was administered. Left linear exercises and anti-inflammatory nutracuticals were implimented. A slow systemic Functional Neurology approach was implemented using various visual, auditory, vestibular, sensory and motor applications, brain based activities, cerebellar activation, complex therapeutic activities, home instructions and dietary changes. Results: The methods and applications of Functional Neurology targeted specific brain structures which are hardly linked to spatial perception. The effect of these non-surgical and non- pharmaceutical applications is beyond what can be described. During the first three days of treatment the patient’s retropulsion was resolved. By the second week of treatment neuropathy symptoms diminished more than 75%. The patient today enjoys a symptom free life with her kids and nine grandchildren.
MULTIPLE SCLEROSIS COUPLED WITH ATAXIA, MUSCLE ATROPHY, DYSAUTONOMIA AND ANHYDROSIS: FUNCTIONAL NEUROLOGY APPROACH
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: A 56-year-old male, presented to our office complaining of insidious neurological dysfunctions that started on 10, 1991. He reported consistent numbness and inability to walk without assistant device since 2009. He also complained of neck pain and low back pain on a scale of 8/10 (10 being the worst pain). History included right shoulder dislocation, whiplash, mononucleosis, a bad reaction to Swine Flu Vaccine in 1977, MVA in 1983 which ended in plastic surgery to his forehead, a bad reaction to Hepatitis B Vaccine in 1988, and was diagnosed with parasites and Lyme disease in 1989. In 1990, he experienced the first episode of anhydrosis. In 1992, he was diagnosed with Multiple Sclerosis and was administered oral steroid, prednisone and Copaxone. In 2010, he had exacerbation of Multiple Sclerosis symptoms. Advanced radiology brain MRI performed on 09/22/2006 described new lesions since the previous study dated 06/26/2002. The report stated progression of callosal volume loss and cerebral atrophy. Methods: Upon examination, on 04-19-2011, spontaneous legs movement was observed. Opthalmoscopic examination showed V:A ratio of 3:1 on the right, optokinetic nystagmus testing (OPK) showed abnormal upward to downward saccades ratio. Horizontal saccades were preserved. Irregular pursuits and square wave jerks were observed. Right soft palate paresis and left facial weakness, cardiac auscultation revealed a split S2. Positive convergence and cardinal fields. Romberg’s stance revealed severe sway. Bilateral positive Babinski sign and jerky myoclonic activity were present. Paresis of left big toe, bilateral dysmetria and a positive Myerson’s sign were all present. Bilateral decreased deep tendon reflexes were observed. Bilateral muscle spasticity in the lower extremity and hypotonia in the upper extremity were observed. Cortical blind spot showed right partial hemianopia. Treatment consisted of Brain-Based therapeutic activities, segmental coupled motion reduction, myofascial release, vestibular stimulation, timed breathing exercises, complex movement activities, visual stimulation, sound stimulation, SEP, activities of daily living, and nutritional consultation. Results: Patient showed progressive improvement in his motor function and decrease in muscle spasticity. Pathological reflexes were resolved. He showed improvement in gait and reported that he was able to take couple of steps without assistance. He reported ability to move
Poster Abstracts 371
his left big toe after he had lost this function for more than 20 years. A laboratory test obtained on 04/21/2012 by his primary showed no signs of Multiple Sclerosis.
HEPATIC STEATOSIS COMPLICATED BY MULTIPLE SYSTEMS FAILURE AND HYPOCAPNIA: PRESENTATION, DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: A 40-year-old female was diagnosed with Hepatic Steatosis, Irritable Bowel Syndrome, Interstitial Cystitis, Chronic diarrhea complicated by Fibromyalgia, and panic attacks. The patient was put on a wide spectrum of medications including oxycodone, which improved her fibromyalgia pain with worsening of all other symptoms. The patient reports that every day it took her about 5 hours to get up from bed in morning and couple of hours later she gets so lethargic and has to lie in bed again. She has interrupted sleep patterns and a sense of bloating. An abdominal ultrasound obtained in 2002 showed a hepatic fatty tumor of 9.5 cm located in the anterior lobe of the liver. Upon review of past medical records the patient denied having been informed about the tumor. Methods: Detailed standard neurological examination was performed. Functional Neurology and Organ Remapping applications were administered. Cerebellar activation exercises were applied on the left side coupled by timed breathing exercises, oxygen therapy and various specific mitochondrial neutraceuticals and phytonutrients. Various other applications were administered at an average of 3 times a week for 2 weeks. During that time patient showed gradual improvement and increase in energy level. Eye exercises of fast saccades to the right and vertical optokinetics were implemented. Results: Within 12 visits the patient symptoms were resolved and stability achieved. An ultrasound obtained within 12 weeks showed the patient hepatic steatosis (a fatty tumor of 9.5 cm) has resolved as well as all other symptoms. The patient is on bi-monthly healthcare maintenance visits with no symptoms whatsoever.
BURNING MOUTH SYNDROME COMPLICATED BY CORTICO-CEREBELLAR DEGENERATION AND SYSTEMIC INFLAMMATION: DIAGNOSIS AND APPLICATIONS OF FUNCTIONAL NEUROLOGY
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: A 65-year-old female presented to our facility with severe pain in her mouth. She reported that she was diagnosed with Burning Mouth Syndrome by the Mayo Clinic and was put on pain medications including Klonopin, Tegretol and Morphine. She also was put on a very strict diet. Her pain was 10/10 (10 being the worst pain). She was informed that her condition was incurable and that she had to stay on medications and manage her symptoms. The
372 Poster Abstracts
patient reported that the pain was constant, felt like “chewing on coal” and would hit the tongue, cheeks, jaw, and teeth, and was getting worse and was non-responsive to medications. Methods: A comprehensive neurological examination was done, using standard neurological tests and diagnostics including videonystagmography (VNG), computerized dynamic posturography and tremorscopic testing. Her vestibulo-ocular reflex (VOR) was absent, pursuits were irregular with saccadic intrusions, left saccadic movement was absent. Dual tasking (freezing), poor memory and cognition, posterior center of pressure (PCOP) and right palatal paresis were observed. The patient had balance and incoordination issues. She also had aberrant vertical to horizontal optokinetic responses. A slow systemic Functional Neurology and Organ Remapping approach was implemented using various visual, auditory, vestibular, sensory evoked potential, sensory and motor applications, brain based activities, cerebellar activation, complex therapeutic activities, home instructions and dietary changes. Results: Within 4 sessions the patient’s burning mouth pain was reduced from 10/10 to 1- 2/10 and kept improving. Faulty pathways lead to misfiring and signal mismatch. Functional Neurology addresses different faulty pathways which lead to brain plasticity. It’s been diagnostically determined that through specific and gradual applications in Functional Neurology the patient’s Burning Mouth Syndrome was contained. Today, the patient is symptom free and enjoys a normal life with her family.
ISCHEMIC STROKE COMPLICATED BY DEGENERATIVE JOINT DISEASE: A FUNCTIONAL NEUROLOGY APPROACH
Gilbert S. Jaudy1 1Private Practice, Palm Desert, CA 92211 USA E-mail: [email protected] Submitted: May 24 2013 Revised: June 3 2013 Accepted June 15 2013
Background and Aims: The patient is a 65-year-old female who presents with an acute ischemic stroke. The patient had numbness and tingling in her upper right side of the arm and hand, dysarthria, and right lower leg circumduction. She stated that since that episode she had had issues in terms of balance and equilibrium. She reported that she was constantly confused, had great difficulty speaking, was dropping things and stuttering. She also has a history of DJD, low back pain, neck pain, muscle spasms, leg cramps, jaw pain, painful joints, migraines, fatigue, fainting and strokes. Methods: The patient had undergone a comprehensive neurological examination using standard neurological tests and diagnostics including videonystagmography (VNG), computerized dynamic posturography, tremorscopic testing. He had sensorimotor deficiencies, posterior center of pressure (PCOP), Myerson’s sign, tachycardia, positive dual tasking and Fukuda. The patient had balance and incoordination issues. He also had slow saccadic movements, aberrant vertical to horizontal optokinetic responses. He also had irregular pursuits, with loss of as gaze stabilization. Cortico-cerebellar activation exercises were applied on the right side coupled by various other applications which were administered at an average of 3 times a week for 3 weeks. Results: During that time patient showed gradual improvement and resolution of tingling and numbness. Within 12 visits the patient symptoms were resolved and stability achieved. Patient is released with prescribed take-home brain-based movements. She currently has no post stroke symptoms.
Poster Abstracts 373
IMPROVED POST-STROKE MOTOR FUNCTION FOLLOWING OSCILLATORY PHASE RESET THERAPY: A CASE REPORT
James Otis1 1Private Practice, Oakland, CA US Email: [email protected] Received: June 3 2013, Revised: June 10 2013d June15 2013
Background: A 59-year-old male presented with history of a right-sided stroke. 14 years post stroke he experienced persistent difficulties with multitasking and organization that prohibited his previous work as a research scientist, and difficulty moving his left hand. Neuropsychological evaluation demonstrated deficits of executive function, and he could not extend the fingers of his left hand with his palm face up. He could not participate in communion at church. Methods: Examination demonstrated an inability to extend his fingers while his arm was supinated. The patient underwent three five-minute sessions of oscillatory phase reset therapy consisting of syncopated, pulsed auditory signals delivered through headphones, over a two day period. Results: On the second day of therapy he was able to open his hand with his palm face up for the first time in fourteen years. He reported improved mental clarity, but this has not been confirmed with neuropsychological evaluation. Conclusion: Oscillatory phase reset therapy aided recovery of motor function fourteen years post stroke. Positive outcomes in this case encourage further study of this strategy in stroke and brain injury rehabilitation.
REDUCTION OF HYPERTHYROID TACHYCARDIA WITH OSCILLATORY PHASE RESET THERAPY: A CASE STUDY
James Otis1 1Private Practice, Oakland, CA USA Email: [email protected] Received: June 3 2013, Revised: June 10 2013 Accepted: June15 2013
Background: A 58-year-old female presented with a two-year history of interrupted sleep, incapacitating early morning headaches, tachycardia, heavy breathing, and a sensation of vibration in her sternum. She could no longer give professional presentations because she could not organize and remember the material. Methods: Thyroid lab tests revealed TSH = 4.83, and TPO antibodies > 1000 IU/mL (reference < 35). The patient underwent a one-month course of oscillatory phase reset therapy consisting of syncopated, pulsed auditory signals delivered through headphones. Therapy sessions were of one-minute duration twice a day for 3 days, followed by five minutes twice daily for the rest of the month. Results: Daily headaches, tachycardia, pounding heart, and heavy breathing were completely resolved with three days, and patient was able to consistently sleep through the night for the first time in two years. At one month patient was able to organize and present professional talks for the first time in two years. Conclusion: Oscillatory phase reset therapy improved autonomic nervous system function and reduced hyperthyroid tachycardia. Positive outcomes in this case encourage further study of this strategy as rehabilitation of autonomic dysregulation. Disclosure: The oscillatory phase reset therapy used in this study is a patent-pending process developed and owned by the author.
374 Poster Abstracts
NORMALIZED QUANTITATIVE EEG FOLLOWING OSCILLATORY PHASE RESET THERAPY
James Otis1 1Private Practice, Oakland, CA USA Email: [email protected] Received: June 3 2013, Revised: June 10 2013 Accepted: June15 2013
Background: A 62-year-old female experienced poor name recall and problems with spatial orientation, progressively worse over a five-year period. Methods: A Quantitative EEG brain map was performed immediately before and immediately after a single five-minute session of oscillatory phase reset therapy consisting of syncopated, pulsed auditory signals delivered through headphones. EEG was recorded from 20 locations around the skull, digitally converted, analyzed, and compared with normed references using New Mind software. The dimensions of analysis included magnitude, dominant frequency, inter-hemispheric connectivity, and inter-hemispheric asymmetry. Results: Patient reported feeling relaxed. New Mind QEEG analysis reported 29% aggregate improvement between before and after eyes-open analysis, and 17% improvement between before and after eyes-closed analysis. Conclusion: Oscillatory phase reset therapy elicits positive changes in neurological function demonstrated by electroencephalographic analysis. Positive results in this case encourage further study of this strategy as a method of functional neurological rehabilitation.
IMPROVEMENT OF CERVICAL DYSTONIA FOLLOWING FUNCTIONAL NEUROLOGICAL INTERVENTION
Thomas van den Hof1 1Private Practice, Harderwijk, The Netherlands Email: [email protected] Received: June 11 Revised: June 15 2013 Accepted: June 19 2013
Background and aims: Standard care for cervical dystonia generally involves periodical botox injection with or without a physical conditioning program. Pathophysiology points to the basal ganglia, vestibular system and cerebellum. Cervical dystonia tends to be present unilaterally suggesting unilateral neurological dysfunction of these structures. Hemisphere specific treatment might prove to be of benefit when stimuli can be targeted to the correct areas. A 39-year-old Caucasian female suffering from right sided cervical dystonia since 2001 (12 years) presented to our clinic. To relieve her complaints she had a botox injection every 9 weeks. Methods: On initial consultation she reported cervical dystonia on the right side leading to pain in the suboccipital area and headaches. Second, she reported the sensation of her left eye moving. Functional neurological evaluation revealed cerebellar dysfunctions consisting of head titubations, impaired motor control, poor ocular motor control particularly to pursuit and saccadic stimuli. Treatment included: breathing exercises, nutritional advice, ocular motor exercises for the left hemisphere. Results: After 1 week of intense functional neurological care (5 times per day for 15-30 minutes each time) the dystonia was drastically reduced. Neck pain and headache decreased. On a follow up visit two months later she was still stable and skipped her botox treatment. Conclusion: A functional neurological approach in which the specific cerebral and cerebellar functional lesions are addressed can be successful in improving and resolving cervical dystonia in a very short period of time in particular patients.
Poster Abstracts 375
VERTIGO IMPROVED THROUGH APPLICATION OF A VESTIBULAR REHABILITATION PROGRAM IN CONJUNCTION WITH BRAIN-BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Matthew Antonucci2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a male in his 60’s who presented to a functional neurology clinic with a 3 year history of vertigo. Episodes of three to eight hour durations would produce dizziness, disorientation, tinnitus, as well as memory and cognitive difficulties. Methods: A centrally maintained vertigo was confirmed through neurological examination. The patient was found to have a 10 Hz tremor on the right arm with decrease right arm swing during gait. Aberrant gaze holding, pursuits, saccades and optokinetic responses were observed and confirmed by videonystagmography. Bilateral, mydriatic pupils with arcus senilis were noted. The patient participated in a one week vestibular rehabilitation program that included multi-axis labyrinthine and otilithic stimulation, specific brain-based eye movement strategies, times-one viewing gaze stabilization exercises, extra-spinal manipulations and gait rehabilitation. Results: The combination of treatment protocols produced profound changes in the patient’s state of being. Patient reported that this intervention eliminated the dizziness and unsteadiness for the first time since its onset. Conclusion: This case of vertigo showed significant improvements after administration of a functional neurologic treatment regimen as described. The authors suggest further investigation into vestibular rehabilitation mechanisms and brain-based approaches to patient treatments with vertigo.
