ARTICLE IN PRESS Hypothesis: The Chaos and Complexity Theory May Help our Understanding of Fibromyalgia and Similar Maladies Manuel Martinez-Lavin, MD, Oscar Infante, DVM, and Claudia Lerma, PhD Background: Modern clinicians are often frustrated by their inability to understand fibromyalgia and similar maladies since these illnesses cannot be explained by the prevailing linear-reductionist medical paradigm. Objective: This article proposes that new concepts derived from the Complexity Theory may help understand the pathogenesis of fibromyalgia, chronic fatigue syndrome, and Gulf War syndrome. Methods: This hypothesis is based on the recent recognition of chaos fractals and complex systems in human physiology. Results: These nonlinear dynamics concepts offer a different perspective to the notion of homeostasis and disease. They propose that the essence of disease is dysfunction and not structural damage. Studies using novel nonlinear instruments have shown that fibromyalgia and similar maladies may be caused by the degraded performance of our main complex adaptive system. This dysfunction explains the multifaceted manifestations of these entities. Conclusions: To understand and alleviate the suffering associated with these complex illnesses, a paradigm shift from reductionism to holism based on the Complexity Theory is suggested. This shift perceives health as resilient adaptation and some chronic illnesses as rigid dysfunction. © 2007 Elsevier Inc. All rights reserved. Semin Arthritis Rheum xx:xxx Keywords: fibromyalgia, chronic fatigue syndrome, chaos, Complexity Theory, irritable bowel, Gulf War syndrome, neuropathic pain, complex adaptive systems, autonomic nervous system The whole is more than the sum of its parts—Aristotle M odern clinicians are often frustrated by their inability to understand common complex syndromes such as fibromyalgia (FM) and similar maladies because such illnesses cannot be properly explained through the prevailing linear-reductionist medical paradigm. This poor understanding often severs the patient–physician relationship and consequently results in persistent patient suffering and dissatisfaction. This article proposes that new paradigms derived from the Complexity Theory may help us better understand these multifaceted syndromes. The focus of the proposal is on FM, but the hypothesis may be also relevant to related overlapping conditions such as the chronic fatigue, Gulf War, and irritable bowel syndromes. The hypothesis is based on the recent recognition of chaos frac- National Institute of Cardiology, Mexico City, Mexico. Address reprint requests to Manuel Martinez-Lavin, MD, National Institute of Cardiology, Juan Badiano 1, 14080 Mexico City, Mexico. E-mail: mmlavin@ infosel.net.mx. 0049-0172/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2007.04.003 tals and complex systems in human physiology (1,2). These nonlinear dynamics concepts offer a different perspective to the notion of health and disease. Studies using nonlinear methods have suggested that FM and similar maladies may be caused by the degraded performance of our complex adaptive systems (3). METHODS New concepts derived from the Complexity Theory are reviewed. Based on this theory, a new perspective on FM is offered. RESULTS The Complexity Theory Scientists frequently view the universe as a linear place, one where the simple rules of cause and effect apply, and where the strength of the response is proportionate to the magnitude of the stimuli. This is analogous to the way one studies a big machine and takes it apart to understand its components, and in that manner, understands the whole. However, after the introduction 1 2 ARTICLE IN PRESS of computer modeling and simulation, it became clear that the universe is full of systems that do not follow this linear behavior. In such networks, proportionality does not hold, and small changes can have striking and unanticipated “chaotic” effects. These systems cannot be understood by analyzing their individual components (1,2). As scientists of all disciplines explored these phenomena, a new field of study emerged, The Complexity Theory, which is based on relationships, emergence, patterns, and iterations. The roots of this theory are found in Poincaré’s “restricted 3-body problem” in the early twentieth century (4) and on the cybernetic model developed by Wiener and Rosenblueth (5). As a consequence of this emerging knowledge, novel concepts appeared. Some of them are essential to comprehend this hypothesis (1,2). Complex systems are macroscopic collections of simple (and often nonlinearly) interacting units that are endowed with the ability to evolve and adapt to a changing environment. The control of a complex system tends to be highly dispersed and decentralized with negative (damping) and positive (amplifying) feedback loops. These features provide resilience in the face of environmental perturbation, thus the term complex adaptive systems. Examples of complex systems are democratic societies, stock markets, ant colonies, the immune system, and the autonomic nervous system (ANS). Emergence is the process of complex pattern formation from more basic constituent parts or behaviors. An example is the interactions between a great number of neurons producing a human brain capable of thought. The constituent neurons are not individually capable of thought. Emergent structures are more than the sum of their parts because the emergent order will not arise if the various parts are simply coexisting; the interaction of these parts is central. Chaos refers to apparently random unpredictable variability that can arise from the operation of complex systems. The unpredictability comes from a property known as “sensitivity to initial conditions,” which means that small changes or perturbations can produce large transformations in the behavior of the system in the long term (“the butterfly effect”). Chaotic systems can also have bifurcations (sudden changes in behavior in response to small change in 1 parameter or property of the system). Chaotic behavior can be