Neurobiological Principles In The Etiopathogenesis Of Disease When Diseases Have A Head

© Med Sci Monit, 2008; 14(11): RA PMID: XXXXXXXX

Received: 2008.XX.XX Accepted: 2008.XX.XX Published: 2008.XX.XX

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Neurobiological principles in the etiopathogenesis of disease: When diseases have a head Boris Mravec1,2, Katarina Ondicova1, Zuzana Valaskova1, Yori Gidron3, Ivan Hulin1 1

Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava, Slovak Republic Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic 3 School of Health Sciences and Social Care, Brunel University, London, United Kingdom 2

Source of support: This study was supported by the Slovak Research and Development Agency under contract No. APVV-0045-06 and by VEGA grants (1/3422/06, 1/4251/07, 1/4312/07)

Summary There is no doubt that the nervous system is involved in the etiopathogenesis of various pathological states and diseases. Interactions between the nervous, endocrine, and immune systems might represent the anatomical and functional basis for understanding the pathways and mechanisms that enable the brain to modulate the progression of disease. The aim of this article is to encourage us to shift our current opinion of the etiopathogenesis of disease to one of highly complex interactions between peripheral tissues and the brain and in this way introduce new diagnostic and therapeutic approaches.

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arthritis • atherosclerosis • cancer • diabetes mellitus • inflammation • metabolic syndrome • neurobiology • stress

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Boris Mravec, Faculty of Medicine, Institute of Pathophysiology, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovak Republic, e-mail: [email protected]

Current Contents/Clinical Medicine • IF(2007)=1.607 • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts • Index Copernicus

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INFLUENCE OF THE BRAIN ON THE ONSET AND PROGRESSION OF DISEASE Experimental data and clinical observations suggest that psychological (e.g. personality, hopelessness, religiosity, depression) and other factors influenced by brain activity affect the genesis and progression of various human diseases (e.g. cardiovascular, metabolic, inflammatory) [1]. Studies in the field of neuroimmunology and psychoneuroimmunology performed during the last decades might provide some understanding of how the brain influences the genesis and progression of disease. The field of psychoneuroimmunology extended gradually from the traditional clinical entities of infection, autoimmunity, and cancer to attain a broader relevance to inflammation, asthma, and cardiovascular and gastrointestinal disease [2]. In the following sections we shall emphasize recent findings that elucidate the involvement of the brain in the etiopathogenesis of various diseases. Furthermore, we introduce diagnostic and therapeutic approaches based on the interactions between the nervous, immune, and endocrine systems and peripheral tissues affected by pathological processes.

A MATTER OF ARGUMENT : IS IT TIME TO EXTEND OUR CONCEPT OF THE NEUROBIOLOGY OF DISEASE? Current work on the neurobiology of disease focuses mainly on neurological and psychiatric disease. However, recent studies support a different view suggesting that the concept of the neurobiology of disease needs to be expanded to the neurobiology of peripheral tissue diseases [3–9] (“peripheral tissues” are tissues outside the nervous system). These assumptions are based mainly on converging data obtained from psychoneuroimmunological studies indicating that the nervous system is involved in a much broader spectrum of pathological states and diseases than was previously recognized (see, for example, [10-13]).

THE REASONS FOR ACCEPTING A BROADER VIEW OF THE NEUROBIOLOGY OF DISEASE Neuroendocrine-immune interactions as a basis for the neurobiology of peripheral tissue diseases Despite the fact that animals are made of an immense number of cells, the activities of these cells are precisely coordinated by three interwoven regulatory systems: the nervous, endocrine, and immune. It is increasingly clear that the exchange of information between these three systems plays an important role in various physiological as well as pathological states [14]. Neuroendocrine interactions The central nervous system (CNS) controls endocrine cells via the hypothalamic-pituitary axis and by efferent pathways of the autonomic nervous system. Moreover, neuroendocrine cells are present in various peripheral organs (e.g. pancreas, lung, thyroid, liver, prostate, skin). Finally, hormones, neurotransmitters, and other soluble molecules signal the neuroendocrine system, exerting a feed-back control [15]. Neuroimmune interactions There has been a growing appreciation that the immune system can be viewed as a sensory organ that detects patho-