ATAXIA IMPROVED THROUGH APPLICATION OF OFF VERTICAL AXIS VESTIBULAR REHABILITATION AND BRAIN-BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 Diana Stephens2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a 20-year-old male who presented to a functional neurology clinic with a twelve year history of progressive ataxia. Symptoms include poor balance and coordination, poor gross and fine motor skills, stiffness, fatigue and inability to walk without assistance. Methods: Ataxia was confirmed by neurologic examination. Aberrant saccades, pursuits, and optokinetic responses were noted. Square wave jerks were present on left gaze fixation. A right beating nystagmus was present on right gaze fixation. Decreased joint position sense and sensation to pinwheel was present in the lower extremity bilaterally. Patellar myotatic stretch reflexes were plus three bilaterally. The patient participated in an in house functional neurological
376 Poster Abstracts
program that included off vertical axis vestibular rehabilitation, passive multi-planar movements of proximal joints, specific eye movement exercises, times-one viewing gaze stabilization exercises, cross-crawl exercises and gait rehabilitation. Results: The combination of treatment protocols produced profound changes in the patient’s state of being. Symptoms associated with the ataxia were dramatically reduced and the patient has been able to walk without assistance as a result of this intervention. Conclusion: This case showed significant improvements after administration of the functional neurologic treatment regimen described. The authors suggest further investigation into vestibular rehabilitation mechanisms and brain-based approaches to patient treatments with ataxic syndromes.
TEENAGE FEMALE WITH MILD TRAUMATIC BRAIN INJURY TREATED THROUGH APPLICATION OF A VESTIBULAR REHABILITATION PROGRAM IN CONJUNCTION WITH BRAIN-BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and James L. Duffy2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a 17-year-old female who presented to a functional neurology clinic with a history of concussions. She complained of headaches, neck pain, sensitivity to light, blurring of vision, dizziness, fatigue, trouble concentrating, balance and spatial awareness problems, sleeping problems, enuresis, depression and anxiety. Methods: A diagnosis of a centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by neurologic examination. Light stimulation produced akesthesia and created a dynamic right correctasia. Decreased myotatic stretch reflexes were observed on the left side of the body. Percussion myotonia was produced bilaterally upon striking of the thenar eminence. The patient participated in a functional neurological program that included off vertical axis vestibular rehabilitation, times-one viewing gaze stabilization exercises, passive multi-planar proximal extremity movements, specific eye movement exercises and gait rehabilitation. Results: The combination of treatment protocols produced a profound change in the patient’s state of being. All signs and symptoms significantly reduced over a short period of time and the patient was able to return to school. Conclusion: This case showed significant improvements as a result of the functional neurologic treatment regimen as described. The authors suggest further investigation into the mechanisms of the vestibular rehabilitation and these brain-based approaches to patient treatments with mild traumatic brain injuries.
Poster Abstracts 377
TEENAGE MALE WITH MILD TRAUMATIC BRAIN INJURY IMPROVED THROUGH APPLICATION OF OFF VERTICAL AXIS VESTIBULAR REHABILITATION WITH BRAIN-BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Jacob Shores2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a 17-year-old male who presented to a functional neurology clinic with a five year history of concussions. Symptoms included headaches, light and sound sensitivity, fogginess, lightheadedness, trouble concentrating and reading, memory difficulties, fatigue, nausea and decreased appetite associated with weight loss. Methods: A centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by examination. A downbeat nystagmus was observed when visual fixation was eliminated. Comprehensive Assessment of Postural Systems (CAPS) testing during perturbed surface, eyes closed, head in neutral parameters, revealed a 59.3% stability score. The patient participated in a vestibular rehabilitation program that included off vertical axis vestibular rehabilitation, specific eye movement exercises, times-one viewing gaze stabilization exercises, somatosensory evoked potential activation of the left brainstem, breathing exercises and passive, multi-planar movements of right proximal extremities. Results: The combination of treatment protocols produced profound changes to all signs and symptoms associated with the mild traumatic brain injury. Follow up CAPS results during perturbed surface, eyes closed, head in neutral parameters, revealed a 74.9% stability score and a return to exercise was achieved. Conclusion: This case showed significant improvements after administration of a functional neurologic treatment regimen as described. The authors suggest further investigation into vestibular rehabilitation mechanisms and brain-based approaches to patient treatments with mild traumatic brain injuries.
TEENAGE FEMALE WITH MILD TRAUMATIC BRAIN INJURY IMPROVED THROUGH APPLICATION OF FUNCTIONAL NEUROLOGICAL THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Jacob Shores2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a 17-year-old female who presented to a functional neurology clinic with a history of concussions. Symptoms include dizziness, lightheadedness, poor balance, headaches, light sensitivity, memory problems, fatigue and nausea. Methods: A centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by examination. Upbeat nystagmus was present when visual fixation was removed. Aberrant saccades and optokinetic responses were observed and confirmed by
378 Poster Abstracts
videonystagmography. During convergence, an accommodation spasm with retropulsion was noted. A scissor gait was observed with decreased left arm swing which was further degraded during dual tasking. The patient participated in a vestibular rehabilitation program that included off vertical axis vestibular rehabilitation, specific brain-based eye movement strategies, times-one viewing gaze stabilization exercises, and gait rehabilitation. Results: The combination of treatment protocols produced profound changes in the patient’s state of being. All signs and symptoms associated with the mild traumatic brain injury were dramatically reduced and she was able to return to her normal daily activities as a result of this treatment. Conclusion: This case of a mild traumatic brain injury showed significant improvements after administration of a functional neurologic treatment regimen as described. The authors suggest further investigation into vestibular rehabilitation mechanisms and brain-based approaches to patient treatment with mild traumatic brain injuries.
MULTIPLE TRAUMATIC BRAIN INJURIES TREATED THROUGH FUNCTIONAL NEUROLOGICAL APPLICATIONS
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Matthew Antonucci2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a 27-year-old female who presented to a functional neurology clinic with a seven year history of concussions. She complained of headaches, fatigue, memory and concentration problems, nausea, depression and speech difficulties. Methods: A diagnosis of a centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by examination. Aberrant gaze fixation, saccades and pursuits were observed and confirmed by videonystagmography. A negative center of pressure with a rightward bias was recorded upon a Comprehensive Assessment of Postural Systems (CAPS) unit. The patient participated in a vestibular rehabilitation program that included off vertical axis vestibular rehabilitation, somatosensory evoked potential stimulation of the right brainstem, times-one viewing gaze stabilization exercises, specific brain-based eye movement therapies and application of low-level laser over the suboccipital musculature. Results: The combination of treatment applications produced a profound reduction in all signs and symptoms. Conclusion: This case of a mild traumatic brain injury showed significant improvements as a result of the functional neurologic treatment regimen as described. The authors suggest further investigation into the mechanisms of the vestibular rehabilitation and these brain- based approaches to patient treatment with mild traumatic brain injuries.
Poster Abstracts 379
IMPROVEMENTS ATTAINED IN MILD TRAUMATIC BRAIN INJURY THROUGH VESTIBULAR REHABILITATION AND BRAIN-BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Derek A. Barton2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a male in his 20’s who presented to a functional neurology clinic with a history of multiple concussions resulting in bilateral headaches, visual disturbances, dizziness and fatigue. Methods: A diagnosis of a centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by examination. Saccadic intrusions were observed within all pursuits. Horizontal saccades were slow with glissades. Optokinetic responses were aberrant and there was an asymmetrical accommodation response. A left beating nystagmus was revealed when fixation was eliminated. Comprehensive Assessment of Postural Systems (CAPS) testing during perturbed surface, eyes closed, head in extension parameters, revealed a 15.5% stability score. The patient participated in a one week, in house, vestibular rehabilitation program that included off vertical axis vestibular rehabilitation, times-one viewing gaze stabilization exercises, somatosensory evoked potential stimulation of the left brainstem, brain-based eye movement strategies and spinal manipulations. Results: The combination of treatment protocols allowed the patient to return to his work place symptom free. Follow up CAPS results during perturbed surface, eyes closed, head in extension parameters, revealed a 53.6 stability score. Conclusion: This case showed significant improvements as a result of the functional neurologic treatment regimen described. The authors suggest further investigation into vestibular rehabilitation and brain-based therapies to patient treatments with mild traumatic brain injuries.
MILD TRAUMATIC BRAIN INJURY IMPROVED THROUGH A FUNCTIONAL NEUROLOGIC APPROACH OF OFF VERTICAL AXIS VESTIBULAR REHABILITATION AND BRAIN-BASED APPLICATIONS
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and James L. Duffy2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a female in her 20’s who presented to a functional neurology clinic with a history multiple concussions resulting in headaches, fatigue, brain fog, nausea, dizziness, and disorientation. Methods: A diagnosis of a centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by examination. Examination revealed a tremor of the right hand and left hemi-facial spasm. Saccadic velocity was decreased in all directions. While performing ten rapid movements of the index finger to thumb, the left hand’s velocity was slow. The patient
380 Poster Abstracts
participated in a one week vestibular rehabilitation program that included off vertical axis vestibular rehabilitation, times-one viewing gaze stabilization exercises, somatosensory evoked potential stimulation of the left brainstem and specific eye movement strategies. Results: The combination of treatment protocols drastically reduced all signs and symptoms over a short period of time and the patient was able to re-enter her workplace as a result of this intervention. Conclusion: Significant improvements as a result of a functional neurologic treatment regimen were produced. The authors suggest further investigation into vestibular rehabilitation and brain-based approaches to patient treatments with mild traumatic brain injuries.
MILD TRAUMATIC BRAIN INJURY TREATED THROUGH APPLICATION OF A VESTIBULAR REHABILITATION PROGRAM IN CONJUNCTION WITH BRAIN- BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Jacob Shores2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe the case of a male in his mid 20’s who presented to a functional neurology clinic with a history of multiple concussions resulting in headaches, loss of consciousness and speech difficulties. Methods: A diagnosis of a centrally maintained vestibulopathy secondary to a mild traumatic brain injury was confirmed by examination. Oculomotor examination revealed mitotic pupils bilaterally, hypometric saccades, saccadic pursuits, and absent optokinetic responses. Bilateral complexus myospasm and left sided hypotonia was noted. Three hesitations were present when performing ten rapid movements of the right index finger to thumb. The patient participated in a one week, in house, vestibular rehabilitation program that included off-vertical-axis vestibular rehabilitation paired with specific eye movement strategies. Results: The combination of treatment protocols produced a significant reduction of all signs and symptoms over a short period of time. Previously absent optokinetic responses were completely restored, and the patient was able to return to work, symptom free, as a result of this intervention. Conclusion: This case showed significant improvements as a result of a functional neurologic treatment regimen as described. The authors suggest further investigation into the mechanisms of the vestibular rehabilitation and brain-based approaches to patient treatments with mild traumatic brain injuries.
Poster Abstracts 381
ANISMUS TREATED THROUGH APPLICATION OF A VESTIBULAR REHABILITATION PROGRAM IN CONJUNCTION WITH BRAIN-BASED THERAPIES
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Jacob Shores2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a male in his 60’s who presented to a functional neurology clinic with a 4 year history of severe, progressing anal pain with associated pain in the left ear and jaw. The patient reported a year before the anal pain there was bilateral numbness on the bottom of both feet which never improved. Patient also reports regular bouts of constipation which last four to five days. Hemorrhoidectomy, disimpaction, ganglion impar block, lidocaine trigger point injection, pudendal block and superior hypogastric block has been performed with no impact on anal pain. All imaging was unremarkable. Methods: A diagnosis of anismus was confirmed by neurologic examination. Aberrant pursuits, saccades and optokinetic responses were observed along and confirmed by videonystagmography. Blepheroclonus was present during gaze stabilization. The patient participated in a functional neurological program that included somatosensory evoked potential stimulation of the right brainstem, specific brain-based eye movement strategies, along with application of low-level laser over the anus. Results: The combination of treatment protocols produced up to 40% decrease of symptoms, as reported by the patient, which was beyond any previous treatment application. Conclusion: This case of anismus showed improvements beyond traditional applications after administration of a functional neurologic treatment regimen as described. The authors suggest further investigation into the mechanisms of these brain-based approaches to patient treatment with anismus.
YOUNG BOY WITH COMPLEX REGIONAL PAIN SYNDROME TREATED THROUGH APPLICATION OF A FUNCTIONAL NEUROLOGICAL PROGRAM
Frederick R. Carrick,1 David J. Traster,2 Susan Esposito,2 Jerome D. Lubbe,2 and Jacob Shores2 1Carrick Institute of Graduate Studies, Cape Canaveral, Florida 32920 USA 2Life University, Marietta, GA USA E-mail: [email protected] Received: June 2 2013 Revised: June 10 2013 Accepted: June 15 2013
Background: We describe a 12-year-old male who presented to a functional neurology clinic with severe pain and an inability to tolerate light touch. A three year history of severe, progressing headaches, and head pain which had progressed down his back and shoulders was reported. The patient also presented with fatigue, light sensitivity and decreased appetite. Methods: A diagnosis of complex regional pain syndrome with associated dysautonomia was confirmed by neurologic examination. Aberrant vertical eye movements were observed and a right beating nystagmus was present during eccentric gaze fixation and confirmed on
382 Poster Abstracts
videonystagmography. This nystagmus matched the frequency of the patient’s midline stereotypies in his hands. Rib excursion measured 0.5 inches and a posterior suboccipital hemangioma was noted. The patient participated in an in house vestibular rehabilitation program that included off vertical axis stimulation and specific brain-based eye movement therapies. Results: The combination of treatment protocols produced a profound change in the patient’s state of being. Pain and ability to tolerate touch significantly reduced over a short period of time and the patient was able to return to school and athletics. Conclusion: This case of complex regional pain syndrome showed significant improvements beyond traditional applications after administration of a functional neurologic treatment regimen as described. The authors suggest further investigation into the mechanisms of the vestibular rehabilitation and these brain-based approaches to patient treatments with complex regional pain syndrome.