seen in different networks of the human body such the nervous or immune systems. Fractal is a geometric concept related to chaos. A fractal is an object composed of subunits that resemble the larger scale structure, a property known as “self-similarity.” Most important human structures have fractal anatomies. Perhaps the best example is the pulmonary circulation. The pulmonary artery branches thousands of times before reaching the capillary bed. The microscopic pulmonary subunits and its larger counterparts are shaped identically. Fractal structures are extremely efficient for transporta- The Chaos and Complexity Theory and fibromyalgia tion, distribution, and exchange. Fractal also has a time domain concept that is applied to complex processes lacking a single time scale (1,2). DISCUSSION The Concept of Disease: Time to Amend the Paradigm The prevailing paradigm considers medicine to be a linear scientific discipline. It views the human body as a big machine that can be understood by carefully examining its parts. This reductionist approach has been useful in understanding many “linear” diseases. The cause– effect of an infection or a tumor causing organ damage led to the very useful clinical–pathologic correlation. Such educational exercises are still the main event in many medical centers and medical journals. Therefore, current scientific thinking demands that a “true” disease must have structural (or at least serological) alteration. According to this view, if a clinical syndrome (the effect) does not have an underlying anatomic alteration (the cause), then either the syndrome is nonexistent or the illness belongs to the realm of psychiatry. This sophism derives in part from Rene Descartes’ philosophy that distinguished between res cogitans and res extensa. The former referred to the soul or mind and was said to be essentially “a thing which thinks.” The latter was the material stuff of the body. Its primary characteristic was extension: it occupied space and was therefore amenable to measurement (6). An alternative view envisioned by Claude Bernard in the nineteenth century, and supported by the Complexity Theory, is to define disease as dysfunction. Structural damage without dysfunction is not disease. Dysfunction with or without structural damage is disease. Thus disease can be broadly defined as a bio-psycho-social alteration that generates suffering (7) and/or decreases longevity. Disorder Is Healthy, Uniformity Leads to Disease Conventional medical wisdom contends that diseases arise from deviances of the orderly machine-like systems of the body. The Complexity Theory challenges this view, suggesting instead that the opposite is true (2). A system in idle equilibrium does not have the internal dynamics enabling it to respond to its environment and will ultimately die. A system in deterministic chaos may have resilience in the face of external stressors. A good example of healthy chaotic behavior is the constant variation of the heart beat (8). In normal circumstances, the heart rate is not fixed, rather it varies constantly in a seemingly random way, particularly during resting conditions. Irregularity of the heart beats follows a circadian rhythm with increased beat dispersion during sleep (9). Analyses of the variability of heart rate, looking at trajectories in the space, and self-similarity properties have revealed chaotic behavior (9,10). ARTICLE IN PRESS M. Martinez-Lavin, O. Infante, and C. Lerma Healthy individuals have widely varying heart beats. In the presence of disease or aging, the system loses complexity and this variability decreases (9). In elderly persons, altered fractal scaling properties of heart rate are a predictor of sudden death (11). The Autonomic Nervous System, a Prototype of a Complex Adaptive System The ANS is an intricate network in vertebrate animals that serves to regulate the most important body functions, including the vital signs. The term “autonomic” reflects the fact that the system is not governed. Blood pressure and heart rate (among many other variables) are finely tuned by harmonious sympathetic–parasympathetic interactions that take place through internal feedback paths. These 2 branches act as amplifying or damping feedback loops constantly adapting the body to environmental changes. The ANS is the interface between mind and body. Autonomic activation transforms emotions like fear or anger into biological functions like paleness, pupil dilation, and tachycardia, among many other reactions. Therefore this network constitutes the main element of the stress response system (12). The ANS has all the features of a complex adaptive system. The performance of this complex adaptive system is very difficult to assess. Static blood or urine measurements of autonomic neurotransmitters do not reflect the dynamic nature of the ANS. The introduction of a nonlinear instrument (heart rate variability analysis) made it possible to follow and estimate the chaotic behavior of this network (9,10). Heart rate variability is under the control of the ANS. Variations in heart period are largely dependent on vagal modulation. Spectral methodology applied to this variability is capable of defining and quantifying sympathetic and parasympathetic influences on the sinus node (13). The Fibromyalgia Problem FM is a chronic syndrome characterized by widespread pain and widespread allodynia. Other distinctive features are paresthesias, sleep disturbances, chronic fatigue, anxiety, and irritable bowel (14). The syndrome affects between 2 and 3% of the general population, the overwhelming majority (⬇90%) being women. FM severely diminishes the quality of life of the afflicted persons (15) and imposes a high economic burden on the society (16). Therefore the condition represents a major health problem for contemporary women. FM strongly overlaps with other prevalent (and controversial) clinical conditions such as the chronic fatigue and Gulf War syndromes. Common to these illnesses is the presence of chronic nonnociceptive pain, unexplainable fatigue, sleep disorders, cognitive