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gens and tissue injury in the internal environment and signals their presence to the CNS during immune activation [16]. Consequently, the neuroendocrine system modulates immune functions at different levels: systematically through the hypothalamic-pituitary-adrenocortical (HPA) axis and hypothalamic-pituitary-gonadal axis, regionally through the release of neurotransmitters in immune organs, and locally through nerve endings and diffuse neuroendocrine cells at the site of different tissues. In turn, mediators released by immune cells (particularly cytokines) signal to the CNS and peripheral nervous system, enabling a bidirectional intersystem communication [15,17]. The multilevel interactions between the nervous, endocrine, and immune systems constitute a basis for the involvement of the CNS in the etiopathogenesis of some pathological states and diseases in which the role of the CNS was previously not recognized or neglected (e.g. atherosclerosis, arthritis, cancer, diabetes mellitus, hemorrhagic shock, ischemia-reperfusion injury, ileus, pancreatitis, sepsis) [18–20]. It is suggested that there is a genetic basis of neuroendocrine-immune-disease interactions [21]. We hypothesize that this genetic basis might predispose some individuals to the development of diseases due to altered interactions between the nervous, endocrine, and immune systems. It may also be possible that certain environmental factors (e.g. toxins, stress) contribute to altering the interactions between these three systems and in this way participate in the etiopathogenesis of peripheral diseases [22,23]. For example, several studies show that exposure of an organism to stress during early developmental periods might alter the reactivity of the HPA axis in adulthood [24,25]. However, it is necessary to note that although our knowledge about how the nervous system functions is expanding rapidly, our understanding of the brain’s role in the etiopathogenesis and progression of various peripheral tissue diseases is probably at its beginning. Neuroendocrine-immune interactions: Wire and wireless connections To understand the mechanisms responsible for the involvement of the CNS in the etiopathogenesis of peripheral tissue diseases, it is necessary to define how the nervous system interacts with the endocrine and immune system. In general, there are two pathways enabling bidirectional communication between these three regulatory systems: wired (neuronal) pathways and wireless (humoral) pathways [26]. These two pathways enable the brain to have a dominant role in the modulation of peripheral tissue activity. The humoral pathways are relatively slow and less informative regarding the location or source of signals, whereas the neural pathways are fast and location-specific.

NEUROBIOLOGY OF PERIPHERAL TISSUE DISEASES Psychoneuroimmunology: integrating the incompatible Whereas research focusing on the involvement of the nervous system in the etiopathogenesis of various diseases can be traced back to the distant past, a description of the pathways enabling the brain to modulate the genesis and progression of disease was vague. A description of the mechanisms relating the “psyche” to certain disorders did not

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take shape until the second half of the 20th century [27]. In his landmark article published in Science, George Engel argued that biological factors such as genetics do not account for all health outcomes; rather, a proper understanding of the etiology and progression of disease must take into account the interactions of psychological and social factors along with biological processes [28]. Health psychology is the domain of psychology predicated on Engel’s ‘‘biopsychosocial model’’ and it encompasses such domains as the effects of psychological and social factors on disease risk, prevention, treatment compliance, morbidity, quality of life, and survival. It was the experimental work of Hugo Besedovsky, George Solomon, and Robert Ader who “integrated the incompatible” and established the scientific basis for a new discipline, psychoneuroimmunology [29]. Psychoneuroimmunology, based on a bidirectional perspective of neuroimmune interactions, provides the understanding of certain complex fundamental mechanisms involved in the biopsychosocial model [27]. Today, psychoneuroimmunology is accepted as a new hybrid discipline and is defined as a study of brain, behavior, and immune system interactions. Furthermore, psychoneuroimmunology provides the framework to investigate the implications of neuroimmune interactions for disease onset and progression. Psychoneuroimmunological studies have shown that positive emotions have positive effects on immune functions, whereas chronic/uncontrollable stressful situations and depression are associated with the suppression of cellular immune functions [30]. Harmful dysregulation of the immune system by stress is mediated by the HPA axis and the sympathoadrenal medullary system. It was shown that stress-induced immune dysregulation can be significant enough to result in health consequences, including reduced immune response to vaccines, slowed wound healing, reactivation of latent herpes viruses, and enhanced risk for more severe diseases [31].