RESOLUTION OF HEAD FOGGINESS, DECREASE OF ESSENTIAL TREMORS, INCREASE OF READING COMPREHENSION AND MENTAL FOCUS FOLLOWING A COURSE OF FUNCTIONAL NEUROLOGICAL TREATMENT
Susan Esposito,1 David Koentop,1 and Frederick R. Carrick2 1Life University, Marietta, GA USA 2Carrick Institute for Graduate Studies, Cape Canaveral FL, USA Email: [email protected] Date Received: June 15 2013 Revised: June 19 2013 Accepted: June 19 2013
Background: A 26-year-old male presented to the functional neurology clinic for assessment of tremors, head fogginess, impaired reading comprehension, and inability to focus. Examination revealed a right hypertropia and 6 Hz tremor of his hands bilaterally. The patient showed decreased ability of gaze stabilization in all visual planes with aberrant saccades and pursuits. The patient’s history included numerous concussions and cranial impacts over years of playing hockey. Methods: A thorough neurological exam including Computerized Dynamic Posturography (CDP) and videonystagmography (VNG) testing confirmed a central vestibular lesion, cortical desynchronization, and inability to gaze fixate. He underwent a two month long program of functional neurological treatment that included complex passive movements of upper and lower extremities, brain-based therapeutic eye exercises, somatosensory evoked potential stimulations, and whole-body multi-axis vestibular rehabilitation. Results: The tremors in his hands completely disappeared immediately after treatment, but subsequently re-emerged with reduced amplitude and frequency. Head fogginess, inability of reading comprehension, decreased mental focus, and aberrant eye motions have reduced substantially. CDP scores improved drastically with eyes closed, head in extension on a perturbed surface from 0 to 46.5% stability. Square wave jerks and other eye movement aberrations were markedly diminished on VNG testing. Conclusion: Functional neurological treatments including vestibular rehabilitation strategies were used with positive outcomes in this case of tremors, head fogginess, impaired reading comprehension and mental focus. Further study in of the use of these strategies is suggested.
Poster Abstracts 383
RESOLUTION OF POST-CHEMOTHERAPY SHORT-TERM MEMORY LOSS, MIGRAINES, DECREASED SENSATION, AND EXPRESSIVE APHASIA FOLLOWING TWO MONTHS OF FUNCTIONAL NEUROLOGY TREATMENT
Susan Esposito,1 David Koentop,1 and Frederick R. Carrick2 1Life University, Marietta, GA USA 2Carrick Institute for Graduate Studies, Cape Canaveral FL, USA Email: [email protected] Date Received: June 15 2013 Revised: June 19 2013 Accepted: June 19 2013
Background: A 50-year-old female presented to a functional neurology clinic for assessment of short term memory loss, constant migraines rated 10/10, anomia, expressive aphasia, fatigue, and leg pain following a 6 month treatment for ovarian cancer. On examination she presented with lid lag, ptosis, decreased left-sided facial tone, posture abnormalities, inability to distinguish smells, and hyperacusis in her left ear. Methods: A thorough neurological exam including Computerized Dynamic Posturography (CDP) and videonystagmography (VNG) testing confirmed a central vestibular lesion, as well as diminished sensation bilaterally. She underwent a two month long program of functional neurological treatment that included complex passive movements of upper and lower extremities, brain-based therapeutic eye exercises, somatosensory evoked potential stimulations, and whole- body multi-axis vestibular rehabilitation. Results: Patient’s memory improved within a week. Her migraines and sensitivity to loud sounds have resolved. Gaze holding has substantially improved, her expressive aphasia has resolved and her anomia had dramatically improved. She also reported no longer feeling “dazed and confused” and no longer had “brain fog”. Conclusion: Functional neurological treatments including vestibular rehabilitation strategies were used with positive outcomes in this case of post-chemotherapy neurological dysfunction. Further study in of the use of these strategies in cases of neurological aberrancies following a course of chemotherapy is warranted.
REDUCTION OF ABERRANT REFLEXOGENIC MUSCLE FIRING PATTERNS AFTER CORRECTION OF EYE MOVEMENTS IN A WORLD-CLASS PROFESSIONAL TENNIS PLAYER WITH LOW BACK PAIN
Frederick R. Carrick,1 Susan Esposito,2 and Benjamin R. Behrendt3 1Carrick Institute for Graduate Studies, Cape Canaveral, FL USA 2Life University, Marietta, GA USA 3Private Practice E-mail: [email protected] Received: June 15 2013 Revised: June 18 2013 Accepted: June 19 2013
Background: A sixteen-year-old world-class professional tennis player was referred to our functional neurology clinic secondary to a significant reduction in ability to play tennis and moderate low back pain (LBP). Methods: MRI, CT, and X-RAY findings of his low back were inconclusive except for mild posterior disc bulging at L3/4, L4/5 and L5/S1. Examination revealed both aberrant cerebellar and functional eye movement findings. He had right hyperopia (extinguished with VOR movements), left corectasia, and accommodation spasm. Saccadic evaluation revealed slower rightward saccades, hypermetric leftward saccades, and irregular phase profile with normal re-fixation. The
384 Poster Abstracts
patient exhibited a slower response on the left to fine motor tasking, which were slower on left. He had sluggish left brachioradialis reflexes, sluggish left achilles reflexes and pendular right patellar reflexes. When playing tennis and during initial eye movements a retrocolic cervical response was observed when looking down. He underwent a two-week therapy program consisting of specific vestibular rehabilitation including multi-axial labyrinthine stimulation, ocular-motor therapy, laser therapy and manipulation. Results: The patient’s aberrant eye movements improved. He no longer had failure of gaze holding. Pursuits at 0.1 Hz improved. Saccades and optokinetic responses improved significantly. Accommodation spasms and spontaneous facial movement became negligible. Retrocolic-cervical responses resolved. His V:A ratio and reflexes returned normal. He no longer had LBP. Conclusion: Unique and specific brain-based exercises, vestibular rehabilitation, correction of aberrant eye movements and manipulation allowed this patient to return to professional tennis. Authors suggest further investigation into treatment of vestibular, ocular-motor therapy to correct performance.
REDUCTION OF DIZZINESS AND ALLODYNIA IN A TEENAGE MALE AFTER FUNCTIONAL NEUROLOGIC TREATMENT
Frederick R. Carrick ,1 Paula Rhodes,2 and Susan Esposito2 1Carrick Institute of Graduate Studies, Cape Canaveral, FL USA 2Life University, Marietta, GA 30060 USA E-mail: [email protected] Received: June 15 2013 Revised: June 19 2013 Accepted: June 20 2013
Background: A young teenage male returned to a Functional Neurology clinic after an exacerbation of dizziness and nausea, and a recent streptococcal infection. The patient had previously been treated successfully at this clinic for symptoms related to a central vestibulopathy, experiencing a reduction in allodynia from pain rated at 6-8/10 to a 4/10 (10 being the worst pain). Methods: Central vestibulopathy was confirmed by videonystagmography (VNG) findings, which revealed aberrancies in gaze holding, pursuits, saccades, and optokinetic responses. Computerized dynamic posturography (CDP) measured instability. The patient received treatment involving gaze holding and eye movement exercises, cerebellar stimulation, and multi-axis vestibular stimulation. Results: After two consecutive days of treatment, this patient experienced a significant reduction in dizziness and increased stability. VNG confirmed improvement in all eye movements. Allodynia was further reduced to a level of 1.5-3/10. Conclusion: Vestibular rehabilitation therapies utilizing frontal eye movement exercises, cerebellar stimulation, multi-axis labyrinthine and otolithic stimulation produced significant improvement in this patient’s dizziness and allodynia. This case suggests the need for further study of Functional Neurologic treatment for cases of central vestibulopathy.
Poster Abstracts 385
IMPROVEMENTS IN HEADACHES, DIZZINESS, BRAIN FOG AND AKATHISIA THROUGH FUNCTIONAL NEUROLOGICAL APPLICATIONS AND VESTIBULAR REHABILITATION
Frederick R. Carrick,1 Susan E. Esposito,2 David Traster2, and Jerome D. Lubbe2 1Carrick Institute for Graduate Studies, Cape Canaveral, FL USA 2Life University, Marietta, GA 30060 USA E-mail:[email protected]
Background: We describe a 39-year-old female who presented to a functional neurology clinic with a previous history of autonomic and vestibular complaints. The patient presented with a constellation of symptoms including severe headaches, dizziness, nausea, akathisia, decreased motivation, brain fog, concentration difficulty, anxiety and memory loss. Methods: During initial examination the patient reported severe headaches rated 8 out of 10 with 10 being the worst pain she has ever experienced. Eye movements were aberrant with an inability to maintain gaze stabilization in all vectors, saccadic intrusions of visual pursuits, square wave jerks with inability to hold gaze, and hypometric saccades with slowing of optokinetic nystagmus. All aberrant eye movements were confirmed by videonystagmography. The patient participated in a one-week vestibular rehabilitation program that included multi-axis labyrinthine and otolithic stimulation paired with specific eye movement exercises. Results: The patient reported a decrease in headache duration and frequency to 2 out of 10 with 0 being no pain. There was a near complete resolution of dizziness, nausea, brain fog and akathisia. There were also improvements noted in ability to concentrate, decreased anxiety and brain fog symptoms. During repeat oculomotor examination the patient exhibited normal and adequate pursuit strategies with improved speed of optokinetic nystagmus as well as complete resolution of square wave jerks while holding gaze. Conclusion: The results of this case suggest the necessity of further research into the functional neurologic model of diagnosis and treatment and the use of multimodal vestibular rehabilitation strategies.
TREATMENT OF SEVERE POST ORTHOSTATIC TACHYCARDIA SYNDROME WITH ASSOCIATED SEIZURE ACTIVITY THROUGH FUNCTIONAL NEUROLOGICAL APPLICATIONS AND BRAIN-BASED APPLICATIONS
Frederick R. Carrick,1 Susan E. Esposito,2 Jerome D. Lubbe,2 David Traster,2 Jacob Shores,2 and Michael Drzewiecki2 1Carrick Institute for Graduate Studies, Cape Canaveral, FL USA 2Life University, Marietta, GA USA E-mail:[email protected] Received: June 15 2013 Revised: June 18 2013 Accepted: June 19 2013
Background: We describe a 16-year-old female who presented to a functional neurology clinic with a previous history of severe post orthostatic tachycardia syndrome with concomitant symptoms of seizures, headaches, fatigue, and severe anxiety. Methods: During examination the patient was unable to stand for any period of time due to orthostatic induced tachycardia and hypoxia. Patient exhibited severe seizure activities and marked tachycardia with movements of three degrees or more while assessing positional changes
386 Poster Abstracts
in symptomatology. The patient exhibited decreased circulation, sensation and warmth in lower extremities bilaterally. The patient was treated using supine positional changes of two degrees elevation per session on a motorized tilt table. Somatosensory evoked potential therapy was applied to the tibial, peroneal and medial nerves bilaterally. Results: The patient experienced a marked reduction in the frequency, intensity and duration of hypoxic and seizure related events related to her post orthostatic tachycardia syndrome, and withstood positional changes of up to 85 degrees without eliciting any seizure episodes or marked increase in heart rate. Following treatment the patient’s experienced marked improvements in complaints related to headaches, anxiety, fatigue, as well as lower extremity circulation, sensation and temperature. Subsequent to all therapies the patient was able to stand in a weight bearing position without elicitation of seizure or orthostatic symptomatology. Conclusion: The results of this case suggest the necessity of further research into the functional neurologic model of diagnosis and treatment and the use of multimodal vestibular rehabilitation strategies in regards to patients with post orthostatic tachycardia syndrome.
IMPROVEMENTS IN PAIN LEVELS, DIZZINESS AND COGNITIVE FUNCTION SUBSEQUENT TO FUNCTIONAL NEUROLOGY TREATMENT
Beatrice D. Tapia1 and Susan E. Esposito1 1Life University, Marietta, GA USA E-mail: [email protected] Received: June 16 2013 Revised: June 18 2013 Accepted: June 18 2013
Background: A 33-year-old male student presented to a chiropractic university clinic with back pain and concussion symptoms. He experienced approximately six episodes of defecation syncope. During one of these episodes he fell and woke up on his right side with neck and back pain. Since the injury he stuttered, had difficulty retaining and connecting information and had intermittent nominal and expressive aphasia. He felt apathetic and irritable. The patient experienced dizziness when reading more than five minutes at a time. Methods: Compromised left cortical function was confirmed through neurological examination. Decreased amplitude of finger tap test bilaterally, worse on right and decreased right arm swing were noted. Aberrancies in gaze holding and saccadic activity were also present. The patient underwent a four-day treatment program at once per week intervals. Treatment consisted of cortical rehabilitation involving gaze holding strategies, eye exercises, complex movement of the extremities and chiropractic spinal adjustments. Results: The patient is able to study for two hours with no dizziness, neck or back pain. Revised Oswestry Disability Index improved from 26% to 2% and Neck Disability Index decreased from 12% to 0% He is feeling more motivated and communication is significantly improved. He retains information more easily. The patient feels “more connected to people”. The patient has not lost consciousness for two weeks. Conclusion: Strategies utilizing complex movements, spinal manipulation and eye exercises demonstrated positive outcomes, which promote the need for further studies.
Poster Abstracts 387
INTUITIVE PROCESSES IN MATHEMATICS INSTRUCTION IN NEUROEDUCATION
Ola Mualem1 1The Baptist School, Nazareth Israel E-mail: [email protected] Received: June 15 2013 Revised: June 19 2013 Accepted: June 19 2013
Background: Evidence exists that the inferior parietal cortex is involved in in symbolic numerical abilities. Cases of epilepsia arithmetices that have been observed when performing mental calculations have all demonstrated EEG abnormalities in the inferior parietal cortex. Cohen and Dehaene have also reported on a case of an individual with a lesion of the inferior parietal cortex who could not determine which number came between 3 and 5 yet could determine which day came between Tuesday and Thursday with number sequencing having been singularly impaired but sequencing spared. Stavy and Tirosh defined three intuitive rules which learners apply predicting errors. These rules include: "More A-More B"; "Same A-Same B"; "You can always continue dividing." In addition this work adds, "if (A) (B) then (B) (A)?" as well as "If (A) (B) then (¬A) (¬B)?" Methods: Students were provided with a questionnaire that consisted of two parts: in the first part, students were asked to answer four questions using "right/wrong" format and if the answer turned out to be "wrong" they were asked to provide an explanation. Two questions relate to claims dealing with the relation between congruent rectangles and their perimeters and the two additional questions relate to claims dealing with rectangles' congruence and their perimeters. Participants included 100 students from the 6th and 7th grades (ages 12-13), half of them (50 students) were 6th graders in elementary school students and the remaining 50 were 7th graders studying in heterogeneous classes in junior high school, in the same socio-economic environment. Results: Approximately one-third of the overall number of students made use of the rule of inversion at least once. A significant negative correlation was found between the use of the rule of inversion and the inclination to solve correctly. Approximately one-half of students applied the rule of negation at least once and a significant negative correlation was found in the use of the rule of negation and the inclination to solve problems correctly. Significant positive correlation was found between the use of the intuitive rules of inversion and the use of the intuitive rule of negation. Conclusions: The results will be discussed in the context of neurological organization of mathematical problem solving capacity with implications for classroom interventions based on solid understanding of nervous system organization.