impairment, anxiety, and depression (17,18). Irritable bowel and temporoman- 3 dibular joint syndrome are, in many instances, localized expressions of the above-mentioned maladies. There are no consistent anatomical or serological abnormalities in FM and similar syndromes. This lack of structural damage led some clinicians to argue that the illnesses were nonexistent. Nevertheless, it is an undisputed fact that physicians are often consulted by persons complaining of vexing pain and fatigue that cannot be explained by any other diagnosis. Autonomic “Decomplexification” in Fibromyalgia and Related Illnesses Different groups of investigators have reported decreased heart rate variability in patients with FM, as well as a monotonous circadian rhythm pattern (2,19-25). These findings are the most consistent alterations so far described in FM. These anomalies can be interpreted as a “decomplexification” of the ANS, with persistent inflexible circadian sympathetic predominance. Similar heart rate abnormalities have been reported in conditions that overlap with FM such as irritable bowel (26,27), chronic fatigue (28), and Gulf War syndrome (22,29). It has been suggested that such autonomic dysfunction explains the multifaceted alterations in FM (30) and that the main complaint of the syndrome (chronic pain) is sympathetically maintained. Emerging evidence suggests that the unbending sympathetic hyperactivity could lead to neuroplasticity, establishing abnormal connections between the sensory neurons and the sympathetic nervous system. This type of neuroplasticity is a well-established phenomenon in the animal model (31). The hormonalinfluenced difference in the behavior of the ANS in women versus men (32) could theoretically explain the marked gender difference in the prevalence of FM. New genomic data reinforce the proposal of FM as sympathetically maintained pain. Catecholamines are the sympathetic neurotransmitters. Healthy women with particular gene polymorphism associated with defective catecholamine clearing enzymes have increased susceptibility to pain (33). The mechanisms whereby a breakdown of the ANS may produce other distinctive FM manifestations have been discussed previously (30). This new information suggests that in FM and related conditions there is degraded performance of the body’s main complex adaptive system, the ANS. The reason for this decomposition remains to be established. It is possibly a combination of environmental and genetic factors. Modern societies have become more stressed (12); they confront a more hostile environment. An example of the new challenges are alterations in circadian rhythmicity. For thousands of years, day and night cycles were harmonious with external cues. Light, noise, and activity during the day; darkness, rest, and quiet at night. Industrialization has clearly disturbed this harmony. Nowadays there is light, activity, and noise at night. Another example of 4 ARTICLE IN PRESS modern stressful situations can be seen in monotonous working conditions. It has been shown that disability in FM is associated with repetitive manual tasks, low income, or inability of affected persons to influence their working environment (34). These and many other stressors of modern societies are likely to have a negative impact on human health. Individuals that are more susceptible to environmental changes (arguably women with defective catecholamine-clearing enzymes) would, thereby, be more prone to become ill. Failed Reductionist Therapies for Fibromyalgia Therapy for FM and related illnesses has followed a linearreductionist paradigm. Conventional physician–patient interaction usually results in tests seeking to probe each of the patient’s symptoms. The information derived from these series of tests is typically nonrevealing. Nevertheless, physicians will write a prescription for several drugs intended to improve each one of the patient’s symptoms. The results are often frustrating. Symptoms may not improve and patients will often end up polymedicated with additional suffering caused by the untoward effects of the drugs. Interventions that have proven to be partly effective in these complex syndromes are those multidisciplinary programs that consider a person as a whole, specifically, education, cognitive behavioral therapy, and several types of exercise programs (35,36). These interventions improve the resting autonomic tone (37). It is clear that current therapies for FM and related illnesses are far from adequate. There is much to be learned about the pathogenesis of these syndromes to offer more coherent therapy. Meanwhile it seems reasonable to use a scientifically holistic approach including education, mind– body interventions, and the judicious use of medications. These interventions can be better delivered in clinics specifically designed for this purpose (36). In conclusion, FM and similar maladies are clinical realities. Attitudes such as denial, scorn, or rejection are unacceptable in a scientific– humanistic medical environment. Reductionist approaches have failed to comprehend these illnesses. These chronic syndromes could be better understood on a bio-psycho-social context rather than attempting to explain such diverse symptoms by the presence of discrete anatomical or serological alterations. The use of nonlinear instruments based on the Complexity Theory has revealed degraded complex adaptive systems in FM and related syndromes. Faulty performance of the ANS provides a coherent explanation for the multifaceted manifestations of these maladies. Understanding these syndromes calls for a shift in paradigms, from reductionism to holism based on the Complexity Theory. This shift would recognize chaos, fractals, and complex systems as essential elements in human physiology and would offer a different perspective in which The Chaos and Complexity Theory and fibromyalgia health is perceived as resilient adaptation, and some chronic illnesses are perceived as rigid dysfunction. REFERENCES 1. Glass L, Mackey MC. 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