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by the vagus nerve binds to a-7 nicotinic receptors on immune cells and consecutively significantly inhibits the synthesis and release of pro-inflammatory cytokines [38]. In contrast to the HPA axis, this cholinergic anti-inflammatory pathway enables more complex, fast, and location-specific regulation of immune system activity by the nervous system [34]. Research has provided evidence for the profound effects the activated anti-inflammatory efferent pathway of the vagus nerve has on various physiological and pathological conditions (e.g. bacterial sepsis, pancreatitis, ileus, and rheumatoid arthritis) [20]. Some questions regarding the cholinergic anti-inflammatory pathway remain unanswered. For example, the relations between the afferent and efferent vagal fibers are unclear. It is possible that higher CNS centers involved in body homeostasis and neuroendocrine modulation, such as the brainstem and hypothalamus, can regulate the efferent vagal antiinflammatory response to peripheral inflammatory signals. Future studies need to investigate this hypothesis in greater depth. Nevertheless, observations in laboratory animals show impressive effects induced by chemical or electrical stimulation of descending vagal pathways on the progression of inflammation-related pathological conditions (e.g. hypovolemic hemorrhagic shock, ischemia-reperfusion injury, pancreatitis, postoperative ileus, and sepsis [39–43]). These effects indicate the importance of the neural regulation of inflammation and its possible relevance to peripheral inflammatory diseases. Inflammatory processes are also modulated by primary afferent nervous fibers. It was found that these fibers play a role in experimental pancreatitis as well as in a mouse model of diabetes mellitus [44,45]. These and other data indicate that the role of axonal reflexes in inflammatory processes is of importance and may occur by the local secretion of neurotransmitters such as substance P and calcitonin generelated peptide [46].

Neurobiology of inflammatory diseases Cash and Wilder [32] had already proposed the idea of neuroendocrine-immune involvement in the pathogenesis of inflammatory diseases. The role of these interactions in the development of autoimmune diseases is supported by experimental and clinical observations. Observations in patients with brain lesions showed the important role the nervous system had in the etiopathogenesis of inflammatory diseases. In patients who developed scleroderma or rheumatoid arthritis after a hemiplegic stroke, the limb was spared in the paretic side affected by the stroke [33], suggesting a role for neuroendocrine-immune interactions in autoimmune diseases. The relatively recent descriptions of neural anti-inflammatory mechanisms, namely that of the cholinergic anti-inflammatory vagal pathway [34], have significantly contributed to the idea of the brain’s critical role in the modulation of the etiopathogenesis of inflammatory diseases. It was traditionally accepted that the central nervous system modulates the activity of the immune system mainly via the HPA axis and the sympathetic nervous system [35,36]. The role of the peripheral HPA axis-like system (e.g. CRH released from autonomic nerves) is still a matter of debate [37]. However, recent discoveries have proved that acetylcholine released

Reciprocal interactions between the immune and nervous systems are now considered to be the major components of the host response in septic shock. It is suggested that because the central nervous system controls a wide range of physiological functions that are crucial in maintaining homeostasis and orchestrating the host response at the behavioral, neuroendocrine, and autonomic levels, disturbances in any of these adaptive functions may deleteriously influence the course of septic shock [47]. Animal experiments show that several central pathways, namely those converging into the paraventricular hypothalamic nucleus, the central modulator of HPA-axis activity, are activated during sepsis [48]. Disruption of the HPA-axis is a common feature in severe sepsis [47]. Do dysfunctions of these brain structures play an etiological role in sepsis or do they occur as its consequence? Similarly, since the autonomic nervous system is involved in the regulation of immune functions, autonomic dysfunction may be a consequence of the progression of autoimmune diseases or it may directly participate in the etiopathogenesis of autoimmune diseases [49]. What are the possible therapeutic consequences of a neurobiological view of inflammatory diseases? Besides electrical and chemical stimulation of the vagus nerve, it was shown that vagal anti-inflammatory mechanisms might also

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be stimulated by high-fat enteral nutrition or by transcutaneous vagal mechanical stimulation [43,50]. Some studies have reassessed the mechanisms responsible for the anti-inflammatory properties of polyunsaturated fatty acids (e.g. in critically ill patients) in relation to the vagal anti-inflammatory pathway [51]. It is suggested that cholecystokinin (CCK) plays a crucial role in the activation of the vagal antiinflammatory pathway by polyunsaturated fatty acids [50]. The importance of CCK as a transduction signal between fat and the cholinergic anti-inflammatory pathway is also supported by findings that the application of CCK induced the anti-inflammatory reaction, as demonstrated by the reduction of acetic acid-induced colitis in rats. On the other hand, perivagal capsaicin prevented this protective effect of CCK [52]. Suppression of cytokine release via the activation of the vagal anti-inflammatory pathway by the intake of dietary fat might help explain why the trillions of microorganisms that reside in the intestine do not stimulate an exaggerated cytokine response [53]. The data discussed above related to vagal anti-inflammatory effects were obtained only from animal studies. Therefore it is not surprising that there is an intensive effort to investigate the role of the anti-inflammatory effects of the vagus nerve in humans [54]. The possibility that nicotine can treat sepsis in humans was partially addressed by Goldstein et al. [55], who showed that cholinergic agonists inhibit lipopolysaccharide-induced whole blood TNF release ex vivo in patients with severe sepsis. These data indicate that selective activation of a-7 nicotinic receptors might provide a potential therapeutic target to decrease cytokine release in sepsis [55]. The effectiveness of mechanical stimulation of the vagus nerve, activation of cholinergic anti-inflammatory vagal pathways by fatty acids, and the application of a-7 nicotine receptor agonists on inflammation in humans need further investigation.