Funct Neurol Rehabil Ergon 2013;3(2-3):389-398 ISSN: 2156-941X © Nova Science Publishers, Inc.
IAFNR NEWS AND EVENTS
Tricia Merlin Assistant Editor, News and Events
Neurology Conferences 2013-14 *F. R. Carrick Research Institute/National Institute for Brain & Rehabilitation Sciences Sponsored Event
March 2013 16-23: 65th AAN Annual Meeting 2013 (American Academy of Neurology), San Diego, USA
April 2013 11-14: The 7th World Congress on Controversies in Neurology (CONY), Istanbul, Turkey
18-21: 9th International Congress on Mental Disorders & Other Non-Motor features in Parkinson's Disease and Related Disorders, Seoul, South Korea
26-27: CSNS Spring Meeting 2013 (Council of State Neurosurgical Societies), New Orleans, USA
27-01: 80th AANS Annual Scientific Meeting (American Association of Neurological Surgeons), New Orleans, USA
May 2013 22-24: Society of British Neurological Surgeon Spring Meeting 2013, Sheffield, UK
31-03: 17th Congress of the European Federation of Neurological Societies (EFNS), Istanbul, Turkey
June 2013
*The Jerusalem International Conference on Neuroplasticity and Cognitive Modifiability 2-5 June 2013 – Jerusalem, Israel http://www.brainconference.com/en/
390 IAFNR News and Events
16-20: 17th International Congress of Parkinson's Disease and Movement Disorders, Sydney, Australia
17-20: 9th International Symposium on Pediatric Pain (ISPP 2013), Stockholm, Sweden
September 2013 08-13: 15th WFNS World Congress of Neurosurgery, Seoul, South Korea
08-13: EANS Annual Meeting 2013 (European Association of Neurosurgical Societies), Prague, Czech Republic
11-14: FENS Featured Regional Meeting (The Federation of European Neuroscience Societies), Prague, Czech Republic
21-26: XXI World Congress of Neurology, Vienna, Austria
22-27: World Congress of Neurology, Vienna, Austria
October 2013 01-04: 3rd World Parkinson Congress 2013, Montreal, Canada
02-04: Eurospine 2013, Liverpook, UK
*IAFNR 2013 4th Annual Conference On Functional Neurology and Rehabilitation 10 -13 October 2013 – Phoenix, AZ USA
19-24: 63rd Annual Meeting of the Congress of Neurological Surgeons, San Francisco, USA
November 2013 09-13: Neuroscience 2013, San Diego, USA
December 2013 08-11: XX WFN World Congress on Parkinson's Disease and Related Disorders (World Federation of Neurology), Geneva, Switzerland
*International Conference on Disorders of Human Consciousness C. Machado, Conference Organizer Havana, Cuba, 3 - 8 December, 2013 Contact J. Groschel at IAFNR for more details. [email protected]
IAFNR News and Events 391
FUNCTIONAL NEUROLOGY PRESS
http://www.hockeywilderness.com/2012/4/23/2961399/guillaume-latendresse-interview-rds- lantichambre http://prohockeytalk.nbcsports.com/2012/04/23/the-latest-gizmo-in-concussion-treatment-whole- body-gyroscopes/ http://www.thedoctorstv.com/videolib/init/5707 http://thestar.blogs.com/olympics/ http://www.nesn.com/.m/2012/03/alexandre-pato-ac-milan-star-will-jet-to-atlanta-to-treat- chronic-thigh-problem.html http://www.cbc.ca/sports/hockeynightincanada/insidehockey/video/#id=2171100044 http://watch.discoverychannel.ca/#clip573633 http://www.cbc.ca/day6/blog/2011/11/25/crosbys-doctor-and-rebuilding-the-brain/ http://communities.washingtontimes.com/neighborhood/stress-and-health-dr- lind/2012/jul/23/olympic-atheletes-chiropractic/ https://rcpt.yousendit.com/1667112355/33acbc4df65ce2b7419c0fa4f7208600
LIFE UNIVERSITY ESTABLISHES FUNCTIONAL NEUROLOGY CLINIC
Patients are streaming to Life University’s Functional Neurology Center in Marietta, Georgia. The University Based Center house state of art Neurological diagnostic instrumentation and is staffed by clinicians who are both Board Certified in Neurology and who are Fellowship trained and Certified in Functional Neurology. Life University has more Board Certified Chiropractic Neurologists on its faculty than any other University with a College of Chiropractic. The Life U Functional Neurology Center is associated with the Carrick Research Institute at Life and is active, not only in clinical care but ongoing neurological research. There are over 100 active clinical studies in progress as well as collaborations with other Institutions that involve both clinical and animal studies. Life U faculty had more poster and platform presentations accepted at the recent IAFNR congress in Orlando than any other Institution. They have submitted more papers to the scientific jury for consideration at the IAFNR Phoenix Scientific Congress this October. The Functional Neurology Center at Life was created in response to a global demand for an Institutional Center specializing in Functional Neurology. It serves the referral needs of physicians and has attended patients from around the globe. In fact, 95% of the patients referred to the center are not from the State of Georgia. The clinic has been highlighted in the press due to its popularity with Olympic Athletes and Professional Sports Personnel from hockey, football, soccer, and basketball. The clinical staff is headed by Prof. Frederick R. Carrick and includes the faculty of the Carrick Institute and Clinical Team Leaders, Susan Esposito, DC, DACNB, FACFN, FABEDS and James Duffy, DC, DACNB, FACFN. The Institutional Clinic is also a center for clinical education and Doctoral Students, Interns and Residents from Life University and other Institutions are scheduled to observe patient rounds and to assist in patient care under the direction of Clinic Staff.
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First trimester doctoral students are embracing a clinical reality, as they are able to observe the diagnosis and treatment of the most difficult neurological cases. Life University has a goal to establish and maintain the best clinical education available for its students and this world center is an important part of that training. Physicians from around the globe are able to attend rounds with their patients and observe patient care first hand. The ability to be present with a difficult patient has been very popular with field doctors who have travelled to Life U from all corners of the world. The experience has empowered them to greater clinical excellence. Patients with neurological compromise may be referred to the Life University Functional Neurology Center by calling (770) 426-2636. For More information, please log onto www.lifeneurologycenter.com
University of the Medical Sciences Havana, Cuba
National Institute for Brain & International Association of Universidad de Ciencias Rehabilitation Sciences Functional Neurology& Médicas de la Habana Nazareth, Israel Rehabilitation Facultad Manuel Fajardo
2013 Pre-admission Seminars Offered by Prof. Gerry Leisman
23-24 February 2013 Ronkonkoma, New York ______
18-20 May 2013 Rockwall, Texas ______
17-18 August 2013 Venue TBA ______
8-9 October Phoenix, AZ (Prior to IAFNR Conference) ______
3-8 December 2013 Havana Cuba + (Presentations to Doctoral Faculty)
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2012 ACCOMPLISHMENTS
1. Journal Development a. Development of the new journal, Functional Neurology, Rehabilitation, and Ergonomics, published by Nova Science Publishers, now finished volumes 1 and 2 with four issues each. (https://www.novapublishers.com/catalog/product_info.php?products_id=16707)
2. External Academic Linkages a. Finalized contractual relationship for doctoral students working in our laboratories from the University of Medical Sciences of Havana. b. Contractual relationship completed and now accepted research fellows into laboratories. i. Articulation agreement with the Mind Sciences Institute at the Massachusetts Institute of Technology (MIT) and Dr. Newton Howard finalized (http://www.brainsciences.org/Research-Team/bsf- fellows.html). ii. Development of articulation agreement with numerous investment groups to fund R&D and patent development. iii. Development of an articulation agreement for BS level engineering students AND MSc. students of Biomedical Engineering at ORT- Braude College in Carmiel to work with The Institute for Brain and Rehabilitation Sciences in Nazareth on joint projects through the Department of Mechanical Engineering’s programme in Biomedical Engineering. iv. Development of articulation agreement with Cornell University on joint R&D projects through Prof David Robertshaw supported by a US Department of State Fullbright grant through Dr. Raed Mualem, IAFNR-Israel. v. Developed affiliation agreement shared faculty and research partnership with the Centro di Intagrativi Rehabilitation Neurologica and the Instututo di Neurologia e Neurochirugia through Prof. Calixto Machado in Havana Cuba.
3. Conference Sponsorships and Organization a. Conference sponsor and participation of Nazareth Academic Institute, ORT- Braude College of Engineering, Carmiel, the Institute for Brain and Rehabilitation Sciences-Nazareth, and M.A.T.I.- Nazareth at the International Association of Functional Neurology and Rehabilitation in October in Phoenix, Arizona, supported, in part, through the Israel Ministry of Trade and Industry. (http://www.frcarrickresearchinstitute.org/userfiles/IAFNRSPEAKERS.pdf). b. Planning of conference with ORT-Braude College of Engineering, The Institute for Brain and Rehabilitation Sciences, NAI, The F. R. Carrick Research Institute and the Department of Industrial Engineering of Ben-Gurion University of the Negev of a conference in 2013 on Applications of Optimization and Functional Connectivities in Havana, Cuba. c. Sponsor through The Institute for Brain and Rehabilitation Sciences, ORT- Braude College of Engineering, and NAI of the 3rd Annual Conference on Chronic Diseases of Childhood, and Child Health and Human Development, Jerusalem 5-8 December 2012 with Harvard University, the University of Kentucky, Hadassah School of Medicine, Department of Paediatrics, and the
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National Institute for Child Health and Human Development. (http://www.isas.co.il/chhd/advisory_committees.php) d. Sponsor and participant of and in conference on Neuroplasticity and Cognitive Modifiability 2-5 June 2013 Jerusalem (http://www.brainconference.com /en/index.php?page_id=8).
4. Grant and External Funding Applications: a. European Union-Neuron 7: Leisman G, Howard N. “Measurement of Optimization of Neuro-Electrophysiological and Cognitive Performance in Autism.” European Research Projects on Novel Methods and Approaches towards the Understanding of Brain Diseases.” Submission of grant application to European Union for Neuron-7 contest collectively with NAI, Institute for Brain and Rehabilitation Sciences-Israel, La Sorbonne Institute for Mathematics and Computational Sciences, and Sigmund Freud University, Vienna, approved by Chief Scientist office Misrad Habriut. 120.000 € (unsuccessful) (unsuccessful for technical reasons and a resubmission is planned). b. Autism Speaks: Leisman G, Melillo R. “The nature of functional connectivities on neurocognitive performance in autistic spectrum disorder: hemispheric balancing as a potential remediative tool.” $80,000 (Trailblazer Award – unsuccessful) c. Q-Bank Greenwich CT US: Leisman G. “Establishing a Rehabilitation Research Laboratory Emphasizing Exploitation of Dual-Use Technologies, Located in the Galilee. $200,000 (pending). d. DARPA US. Howard N, Leisman G. (with MIT & Cntr. For Adv. Defense Studies) “Discovering and Modeling Narrative Influence on Neurobiology” DARPA-BAA-12-03 NARRATIVE NETWORK. DARPA (USA) $10,318,136 (Unsuccessful) e. Eugene Kahane Foundation: Leisman G, Mualem R. “Rehabilitation Research Laboratory.” Submission to the Eugene Kahana Foundation for laboratory funding $197,430 – successful pending final determination of the award. f. Mcknight Endowment Fund for Neuroscience Memory and Cognitive Disorder Award 2013 McKnight Neuroscience. Leisman G, Rosner A. “The Development of Functional Connectivities in Pre/Post-Natal Development of Consciousness: When Does the Human Become Conscious?” $386,000 (pending) g. The International College of Applied Kinesiology. Leisman G. “The Effects of Therapy Localization on IEMG” successful $29,650 h. Brain and Behaviour Research Foundation: Leisman G. “Measurement of Optimization of Neuro-Electrophysiological and Cognitive Performance in Autism”, 2012 NARSAD Distinguished Investigator Grant $97,610 (pending) i. Simmons Foundation: Optimization of Cognitive Performance in Autism, $250,000 (pending).
5. Recent Conference Presentations a. Leisman G. The Development of Functional Connectivities in the Pre- and Post- Natal Development of Consciousness. [Invited Speaker, International Symposium of Disorders of consciousness, Havana, Cuba 6-8, December 2011] (http://www.engraciacal.com/scientificprogram/abstracts/tabid/64/Default.aspx) b. Leisman G. The Development of Functional Connectivities in the Pre- and Post- Natal Development of Consciousness. [Invited Opening Lecture International Symposium of Disorders of Consciousness, Havana, Cuba, December 6 – 8, 2011].
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(http://www.engraciacal.com/ScientificProgram/SubmittedAbstracts/tabid/72/De fault.aspx) c. Leisman G, Melillo R, Machado C. Functional Disconnectivities in Autistic Spectrum Individuals. [Paper presented at the International Symposium of Disorders of Consciousness, Havana, Cuba, December 6–8, 2011]. (http://www.engraciacal.com/ScientificProgram/SubmittedAbstracts/tabid/72/De fault.aspx) d. Pérez-Nellar J, Machado C, Rodríguez-Rojas R, Estévez M., Chinchilla M, Carrick, FR, Melillo R, Leisman G. Structural Neuroimaging Assessment of PVS Patients [Paper presented at the International Symposium of Disorders of Consciousness, Havana, Cuba, December 6 – 8, 2011]. (http://www.engraciacal.com/ScientificProgram/SubmittedAbstracts/tabid/72/De fault.aspx) e. Batista-García-Ramó K, Rodríguez-Rojas R, Carballo-Barreda M, Machado C, Melillo R, Leisman G. Tractography Assessment in Autism Spectrum Disorders. [Paper presented at the International Symposium of Disorders of Consciousness, Havana, Cuba, December 6 – 8, 2011]. (http://www.engraciacal.com/ ScientificProgram/SubmittedAbstracts/tabid/72/Default.aspx) f. Pérez-Nellar J, Machado C, Rodríguez-Rojas R, Estévez M, Chinchilla M, Carrick FR, Melillo R, Leisman G. Neuroimaging in Non-Fatal Central Transtentorial Herniation. [Paper presented at the International Symposium of Disorders of Consciousness, Havana, Cuba, December 6 – 8, 2011]. (http://www.engraciacal.com/ScientificProgram/SubmittedAbstracts/tabid/72/De fault.aspx) g. Leisman G. Children’s Language Production: How Cognitive Neuroscience & Industrial Engineering Can Inform Public Education Policy and Practice [Invited Paper Presented at the Oxford University Roundtable on Public Policy, 11-15 March, 2012] (http://www.oxfordroundtable.com/index.php/view/Sessions- Item/id/141) h. Rosner AF, Leisman G, Gilchriest J. Reliability and validity of therapy localization in applied kinesiology. [Paper to be presented at the Society for Neuroscience, New Orleans, October 16-18, 2012] (http://www.sfn.org/am2012/) i. Leisman G. The Brain on Art: Auditory, Visual, Spatial Aesthetic, and Artistic Training Facilitates Brain Plasticity [Invited presentation, International Association of Functional Neurology and Rehabilitation, Phoneix, AZ USA 24- 28 October, 2012] (http://www.frcarrickresearchinstitute.org/conference) j. Jubran F, Leisman G. Intersensory Integration in Functional Neurology: An Engineer's Perspective of Music as an Interventionary Medium. [Paper presented, International Association of Functional Neurology and Rehabilitation, Phoenix, AZ USA 24-28 October, 2012] (http://www.frcarrick researchinstitute.org/conference) k. Leisman G, Melillo R, Machado C, Rodriguez-Rojas R, Batista K, Carballo M, Mualem R. Functional Disconnectivities in Autistic Spectrum Individuals [Paper to be presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] l. Leisman G. Functional Connectivities in the Post-Natal Development of Consciousness. [Paper to be presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (www.isas.co.il/chhd/Child_Development_Brochure.pdf) m. Estévez M, Machado C, Leisman G, Melillo R, Machado A, Hernández-Cruz A, Arias A, Rodríguez-Rojas R, Carballo M. Eegconn: A Software Tool for Offline
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Qeeg Analysis, Including Spectral Univariate and Bivariate Processes and Linear and Non-Linear Indices of Brain Connectivity in Autistic Spectrum Disorder. [Paper to be presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (www.isas.co.il/chhd/Child_Development_Brochure.pdf) n. Rodriguez-Rojas R, Batista K, Carballo, M, Machado C, Leisman G, Estévez M, Melillo R. Anatomical And Topological Connectivity Reveal Different Attributes of Disrupted Small-World Networks in Autistic Children. [Paper to be presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (www.isas.co.il/chhd/Child_ Development_Brochure.pdf) o. Jammalieh J, Mualem R, Leisman G. Clinical effects of the development of physiological rhythms in premature infants. [Paper presented at the International Conference of Child Health and Human Development, Jerusalem, Israel December, 2012] (http://www.isas.co.il/chhd/)
6. Recent Books and Chapters a. Melillo RM, Leisman G. Neurobehavioral Disorders of Childhood Beijing, China: People's Medical Publishing House (PMPH) 2010 [Chinese Translation]. b. Leisman G,Melillo R. The Development of the Frontal Lobes in Infancy and Childhood: Asymmetry and the Nature of Temperament and Adjustment. In: Cavanna, A.E. (Ed.) Frontal Lobe: Anatomy, Functions and Injuries. Hauppauge, NY: Nova Scientific Publishers, 2012. (https://www.novapublishers.com /catalog/product_info.php?products_id=33647) c. Leisman. G, Melillo R. The Basal Ganglia: Motor and Cognitive Relationships in a Clinical Neurobehavioral Context In: E. Franz (Ed) Leisman G, Melillo R. The Basal Ganglia: Motor and Cognitive Relationships in a Clinical Neurobehavioral Context. In: Franz E, editor. Basal Ganglia. Rijeka, Croatia: InTech; 2012. [ISBN 980-953- 307-193-5] d. Leisman G, Melillo R, Mualem R, Machado C. The effect of music training and production on functional brain organization and cerebral asymmetry. In: Kravchuk T, Groysman A, Soddu C, Colabella E, Leisman G, editors. Art, Science and Technology. Mialno, Italy: Domus Argenia Publisher; 2012. pp. 133-139. [ISBN: 978-88-96610-24-4] (www.artscience-ebookshop.com/1stAST_proceedings.pdf) e. Leisman G. Behavioral Disorders: New Research. Hauppauge, NY: Nova Scientific Publishers; 2013 [In Press].
7. Published Papers in Indexed Peer-reviewed Journals a. Leisman G, Melillo R. Functional Disconnectivities in Autistic Spectrum Disorder as a Potent Model for Explaining Disorders of Consciousness and Cognition in the Brain and Nervous System. Funct Neurol Rehabil Ergon. 2011;1(1):101-145. (https://www.novapublishers.com/catalog/product_info.php?products_id=21547) b. Leisman G, Machado C. Considering Consciousness Clinically. Funct Neurol Rehabil Ergon. 2011;1(1):17-23. (https://www.novapublishers.com/catalog /product_info.php?products_id=21537) c. Carrick FR, Pagnacco G, Oggero E, Sullivan S, Barton D, Esposito S, Leisman G, Melillo R. The Effects of Whole Body Rotations in the Pitch and Yaw Planes on Postural Stability. Funct Neurol Rehabil Ergon. 2011;1(2):167-179. (https://www.novapublishers.com/catalog/product_info.php?products_id=23933) d. Leisman G. Brain Networks, Plasticity, and Functional Connectivities Inform Current Directions. Funct Neurol Rehabil Ergon. 2011;1(2):315-356. (https://www.novapublishers.com/catalog/product_info.php?products_id=23945)
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e. Machado C, Estévez M, Rodríguez R, Carballo M, Pérez-Nellar J, Gutiérrez J, Fleitas M, Leisman G. Are Persistent Vegetative State Patients Isolated from the Outside World? Funct Neurol Rehabil Ergon. 2011;1(2):357-377. (https://www.novapublishers.com/catalog/product_info.php?products_id=23947). f. Machado C, Estévez M, Carrick F, Melillo R, Leisman G. qEEG may increase the reliability of diagnostic and prognostic procedures in cerebral arterial gas embolism. Clinical Neurophysiology. 2012;123(2):225-226. (http://www.ncbi.nlm.nih.gov /pubmed/21784702) (http://www.sciencedirect.com/science/article/pii/S1388245711004615) g. Machado C, Estevez M, Rodriguez R, Carrick FR, Melillo R, Leisman G. Bilateral N20 Absence in Post-Anoxic Coma: Do You Pay Attention? Clinical Neurophysiology. 2012;123(1). (http://dx.doi.org/10.1016/j.clinph.2011.11.008) h. Leisman G, Melillo R. The Development of the Frontal Lobes in Infancy and Childhood: Asymmetry and the Nature of Temperament and Adjustment. In: Cavanna AE, editor. Frontal Lobe: Anatomy, Functions and Injuries. Hauppauge, NY: Nova Scientific Publishers; 2012. i. Leisman G, Melillo R. The Basal Ganglia: Motor and Cognitive Relationships in a Clinical Neurobehavioral Context. In: E. Franz E, editor. Basal Ganglia. Rijeka, Croatia: InTech; 2012. [ISBN 980-953-307-193-5] j. Leisman, G and Melillo, R. EEG Coherence Measures Functional Disconnectivities in Autism. Journal of Pediatric Research, 2013 [in Press]. k. Machado C, Estevez M, Rodriguez R, Carrick FR, Melillo R, Leisman G. Bilateral N20 Absence in Post-Anoxic Coma: Do You Pay Attention? Clinical Neurophysiology. 2012;123(1):1264-1266. (http://dx.doi.org/10.1016/j.clinph. 2011.11.008). l. Leisman G, Machado C, Melillo R, Mualem R. Intentionality and “Free- Will” From a Neurodevelopmental Perspective. Frontiers of Integrative Neuroscience. 2012;6:36. doi: 10.3389/ fnint.2012.00036 (http://www.frontiersin.org/Integrative _Neuroscience/10.3389/fnint.2012.00036/ful m. Leisman G. Children’s Language Production: How Cognitive Neuroscience & Industrial Engineering Can Inform Public Education Policy and Practice Forum on Public Policy. A Journal of the Oxford Roundtable. 2012;2012(1):1-14. (http://forumonpublicpolicy.com/vol2012.no1/archive/leisman.pdf)(http://forumonpu blicpolicy.com/vol2012.no1/earlychild2012.html) n. Leisman G. Auditory, Visual and Spatial Aesthetic and Artistic Training Facilitates Brain Plasticity: The Arts as a Vehicle for Rehabilitation. Funct Neurol Rehabil Ergon. 2012;2(3):251-266. (https://www.novapublishers.com/catalog/product_ info.php?products_id=36803) o. Jubran F, Leisman G. Intersensory Integration in Functional Neurology: An Engineer's Perspective of Music as an Interventionary. Funct Neurol Rehabil Ergon. 2012;2(3):215-222. (https://www.novapublishers.com/catalog/product_info.php?products_id=36803) p. Machado-Ferrer Y, Estevez M, Machado C, Hernández-Cruz, Leisman G, Carrick FR, Melillo R, Beltrán C. Heart Rate Variability for Assessing Comatose Patients with Different Glasgow Coma Scale Scores. Clinical Neurophysiology. 2012;123(3):572-581.
8. Papers in Indexed Peer-Reviewed Journals Currently In Press. a. Leisman G. Cognitive Science Applied to Medical Expertise. Journal of the Royal Society of Medicine. 2012 (in Press).
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b. Leisman G, Melillo R. Functional Disconnectivities in Autism. International Journal of Adolescent Medicine and Health. 2012 [in Press] c. Machado C, Estevez M, Rodriguez R, Perez-Nellar J, Chinchilla M, Carrick FR, Leisman, G, Melillo R, Gutierrez J, Carballo M, Machado A, Olivares A, Perez-Cruz N, Belttran C. Zolpidem Arousing Effect in Persistent Vegetative State Patients: Autonomic, EEG and Behavioral Assessment. Clinical Neurophysiology. 2012. [InPress].
Funct Neurol Rehabil Ergon 2013;3(2-3):399-409 ISSN: 2156-941X © Nova Science Publishers, Inc.
LITERATURE CALLING
A REVIEW OF RECENT PUBLICATIONS OF INTEREST TO FUNCTIONAL NEUROLOGY
An fMRI-Based Neurologic Signature of Physical Pain
Wager TD, Atlas LY, Lindquist MA, Roy M, Woo C-W, Kross E. New Eng J Med. 2013;368:1388-1397.
BACKGROUND: Persistent pain is measured by means of self-report, the sole reliance on which hampers diagnosis and treatment. Functional magnetic resonance imaging (fMRI) holds promise for identifying objective measures of pain, but brain measures that are sensitive and specific to physical pain have not yet been identified. METHODS: In four studies involving a total of 114 participants, we developed an fMRI-based measure that predicts pain intensity at the level of the individual person. In study 1, we used machine-learning analyses to identify a pattern of fMRI activity across brain regions — a neurologic signature — that was associated with heat- induced pain. The pattern included the thalamus, the posterior and anterior insulae, the secondary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray matter, and other regions. In study 2, we tested the sensitivity and specificity of the signature to pain versus warmth in a new sample. In study 3, we assessed specificity relative to social pain, which activates many of the same brain regions as physical pain. In study 4, we assessed the responsiveness of the measure to the analgesic agent remifentanil. RESULTS: In study 1, the neurologic signature showed sensitivity and specificity of 94% or more (95% confidence interval [CI], 89 to 98) in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall. In study 2, the signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity (95% CI, 84 to 100). In study 3, it discriminated between physical pain and social pain with 85% sensitivity (95% CI, 76 to 94) and 73% specificity (95% CI, 61 to 84) and with 95% sensitivity and specificity in a forced-choice test of which of two conditions was more painful. In study 4, the strength of the signature response was substantially reduced when remifentanil was administered. CONCLUSIONS: It is possible to use fMRI to assess pain elicited by noxious heat in healthy persons. Future studies are needed to assess whether the signature predicts clinical pain. (Funded by the National Institute on Drug Abuse and others.)
Mom’s Obesity May Affect Unborn Child’s Brain
Feb. 11, 2013 Courtesy of the Society for Maternal-Fetal Medicine and World Science staff
Obesity in a pregnant mother may lead to abnormal brain development in the fetus, scientists are warning, based on a finding of abnormal patterns of genetic activity in such fetuses. Although the implications are unclear, scientists called the findings a potentially major concern, given that an estimated one in three U.S. women are obese at conception. Researchers from Tufts Medical Center in Boston plan to present the findings on Feb. 15 at the Society for Maternal-Fetal Medicine’s annual meeting in San Francisco.
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“Women won’t be surprised to hear being obese while pregnant can lead to obesity in the child,” said Andrea Edlow, lead author of the study. “But what might surprise them is the potential effect it has on the brain development of their unborn child.” The study examined the fetal devel- opment of 16 pregnant women, eight obese and eight lean. As early as the second trimester, obese women’s fetuses were found to have different patterns of gene activity, suggestive of abnormal brain development. During gestation, fetuses go through apoptosis—a normal process of programmed “suicide” by certain brain cells. This constitutes a sort of pruning, a clearing out space for new growth, said Diana Bianchi, senior author of the study and executive director of the Mother Infant Research In- stitute at Tufts. Fetuses of obese women had genetic activity indicating decreased apoptosis, an important part of normal fetal brain development, she explained. It’s unclear what effect this will ultimately have on the developed brain, she added, but she said maternal obesity is a rapidly growing prob- lem in the United States and has been associated with increased rates of autism and altered appe- tite regulation. Bianchi and Edlow say their next step will be to use laboratory mice to further study the observed genetic differences.
How Do You Learn to Walk? Thousands of Steps and Dozens of Falls per Day
Adolph KE, Cole WG, Komati M, Garciaguirre JS, Badaly D, Lingeman JM, Chan G, Sotsky RB. Psychological Science. 2012; 23(11):1387-1394.
A century of research on the development of walking has examined periodic gait over a straight, uniform path. The current study provides the first corpus of natural infant locomotion derived from spontaneous activity during free play. Locomotor experience was immense: Twelve- to 19-month-olds averaged 2,368 steps and 17 falls per hour. Novice walkers traveled farther faster than expert crawlers, but had comparable fall rates, which suggests that increased efficiency without increased cost motivates expert crawlers to transition to walking. After walking onset, natural locomotion improved dramatically: Infants took more steps, traveled farther distances, and fell less. Walking was distributed in short bouts with variable paths—frequently too short or irregular to qualify as periodic gait. Nonetheless, measures of periodic gait and of natural locomotion were correlated, which indicates that better walkers spontaneously walk more and fall less. Immense amounts of time-distributed, variable practice constitute the natural practice regimen for learning to walk.
Distinct Attention Networks for Feature Enhancement and Suppression in Vision
Bridwell DA, Srinivasan R. Psychological Sciences. 2012 Oct 1;23(10):1151-1158.
Attention biases sensory processing toward neurons containing information about behaviorally relevant events. These attentional biases apparently reflect the combined influence of feature enhancement and suppression. We examined the separate influence of enhancement and suppression in visual processing by determining whether responses to an unattended flicker were modulated when the flicker features matched target features at the attended location, competed with those features, or were neutral. We found that suppression primarily modulated parietal networks with a preferred frequency in the lower alpha band (f2 = 8 Hz), and enhancement primarily influenced parietal networks with a preferred frequency in the upper alpha band (f2 = 12 Hz). These responses were coupled with perception, with large responses to the unattended flicker leading to subsequently detected targets when the target features matched the flicker features (i.e., during enhancement). Our results suggest that enhancement and suppression are two distinct processes that work together to shape visual perception.
Literature Calling 401
Growing Up with Asperger’s Syndrome: Developmental Trajectory of Autobiographical Memory
Bon L, Baleyte J-M, Piolino P, Desgranges B, Eustache F and Guillery-Girard B. Front Psychol. 2013; 3:605. doi: 10.3389/fpsyg.2012.00605
Autobiographical memory (AM) and social cognition share common properties and both are affected in autism spectrum disorders (ASD). So far, most of the scant research in ASD has concerned adults, systematically reporting impairment of the episodic component. The only study to be conducted with children concluded that they have poorer personal semantic knowledge than typical developing children. The present study explores the development of both components of AM in an 8-year-old boy diagnosed with Asperger’s syndrome, based on three examinations in 2007, 2008, and 2010. On each occasion, he underwent a general neuropsychological assessment including theory of mind (ToM) tasks, and a specially designed AM task allowing us to test both the semantic and the episodic components for three lifetime periods (current year, previous year, and earlier years). We observed difficulties in strategic retrieval and ToM, with a significant improvement between the second and third examinations. Regarding AM, different patterns of performance were noted in all three examinations: (1) relative preservation of current year personal knowledge, but impairment for the previous and earlier years, and (2) impairment of episodic memory for the current and previous year, but performances similar to those of controls for the earlier years. The first pattern can be explained by abnormal forgetting and by the semanticization mechanism, which needs verbal communication and social interaction to be efficient. The second pattern suggests that the development of episodic memory only reached the stage of “event memory.” This term refers to memory for personal events lacking in details or spatiotemporal specificity, and is usually observed in children younger than five. We conclude that the abnormal functioning of social cognition in ASD, encompassing social, and personal points of view, has an impact on both components of AM.
Cognition-Emotion Dysinteraction In Schizophrenia
Anticevic A, Corlett PR. Front Psychol. 2012;3:392. doi: 10.3389/fpsyg.2012.00392. This article was submitted to Frontiers in Emotion Science, a specialty of Frontiers in Psychology
Evolving theories of schizophrenia emphasize a “disconnection” in distributed fronto-striatal- limbic neural systems, which may give rise to breakdowns in cognition and emotional function. We discuss these diverse domains of function from the perspective of disrupted neural circuits involved in “cold” cognitive vs. “hot” affective operations and the interplay between these processes. We focus on three research areas that highlight cognition-emotion dysinteractions in schizophrenia: First, we discuss the role of cognitive deficits in the “maintenance” of emotional information. We review recent evidence suggesting that motivational abnormalities in schizophrenia may in part arise due to a disrupted ability to “maintain” affective information over time. Here, dysfunction in a prototypical “cold” cognitive operation may result in “affective” deficits in schizophrenia. Second, we discuss abnormalities in the detection and ascription of salience, manifest as excessive processing of non-emotional stimuli and inappropriate distractibility. We review emerging evidence suggesting deficits in some, but not other, specific emotional processes in schizophrenia – namely an intact ability to perceive emotion “in-the- moment” but poor prospective valuation of stimuli and heightened reactivity to stimuli that ought to be filtered. Third, we discuss abnormalities in learning mechanisms that may give rise to delusions, the fixed, false, and often emotionally charged beliefs that accompany psychosis. We highlight the role of affect in aberrant belief formation, mostly ignored by current theoretical models. Together, we attempt to provide a consilient overview for how breakdowns in neural systems underlying affect and cognition in psychosis interact across symptom domains. We conclude with a brief treatment of the neurobiology of schizophrenia and the need to close our
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explanatory gap between cellular-level hypotheses and complex behavioral symptoms observed in this illness.
Toward A Neurobiology Of Unrealistic Optimism
Shah P. Front Psychol. 2012;3:344. doi: 10.3389/ fpsyg.2012.00344
Research spanning three decades has found that human judgment is characterized by unrealistic optimism (or “optimism bias”), the tendency to underestimate the likelihood of negative events and overestimate the likelihood of positive events (Weinstein, 1980). This work has recently garnered much interest, some question its existence (Harris and Hahn, 2011), while others have found support for it by using novel experiments (Massey et al., 2011; Simmons and Massey, 2012). Most recently, attention has turned to investigating the neural underpinnings of this phenomenon (Sharot et al., 2007, 2011). A new study (Sharot et al., 2012) has now shown that optimism bias is increased by up-regulating dopaminer- gic function via dihydroxy-l- phenylalanine (l-DOPA). Sharot et al. (2012) propose that this process occurs as l-DOPA attenuates belief updating in response to bad news about the future. In light of such evidence, the implications for future research on unrealistic optimism are discussed. Unrealistic optimism is recognized as one of the major human cognitive biases (Kahneman, 2011). It has been the focus of much research, particularly in social and clinical psychology; here it is argued that optimism bias is not just a pervasive feature of human judgment, but a crucial requirement to guard against depression (Taylor and Brown, 1988). Despite the wealth of research, this work has been scrutinized, as many question (e.g., Moore and Small, 2008) the methods used in the majority of studies where the “comparison approach” is used, i.e., where optimism bias is interpreted by optimistic comparisons of one’s personal risk, relative to the average person. A compelling demonstration of how optimism research may be riddled with statistical artifacts has recently emerged (Harris and Hahn, 2011). In contrast, Sharot et al. (2011) provided a promising, new approach to investigate optimism bias, via the concept of belief change. Sharot and colleagues reported that unrealistic optimism persists “in the face of reality” because good (versus bad) news is incorporated significantly more into one’s beliefs of personal risk. They reported that this asymmetric “updating” originates from a prediction error bias which correlates (determined by functional magnetic resonance imaging) with activity in various regions of the frontal cortex. Importantly, on first glance, this method does not appear to suffer from the problems inherent in the comparison approach of optimism research, and their findings have been interpreted as evidence of unrealistic optimism. This has naturally shifted attention towards the neurobiology underlying this phenomenon.
Music and Early Language Acquisition
Brandt A, Gebrian M and Slevc LR. Front Psychol. 2012;3:327. doi: 10.3389/fpsyg.2012.00327
Language is typically viewed as fundamental to human intelligence. Music, while recognized as a human universal, is often treated as an ancillary ability – one dependent on or derivative of language. In contrast, we argue that it is more productive from a developmental perspective to describe spoken language as a special type of music. A review of existing studies presents a compelling case that musical hearing and ability is essential to language acquisition. In addition, we challenge the prevailing view that music cognition matures more slowly than language and is more difficult; instead, we argue that music learning matches the speed and effort of language acquisition. We conclude that music merits a central place in our understanding of human development.
Literature Calling 403
Freezing of Gait in Parkinson’s Disease: Disturbances in Automaticity and Control
Vandenbossche J, Deroost N, Soetens E, Coomans D, Spildooren J, Vercruysse S, Nieuwboer A, Kerckhofs E. Front Hum Neurosci. 2013;6:356. doi: 10.3389/fnhum.2012.00356
Recent studies emphasize a key role of controlled operations, such as set-shifting and inhibition, in the occurrence of freezing of gait (FOG) in Parkinson’s disease (PD). However, FOG can also be characterized as a de-automatization disorder, showing impairments in both the execution and acquisition of automaticity. The observed deficits in automaticity and executive functioning indicate that both processes are malfunctioning in freezers. Therefore, to explain FOG from a cognitive-based perspective, we present a model describing the pathways involved in automatic and controlled processes prior to a FOG episode. Crucially, we focus on disturbances in automaticity and control, regulated by the frontostriatal circuitry. In complex situations, non- freezing PD patients may compensate for deficits in automaticity by switching to increased cognitive control. However, as both automatic and controlled processes are more severely impaired in freezers, this hampers cognitive compensation in FOG, resulting in a potential breakdown. Future directions for cognitive rehabilitation are proposed, based on the cognitive model we put forward.
“Doctor” Or “Darling”? Decoding the Communication Partner from Ecog of the Anterior Temporal Lobe During Non-Experimental, Real-Life Social Interaction
Derix J, Iljina O, Schulze-Bonhage A, Aertsen A and Ball T. Front Hum Neurosci. 2012;6:251. doi: 10.3389/fnhum.2012.00251
Human brain processes underlying real-life social interaction in everyday situations have been difficult to study and have, until now, remained largely unknown. Here, we investigated whether electrocorticography (ECoG) recorded for pre-neurosurgical diagnostics during the daily hospital life of epilepsy patients could provide a way to elucidate the neural correlates of non- experimental social interaction. We identified time periods in which patients were involved in conversations with either their respective life partners (Condition 1; C1) or attending physicians (Condition 2; C2). These two conditions can be expected to differentially involve subfunctions of social interaction which have been associated with activity in the anterior temporal lobe (ATL), including the temporal pole (TP). Therefore, we specifically focused on ECoG recordings from this brain region and investigated spectral power modulations in the alpha (8–12Hz) and theta (3– 5Hz) frequency ranges, which have been previously assumed to play an important role in the processing of social interaction. We hypothesized that brain activity in this region might be sensitive to differences in the two interaction situations and tested whether these differences can be detected by single-trial decoding. Condition-specific effects in both theta and alpha bands were observed: the left and right TP exclusively showed increased power in C1 compared to C2, whereas more posterior parts of the ATL exhibited similar (C1 > C2) and also contrary (C2 > C1) effects. Single-trial decoding accuracies for classification of these effects were highly above chance. Our findings demonstrate that it is possible to study the neural correlates of human social interaction in non-experimental conditions. Decoding the identity of the communication partner and adjusting the speech output accordingly may be useful in the emerging field of brain-machine interfacing for restoration of expressive speech.
404 Literature Calling
Differential Vulnerability of Substantia Nigra and Corpus Striatum to Oxidative Insult Induced by Reduced Dietary Levels of Essential Fatty Acids
Cardoso HD, Passos PP, Lagranha CJ, Ferraz AC, Santos Junior EF, Oliveira RS, Oliveira PEL, Santos RCF, Santana DF, Borba JMC, Rocha-de-Melo A, Guedes RCA, Navarro DMAF, Santos GKN, Borner R, Picanço- Diniz CW, Beltrão EI, Silva JF, Rodrigues MCA and Andrade da Costa BL. Front Hum Neurosci. 2012;6:249. doi: 10.3389/ fnhum. 2012.00249
Oxidative stress (OS) has been implicated in the etiology of certain neurodegenerative disorders. Some of these disorders have been associated with unbalanced levels of essential fatty acids (EFA). The response of certain brain regions to OS, however, is not uniform and a selective vulnerability or resilience can occur. In our previous study on rat brains, we observed that a two- generation EFA dietary restriction reduced the number and size of dopaminergic neurons in the substantia nigra (SN) rostro-dorso-medial. To understand whether OS contributes to this effect, we assessed the status of lipid peroxidation (LP) and anti-oxidant markers in both SN and corpus striatum (CS) of rats submitted to this dietary treatment for one (F1) or two (F2) generations. Wistar rats were raised from conception on control or experimental diets containing adequate or reduced levels of linoleic and α-linolenic fatty acids, respectively. LP was measured using the thiobarbituric acid reaction method (TBARS) and the total superoxide dismutase (t-SOD) and catalase (CAT) enzymatic activities were assessed. The experimental diet significantly reduced the docosahexaenoic acid (DHA) levels of SN phospholipids in the F1 (∼28%) and F2 (∼50%) groups. In F1 adult animals of the experimental group there was no LP in both SN and CS. Consistently, there was a significant increase in the t-SOD activity (p < 0.01) in both regions. In EF2 young animals, degeneration in dopaminergic and non-dopaminergic neurons and a significant increase in LP (p < 0.01) and decrease in the CAT activity (p < 0.001) were detected in the SN, while no inter-group difference was found for these parameters in the CS. Conversely, a significant increase in t-SOD activity (p < 0.05) was detected in the CS of the experimental group compared to the control. The results show that unbalanced EFA dietary levels reduce the redox balance in the SN and reveal mechanisms of resilience in the CS under this stressful condition.
The Cinema- Cognition Dialogue: A Match Made In Brain
Dudai Y. Front Hum Neurosci. 2012;6:248. doi: 10.3389/fnhum.2012.00248
That human evolution amalgamates biological and cultural change is taken as a given, and that the interaction of brain, body, and culture is more reciprocal then initially thought becomes apparent as the science of evolution evolves (Jablonka and Lamb, 2005). The contribution of science and technology to this evolutionary process is probably the first to come to mind. The biology of Homo sapiens permits and promotes the development of technologies and artefacts that enable us to sense and reach physical niches previously inaccessible. This extends our biological capabilities, but is also expected to create selective pressures on these capabilities. The jury is yet out on the pace at which critical biological changes take place in evolution. There is no question, however, that the kinetics of technological and cultural change is much faster, rendering the latter particularly important in the biography of the individual and the species alike. The capacity of art to enrich human capabilities is recurrently discussed by philosophers and critics (e.g., Arsitotle/Poetics, Richards, 1925; Smith and Parks, 1951; Gibbs, 1994). Yet less attention is commonly allotted to the role of the arts in the aforementioned ongoing evolutional tango. My position is that the art of cinema is particularly suited to explore the intriguing dialogue between art and the brain. Further, in the following set of brief notes, intended mainly to trigger further thinking on the subject, I posit that cinema provides an unparalleled and highly rewarding experimentation space for the mind of the individual consumer of that art. In parallel, it also provides a useful and promising device for investigating brain and cognition.
Literature Calling 405
Human Striatum Is Differentially Activated by Delayed, Omitted, and Immediate Registering Feedback
Kohrs C, Angenstein N, Scheich H and Brechmann A. Front Hum Neurosci. 2012;6:243. doi: 10.3389/fnhum. 2012.00243
The temporal contingency of feedback during conversations is an essential requirement of a successful dialog. In the current study, we investigated the effects of delayed and omitted registering feedback on fMRI activation and compared both unexpected conditions to immediate feedback. In the majority of trials of an auditory task, participants received an immediate visual feedback which merely indicated that a button press was registered but not whether the response was correct or not. In a minority of trials, and thus unexpectedly, the feedback was omitted, or delayed by 500 ms. The results reveal a response hierarchy of activation strength in the dorsal striatum and the substantia nigra: the response to the delayed feedback was larger compared to immediate feedback and immediate feedback showed a larger activation compared to the omission of feedback. This suggests that brain regions typically involved in reward processing are also activated by non-rewarding, registering feedback. Furthermore, the comparison with immediate feedback revealed that both omitted and delayed feedback significantly modulated activity in a network of brain regions that reflects attentional demand and adjustments in cognitive and action control, i.e., the posterior medial frontal cortex (pMFC), right dorsolateral prefrontal cortex (dlPFC), bilateral anterior insula (aI), inferior frontal gyrus (Gfi), and inferior parietal lobe (Lpi). This finding emphasizes the importance of immediate feedback in human–computer interaction, as the effects of delayed feedback on brain activity in the described network seem to be similar to that of omitted feedback.
The Fuzzy Brain. Vagueness and Mapping Connec- Tivity of the Human Cerebral Cortex
Haueis P. Front Neuroanat. 2012;6:37. doi: 10.3389/ fnana.2012.00037
While the past century of neuroscientific research has brought considerable progress in defining the boundaries of the human cerebral cortex, there are cases in which the demarcation of one area from another remains fuzzy. Despite the existence of clearly demarcated areas, examples of gradual transitions between areas are known since early cytoarchitectonic studies. Since multi- modal anatomical approaches and functional connectivity studies brought renewed attention to the topic, a better understanding of the theoretical and methodological implications of fuzzy boundaries in brain science can be conceptually useful. This article provides a preliminary conceptual framework to understand this problem by applying philosophical theories of vagueness to three levels of neuroanatomical research. For the first two levels (cytoarchitectonics and fMRI studies), vagueness will be distinguished from other forms of uncertainty, such as imprecise measurement or ambiguous causal sources of activation. The article proceeds to discuss the implications of these levels for the anatomical study of connectivity between cortical areas. There, vagueness gets imported into connectivity studies since the network structure is dependent on the parcellation scheme and thresholds have to be used to delineate functional boundaries. Functional connectivity may introduce an additional form of vagueness, as it is an organizational principle of the brain. The article concludes by discussing what steps are appropriate to define areal boundaries more precisely.
406 Literature Calling
Functional Disconnection of Frontal Cortex and Visual Cortex in Attention- Deficit/Hyperactivity Disorder
Mazaheri A, Coffey-Corina S, Mangun GR, Bekker EM, Berry AS, Corbett BA. Biol Psychiatry. 2010 Apr 1;67(7):617-23.
BACKGROUND: Current pathophysiologic models of attention-deficit/hyperactivity disorder (ADHD) suggest that impaired functional connectivity within brain attention networks may contribute to the disorder. In this electroencephalographic (EEG) study, we analyzed cross- frequency amplitude correlations to investigate differences in cue-induced functional connectivity in typically developing children and children with ADHD. METHODS: Electroencephalographic activity was recorded in 25 children aged 8 to 12 years (14 with ADHD) while they performed a cross-modal attention task in which cues signaled the most likely (.75 probability) modality of an upcoming target. The power spectra of the EEG in the theta (3-5 Hz) and alpha (8-12 Hz) bands were calculated for the 1-sec interval after the cue and before the target while subjects prepared to discriminate the expected target. RESULTS: Both groups showed behavioral benefits of the predictive attentional cues, being faster and more accurate for validly cued targets (e.g., visual target preceded by a cue predicting a visual target) than to invalidly cued targets (e.g., visual target preceded by a cue predicting an auditory target); in addition, independent of cue-target validity, typical children were faster to respond overall. In the typically developing children, the alpha activity was differentially modulated by the two cues and anticorrelated with midfrontal theta activity; these EEG correlates of attentional control were not observed in the children with ADHD. CONCLUSIONS: Our findings provide neurophysiological evidence for a specific deficit in top-down attentional control in children with ADHD that is manifested as a functional disconnection between frontal and occipital cortex.
New Form of Brain Plasticity: How Social Isolation Disrupts Production
ScienceDaily (Nov. 11, 2012)
Animals that are socially isolated for prolonged periods make less myelin in the region of the brain responsible for complex emotional and cognitive behavior, researchers at the University at Buffalo and Mt. Sinai School of Medicine report in Nature Neuroscience online. The research sheds new light on brain plasticity, the brain's ability to adapt to environmental changes. It reveals that neurons aren't the only brain structures that undergo changes in response to an individual's environment and experience, according to one of the paper's lead authors, Karen Dietz, PhD, research scientist in the Department of Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences. Dietz did the work while a postdoctoral researcher at Mt. Sinai School of Medicine; Jia Liu, PhD, a Mt. Sinai postdoctoral researcher, is the other lead author. The paper notes that changes in the brain's white matter, or myelin, have been seen before in psychiatric disorders, and demyelinating disorders have also had an association with depression. Recently, myelin changes were also seen in very young animals or adolescents responding to environmental changes. "This research reveals for the first time a role for myelin in adult psychiatric disorders," Dietz says. "It demonstrates that plasticity in the brain is not restricted to neurons, but actively occurs in glial cells, such as the oligodendrocytes, which produce myelin." Myelin is the crucial fatty material that wraps the axons of neurons and allows them to signal effectively. Normal nerve function is lost in demyelinating disorders, such as MS and the rare, fatal, childhood disease, Krabbe's disease. This paper reveals that the stress of social isolation disrupts the sequence in which the myelin-making cells, the oligodendrocytes, are formed. In the experiment, adult mice, normally social animals, were isolated for eight weeks to induce a depressive-like state. They were then
Literature Calling 407 introduced to a "novel" mouse, one they hadn't seen before; while mice are normally highly motivated to be social, those who had been socially isolated did not show any interest in interacting with the new mouse, a model of social avoidance and withdrawal. Brain tissue analysis of the socially isolated animals revealed significantly lower than normal levels of gene transcription for oligodendrocyte cells in the prefrontal cortex, a brain region responsible for emotional and cognitive behavior. "This research provides the first explanation of the mechanism behind how this brain plasticity occurs," says Dietz, "showing how this change in the level of social interaction of the adult animal resulted in changes in oligodendrocytes." The key change was that cellular nuclei in the prefrontal cortex contained less heterochromatin, a tightly packed form of DNA material, which is unavailable for gene expression. "This process of DNA compaction is what signifies that the oligodendrocytes have matured, allowing them to produce normal amounts of myelin," says Dietz. "We have observed in socially isolated animals that there isn't as much compaction, and the oligodendrocytes look more immature. As adults age, normally, you would see more compaction, but when social isolation interferes, there's less compaction and therefore, less myelin being made." She adds, however, that the research also showed that myelin production went back to normal after a period of social integration, suggesting that environmental intervention was sufficient to reverse the negative consequences of adult social isolation. The new paper, together with a report published earlier this year by another group showing myelin changes triggered by social isolation early in life will broaden investigations into brain plasticity, says David Dietz, PhD, one of the paper's co-authors, an assistant professor of pharmacology and toxicology at UB. In addition, adds Karen Dietz, the work has implications for future questions regarding MS and other myelin disorders. "This research suggests that maybe recovery from an MS episode might be enhanced by social interaction," she says. "This opens another avenue of investigation of how mood and myelin disorders may interact with one another." Major funding for the research came from the National Institutes of Health.
Music and Early Language Acquisition
Brandt A, Gebrian M, Slevc LR. Front Psychol. 2012;3:327. doi: 10.3389/fpsyg.2012.00327
Language is typically viewed as fundamental to human intelligence. Music, while recognizedas a human universal, is often treated as an ancillary ability – one dependent on or derivative of language. In contrast, we argue that it is more productive from a developmental perspective to describe spoken language as a special type of music. A review of existing studies presents a compelling case that musical hearing and ability is essential to language acquisition. In addition, we challenge the prevailing view that music cognition matures more slowly than language and is more difficult; instead, we argue that music learning matches the speed and effort of language acquisition. We conclude that music merits a central place in our understanding of human development.
Playing "Duck Duck Goose" with Neurons: Change Detection through Connectivity Reduction
Tian X, Huber DE. Psychol Sci. 2013 Jun 1;24(6):819-27. doi: 10.1177/0956797612459765. Epub 2013 Apr 9.
Reduced connectivity between sending and receiving neurons (i.e., synaptic depression) may facilitate change detection by reducing responses for recently viewed objects so new objects can be highlighted. In the experiment reported here, we investigated high-level change detection following semantic satiation, which is the loss of meaning following repetition of a word. A
408 Literature Calling
computer simulation of a word-reading neural network with synaptic depression identified key predictions of connectivity reduction. A dynamic-causal-modeling analysis of magnetoencephalography (MEG) responses collected during a category-matching task identified connectivity reduction between a cortical region related to orthography and a cortical region related to semantics as the cause of the reduced MEG response to a repeated word. As predicted, prior repetitions of a category-matching word presented immediately after the repeated word enhanced semantic novelty, as measured with the M400 component. These results demonstrate that a combination of neural-network modeling and connectivity analyses can reveal the manner in which connectivity fluctuations underlie cognitive functions.
Small Quantities of Marijuana Protect Against Brain Damage
Ephrati A. June 9th, 2013 in Health » Israel.
Researchers from the Sackler Faculty of Medicine at Tel Aviv University found that a very low dose of the active ingredient in marijuana (THC) may protect brain cells before and after brain injury, and can also protect against the development of cardiac damage. The research was published in the journal Experimental Brain Research. In the last decade, numerous studies have been conducted on marijuana’s therapeutic properties. It is well known that medical cannabis is used to alleviate the suffering of people with serious diseases including cancer and post-traumatic stress disorder – helping them cope with pain, insomnia, lack of appetite and other symptoms. Professor Joseph Sarne, who is responsible for the research along with Professor Edith Hochhauser of the Felsenstein Medical Research Center, and the Rabin Medical Center, has found that a minimal dose of THC, marijuana’s psychoactive ingredient, protects the brain from long- term cognitive damage. This works to varying degrees, and protects against damage that may be caused by lack of oxygen, drug use or other complications. Triggering the brain’s natural protection In previous studies, researchers injected high doses of THC into subjects in a very short time: up to four hours before or after brain injury. Professor Sarne’s study however, shows that a small dose of THC, 1000 times smaller than the quantity found in a regular marijuana cigarette, injected into mice prevents the development of brain damage. According to him, the tiny dose activates the brain’s protective abilities, including increased neural growth that protects nerve cells in the brain, and preserves cognitive abilities over time. “This treatment is safe and effective in many cases of brain injury in humans,” he says. “Our treatment has several important benefits,” concludes Sarne. “First of all, we are considering a long-term period, which allows treating damage after it has occurred and prevents damage that could occur in the future. Additionally, due to the lower dosage, the method is also safe to use as a preventative treatment over time, and for different chronic conditions.”
Dynamics of Hippocampal Neurogenesis in Adult Humans
Spalding KL, Bergmann O, Alkass K, Bernard S, Salehpour M, Huttner HB, Boström E, Westerlund I, Vial C, Buchholz B, Possnert G, Mash DC, Druid H, Frisén J. Cell. 2013;153(6);1219-27.
Adult-born hippocampal neurons are important for cognitive plasticity in rodents. There is evidence for hippocampal neurogenesis in adult humans, although whether its extent is sufficient to have functional significance has been questioned. We have assessed the generation of hippocampal cells in humans by measuring the concentration of nuclear-bomb-test-derived 14C in genomic DNA, and we present an integrated model of the cell turnover dynamics. We found that a large subpopulation of hippocampal neurons constituting one-third of the neurons is subject to exchange. In adult humans, 700 new neurons are added in each hippocampus per day,
Literature Calling 409 corresponding to an annual turnover of 1.75% of the neurons within the renewing fraction, with a modest decline during aging. We conclude that neurons are generated throughout adulthood and that the rates are comparable in middle-aged humans and mice, suggesting that adult hippocampal neurogenesis may contribute to human brain function.
International Association of Functional Neurology and Rehabilitation
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POSTER PRESENTATION REQUIREMENTS FOR 2013 ANNUAL CONFERENCE OCTOBER 10-13, 2013 PHOENIX, AZ
• Abstracts must be original and must not be or have been published or presented at any other meeting prior to the congress.
• Abstracts must be submitted in English.
• Abstracts must be received by the announced deadline. Abstracts received after the deadline will not be considered.
• The presenting author is required to ensure that all co-authors are aware of the content of the abstract before submission.
• Presenting author's contact details must be included. (Email address, postal address, daytime and evening phone number, author and co-authors' details, full first and family name(s)) Authors' names must be in upper and lower case.
• Affiliation details (department, institution, hospital, city, state, country) must be included.
• Abstract title must be limited to 20 words in upper case.
• Abstract text must be limited to 250 words, including acknowledgements.
• Abstracts should clearly state: background and aims, methods, results, conclusion.
• Use only standard abbreviations. Place special or unusual abbreviations in parentheses after the full word appears the first time. Use generic names of supplements or drugs. Do not use product identifiers. Express numbers as numerals.
• Case studies are of real cases and all identity to a patient must be kept confidential. Do not use names or identifying initials.
• Tables, graphs and images:
• A maximum of 3 tables of up to 10 rows x 10 columns can be included per abstract.
• Each image included in the abstract is worth 30 words. A maximum of 3 images can be included per abstract.
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• All accepted poster abstracts will be printed in the conference issue of the Journal of Functional Neurology, Rehabilitation and Ergonomics.
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Dr. Gerry Leisman F.R. Carrick Research Institute 2487 S. Gilbert Rd. #106-116 Gilbert, AZ 85295 Phone: (480) 926-1115 Email: [email protected] Web: www.frcarrickresearchinstitute.org
The International Association for Functional Neurology and Rehabilitation was founded in 2010 to promote, protect, and advance interdisciplinary scientific and clinical Functional Neurology and Rehabilitation Sciences at the national and international levels. We plan to be one of the fastest- growing, most respected and diverse organizations in the field world-wide.
MEMBER BENEFITS
2013-2014
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IAFNR-Journal – Functional Neurology, Rehabilitation, and Ergonomics published by Nova Science Publishers, Inc. with Drs. Gerry Leisman and Robert Melillo as Editors-in-Chief.
Stay up-to-date on the latest scientific research in Functional Neurology, as well as reports of trends in the field, special issues on pertinent topics, abstracts of the annual conference, and timely news of organizational activities. The journal will be published four times yearly.
The aim and scope of this interdisciplinary journal is to provide a forum for the fields of Functional Neurology, Rehabilitation Sciences, Neuropsychology, Clinical Neurology, Human Factors and Ergonomics, and vocational assessment and training to present critical ideas, theories, proof-of- concept for technology solutions, and data-based evaluative research to facilitate more effective functional development in children and adults.
FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to Functional Neurology, Man-Machine Interaction, Rehabilitation Sciences, brain- behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome.
FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation.
IAFNR-Annual Convention – Our 4th Annual Convention in Phoenix, Arizona will take place October 10-13, 2013. Please contact us for more information and to register for the event!
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[ ] Sustaining Member° [ ] Sustaining Member and Fellow°
*Fellowship status is granted by the IAFNR in recognition of significant and sustained contribution to the field of Functional Neurology and Rehabilitation Sciences of greater than ten years.
+Life membership provides IAFNR membership at the appropriate grade of Member and/or Fellow status for life with the payment of a single membership fee indicated below and never having to pay dues, the journal subscription will be included for life.
°Sustaining membership and/or fellowship is obtained by a multiyear dues payment as indicated below.
PAYMENT INFORMATION
[ ] Check enclosed made payable to: International Association for Functional Neurology and Rehabilitation (IAFNR)
Please Charge my: [ ] Visa [ ] MasterCard [ ] American Express
Card Number: ______
Exp Date: ______CVV: ______Billing Zip Code: ______
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OPTIONAL DONATION TO RESEARCH
• Please charge my charge card $______in monthly installments (for donations to the F. R. Carrick Institute only-see below).
MEMBERSHIP CATEGORIES
[ ] 3 Year Member (through 12/31/15) $750
[ ] 2 Year Member (through 12/31/14) $500
[ ] 1 Year Member (including FNRE journal subscription)
JOURNAL SUBSCRIPTION TYPE (PLEASE ONLY CHOOSE ONE)
[ ] Hard Copy $295
[ ] Electronic Copy as .pdf $295
[ ] Student $175 (including Postdoc/intern/resident)
[ ] Retired (Over 65) $195 [ ] Retired (No journals) $50
[ ] Spouse Member (No journals) $100
Spouse’s Name: ______
[ ] Lifetime Member $5,000
[ ] Optional contribution to the F. R. Carrick Institute $ ______(Optional contributions may be made in installments – see above)
Please send your remittance to any of the following:
Membership Department International Association of Functional Neurology and Rehabilitation 2487 S. Gilbert Road, Suite #106-116 Gilbert, AZ 85295, USA Fax: 1-480-813-1868 Email: [email protected]
AIM AND SCOPE OF THE JOURNAL
The aim and scope of this interdisciplinary journal is to provide a forum for the fields of biomedical and rehabilitation engineering, neuropsychology, clinical neurology, human factors and ergonomics, and vocational assessment and training to present critical ideas, theories, proof-of-concept for technology solutions, and data-based evaluative research to facilitate return to work or more effective functional development in children and adults.
FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to functional neurology, man-machine interactions, rehabilitation sciences, brain-behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome.
FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation.
Description of the Fields Covered
Assessment & Rehabilitation in Neurological Disorders
Diseases and trauma of the brain Cognitive, language, motor, sensory (e.g. visual, auditory, pain, vestibular, etc) and behavioral disorders Developmental disabilities Autism in childhood and adults Diseases and trauma of the spinal cord Neuropathy, myopathy, and peripheral nerve lesions Diseases and trauma impacting on vestibular function
Assessment & Rehabilitation in Orthopedic and Musculoskeletal Disorders
Limb disease, trauma, and amputation Rheumatic diseases; osteoporosis Back and neck pain
Assessment & Rehabilitation in Other Specific Populations
Geriatric rehabilitation Pediatric rehabilitation Special medical conditions (e.g., heart disease; respiratory disorders; cancer; burns; vegetative state)
Topics of General Interest in P&RM
Organization and management of rehabilitation services: rehabilitation in the framework of hospitalization and in the community; quality control in rehabilitation; vocational rehabilitation.
Scope of the specialty: educational needs; ethical and medico-legal aspects; role for alternative/complementary medicine practices in P&RM.
Functional assessment & outcome measurement at various levels: impairment; disability (activity); handicap (participation); quality-of-life (QOL); WHO-ICF system.
Management of commonly encountered disabling conditions: pain; sexual disability; spasticity; postural instability & recurrent falls; wounds; sleep disorders; disability related emotional disorders.
Other topics of general interest in P&RM: secondary and tertiary prevention in medical rehabilitation; nursing of disabled persons; sports medicine and sports for the disabled; rehabilitation of terror victims; electrodiagnosis; kinesiology; walking analysis; movement analysis; posturography; orthotic devices; advanced technologies in P&RM; augmentative devices; neuromuscular electrical stimulation; biofeedback; ergonomic considerations in the home and workplace of disabled persons.
Rationale for Why the Journal Is Needed
The field of Rehabilitation does not presently exist as a cohesive discipline. Rehabilitation specialists define themselves as neurologists, practitioners of physical medicine and rehabilitation, vocational experts, engineers, psychologists, educators, social workers, physical therapists, occupational therapists and the like. The intrinsic cross-disciplinary nature of the rehabilitation process and the requirement for clinical-driven applied and basic science is not represented in any presently published journal, or for that matter, professional organization.
The International Association of Functional Neurology and Rehabilitation and the F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neuroscience, the host organization and research institution for the journal FNRE, is addressing the foregoing by training interdisciplinary rehabilitation professionals whose dissertations also require patent and product development, the establishment of cross-disciplinary research laboratories and projects, the transfer of technology into community based services such as free medical equipment and services for those in need of getting to or back to work, regional clinical program integration systems, and international academic and research cooperative agreements. It is expected that the proposed journal will strongly reflect the structure and philosophy of science and practice.
Description of the Peer Review Process
Papers will be solicited through the organs of fields impacting on rehabilitation science. Peer review will be performed on each paper but will be blind. Periodically, papers linking a particular cogent theme applied to rehabilitation will be compended within a single issue and published in book form. Papers will be ranked as accepted without revision, accepted but with minor revision, requiring major rework and an additional review, or rejected. We do desire to create dialogue within the rehabilitation community, and reviewer’s comments, when appropriate, will be included with the published paper.
INSTRUCTIONS FOR AUTHORS
Manuscripts for the Journal of Functional Neurology, Rehabilitation, and Ergonomics (FNRE) may be submitted to the Editor-in-Chief at the F. R. Carrick Institute for Clinical Ergonomics, Rehabilitation, and Applied Neurosciences (CERAN), 647 Franklin Avenue, Garden City New York 11530 USA. Articles must also be submitted by email: to [email protected].
Type of Manuscripts Accepted
FNRE accepts review papers, articles of original research, data-based and controlled case studies pertaining to Functional Neurology, Man-Machine Interaction, Rehabilitation Sciences, brain- behavior relationships, and in applied cognitive neuroscience that relate to translational research. Engineering proof-of-concept applied to functional neurology as ergonomics are also welcome.
FNRE also welcomes commentary on either the review papers or on original research as the journal intends to be an archival source of discussion of new advances in rehabilitation.
Manuscript Requirements
[1] Manuscripts must be written in English and be typewritten with double spacing throughout the entire text and with margins of at least 2.5 cm. An original on 8½" 11" heavy duty white bond paper and two duplicate copies should be provided. An email copy as a file attachment in MS WORD for WINDOWS or a text file must also be submitted by email to the above indicated email address.
[2] Each manuscript must have a title (first) page that includes the title, the authors’ full names, the laboratory or origin of the data, a running head, a list of 6-8 key words and the name, address and FAX number of the person to whom correspondence and proofs should be mailed.
[3] Full length review articles should be divided into sections in the following order: Synopsis, Body (with relevant sub-headings), Acknowledgements, and References. Short notes should contain no sections. Number pages consecutively.
[4] Abbreviations should be defined when first used by placing in parentheses after the full term; e.g., acetylcholin-esterase (AChE).
[5] References will follow the "Uniform requirements for manuscripts submitted to biomedical journals" format (also called the Vancouver style, see http://www.icmje.org/index.html) determined by the International Committee of Medical Journal Editors and used for PubMed/Medline journals. Abbreviations of journal names should conform to the Index Medicus.
References in specific
References (maximum of 25 for articles, 40 for review articles and 5 for case reports) should be cited consecutively (enclosing the number in parenthesis) in the text and listed in the same numerical order at the end of the paper. The Vancouver Style is required (http://www.icmje.org/).The first reference in the text should be (1) and the next (2) and so forth and then listed accordingly at the end of the paper after discussion or after acknowledgements.
Examples:
Journal article Damianopoulos EN, Carey RJ. Pavlovian conditioning of CNS drug effects: a critical review and new experimental design. Rev Neurosci 1992; 3: 65-77. Note: no comma in between name an initials, no italics or bold, no capitol letters in title except at the begining of sentence, no period between jorunal name and year, year;vol:page-page without space betwwen and last page number shortened. All authors must be cited. Journal name abbreviated according to the international standard found at PubMed Journal Database. (http://www.ncbi.nlm.nih.gov/sites/entrez?db=journals)
Book Melillo R, Leisman G Neurobehavioral disorders of childhood: An evolutionary approach. New York: Kluwer, 2004.
Book chapter Leisman G, Melillo R. Cortical asymmetry and learning efficiency: A direction for the rehabilitation process. In: Randall SV Learning disabilities: New research. Hauppauge, NY: Nova. 2006: 1-24.
Research report Shek DTL. A positive youth development program in Hong Kong. Hong Kong: Soc Welfare Pract Res Centre, Univ Hong Kong, 2004. (Chinese)
Unpublished thesis Kaplan SJ. Post-hospital home health care: The elderly’s access and utilization. Dissertation. St Louis: MO: Washington Univ, 1995.
Internet materials / publication Internet journal: Morse SS. Factors in the emergence of infectious diseases. Emer Infect Dis 2006;5:1.
Internet material Morse SS. Factors in the emergence of infectious diseases. Emer Infect Dis 2006. Accessed 2007 Jun 05. URL: http://www.cdc.gov/ncidod/EID/eid.htm
[6] Case studies. FNRE will publish limited case-study material as long as the appropriate format is followed including the format for references, figures and tables. The conclusions must be supportable by laboratory-based evidence presented within the case study. The authors of case study material are strongly encouraged to study the following websites that may be useful in increasing the likelihood of the material being published (e.g. http://www.bgfl.org/bgfl/18.cfm?s=18&m=473&p=261,index or http://www.bmhlinguistics.org/joomla2/guidelines-for-writing-case-studies).
[7] Copyright responsibility. This is the author’s own responsibility. If any figure(s), illustration(s), table(s) or extended quotation(s) etc. are to be taken from material(s) previously published, the author(s) must secure reproduction permission from the copyright owner. Only original papers will be accepted, and copyright of published papers will be retained by the publisher.
[8] Transfer of author copyright. Please include a signed release of copyright to Nova Publishers with your manuscript. Include the title of the article being sub-mitted, as well as the date. Include the signatures of co-authors.
[9] Manuscript editing. All accepted manuscripts are subject to manuscript editing.
[10] The original manuscript and diagrams will be discarded one month after publication unless there is a written request for the material to be returned to the author.
Indexed and abstracted by: The journal will be indexed and abstracted by BIOSIS, EMBASE/Excerpta Medica, Index Medicus, Neuroscience Citation Index, Reference Update, Research Alert, IEEE/EMBS.
Conflict-of-Interest Statement Public trust in the peer review process and the credibility of published articles depend in part on how well conflict of interest is handled during writing, peer review, and editorial decision making. Conflict of interest exists when an author (or the author's institution), reviewer, or editor has financial or personal relationships that inappropriately influence (bias) his or her actions (such relationships are also known as dual commitments, competing interests, or competing loyalties). These relationships vary from those with negligible potential to those with great potential to influence judgment, and not all relationships represent true conflict of interest. The potential for conflict of interest can exist whether or not an individual believes that the relationship affects his or her scientific judgment. Financial relationships (such as employment, consultancies, stock ownership, honoraria, paid expert testimony) are the most easily identifiable conflicts of interest and the most likely to undermine the credibility of the journal, the authors, and of science itself. However, conflicts can occur for other reasons, such as personal relationships, academic competition, and intellectual passion.
- International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals") - February 2006
Functional Neurology, Rehabilitation, and Ergonomics requires all authors and reviewers to declare any conflict of interest that may be inherent in their submissions.
Statement of Informed Consent Patients have a right to privacy that should not be infringed without informed consent. Identifying information, including patients' names, initials, or hospital numbers, should not be published in written descriptions, photographs, and pedigrees unless the information is essential for scientific purposes and the patient (or parent or guardian) gives written informed consent for publication. Informed consent for this purpose requires that a patient who is identifiable be shown the manuscript to be published. Authors should identify Individuals who provide writing assistance and disclose the funding source for this assistance.
Identifying details should be omitted if they are not essential. Complete anonymity is difficult to achieve, however, and informed consent should be obtained if there is any doubt. For example, masking the eye region in photographs of patients is inadequate protection of anonymity. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.
- International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals"_ - February 2006
Statement of Human and Animal Rights When reporting experiments on human subjects, authors should indicate whether the procedures followed were in accordance with the ethical standards of the responsible committee on human
experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). If doubt exists whether the research was conducted in accordance with the Helsinki Declaration, the authors must explain the rationale for their approach, and demonstrate that the institutional review body explicitly approved the doubtful aspects of the study. When reporting experiments on animals, authors should be asked to indicate whether the institutional and national guide for the care and use of laboratory animals was followed.
- International Committee of Medical Journal Editors ("Uniform Requirements for Manuscripts Submitted to Biomedical Journals") - February 2006
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2008, Jun;26(6):854-9. Pain Autoimmunity modulation Jorgensen WA, et al. Electrochemical therapy of pelvic pain: effects of PEMF Nindl G, et al. Experiments showing that electromagnetic fields can be on tissue trauma. Eur J Surg Suppl. 1994;(574):83-6. used to treat inflammatory diseases. Biomed Sci Instrum. 2000;36:7-13. Bone healing Migraines Chang K, et al. Effects of different intensities of extremely low frequency Pelka RB, et al. PEMF for migraine and other headaches: a double-blind, PEMFs on formation of osteoclast-like cells. Bioelectromagnetics. 2003 placebo-controlled study. Adv Ther. 2001 May-Jun;18(3):101-9. Sep;24(6):431-9.
Depression Wound healing Sandyk R. Suicidal behavior is attenuated in patients with multiple Patiño O, et al. [Effect of magnetic fields on skin wound healing. Experimenta sclerosis by treatment with electromagnetic fields. Int J Neurosci. 1996 study]. Medicina (B Aires). 1996;56(1):41-4.
Oct;87(1-2):5-15. Multiple Sclerosis Balance Lappin MS, et al. Effects of PEMF therapy on multiple sclerosis fatigue and Thomas AW, et al. Human subjects exposed to a specific (200 microT) quality of life: a double-blind, placebo controlled trial. Altern Ther Health Med. PEMFs: effects on normal standing balance. Neurosci Lett. 2001 Jan 2003 Jul-Aug;9(4):38-48.
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