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idence indicates that the brain’s role in the etiopathogenesis of hypertension is crucial [61–65]. This has also been supported by findings of increased activity in brain centers regulating the functions of the sympathetic nervous system including the A5 noradrenergic nuclei in the pons and raphe nuclei [66], the central role of the brain in salt-sensitive hypertension [67], and alteration of the brain’s reninangiotensin system in hypertension [68]. Findings related to the role of the sympathetic nervous system in hypertension provide the basis for the hypothesis of the sympathetic neurobiology of essential hypertension [69]. It is also suggested that alterations in the sensory innervation of cardiovascular tissues might participate in the development of hypertension [70]. Neuroimaging in humans recently demonstrated correlations between stress-induced increases in blood pressure and enhanced activity in the cingulate, insular, and prefrontal parts of the cortex as well as in the cerebellum [71]. Therefore the concept of the neurobiology of hypertension might include elevated CNS activity in regions that modulate cardiovascular activity, sympathetic dysfunction, as well as altered sensory innervation of cardiovascular tissues.

Neurobiology of cardiovascular diseases

While the role of the brain and the sympathetic nervous system in the etiopathogenesis of hypertension is widely accepted, research concerning atherosclerosis, arrhythmias, and heart failure has focused almost exclusively on the role of the heart and vascular tissues. Nevertheless, recent data suggest that the brain is also involved in the etiopathogenesis of these diseases [72]. The nerves surrounding arteries have long been known to be involved in the regulation of vascular tone by releasing catecholamines, acetylcholine, nitric oxide, and neuropeptides [73,74]. The sympathetic nerves innervating vessels release several co-transmitters, including neuropeptide Y (NPY). In the periphery, NPY has most often been known as a vasoconstrictor. However, NPY has recently emerged as a growth factor for a variety of cells, including vascular smooth muscle cells and endothelial cells. It is suggested that an increase in the release of NPY from sympathetic nerve endings during stressful situations (e.g. ischemia) might promote atherosclerosis by stimulating vascular smooth muscle cell proliferation [75]. On the other hand, Gidron et al. [18] suggest that parasympathetic dysfunction is also involved in the etiopathogenesis of atherosclerosis. They hypothesize that the nervous system might modulate the development and progression of atherosclerosis via the vagus nerve. This is based on the role of the vagus nerve in transmitting information about peripheral inflammation to the CNS [76] and the anti-inflammatory effects of vagal stimulation on pro-inflammatory cytokines in the heart [42]. Vagal effects on inflammation are important since they affect the onset and prognosis of coronary artery disease [77]. On the other hand, stress-induced activation of the sympathetic nervous system might locally induce pro-inflammatory processes [78,79]. Therefore it can be suggested that an altered balance of activities in the autonomic nervous system might be a neurobiological mechanism participating in the etiopathogenesis of atherosclerosis.

The study of the etiopathogenesis of cardiovascular disease (e.g. hypertension and atherosclerosis) has focused on dysfunction at the level of peripheral tissues (e.g. heart, vessels, and kidney) as well as the level of the brain (e.g. hypothalamic and brainstem structures). An increasing body of ev-

Recent stimulation experiments and clinical lesion studies indicate that the brain (e.g. insular cortex) is also involved in the development of arrhythmias [80]. Interestingly, Pokorovskij [81] suggests that along with the existence of the intracardiac pacemaker, a generator of the cardiac rhythm

Hypnosis, imagery, relaxation, and other complementary and alternative medical therapies are suggested for the treatment of various pathological processes, including autoimmune diseases [56,57]. We believe that the beneficial effects of hypnosis on inflammatory disease support a neurobiological view of inflammatory processes. This assumption is also supported by Oke and Tracey [58], who suggest that cholinergic anti-inflammatory effects of the vagus nerve might mediate the beneficial effects of complementary and alternative medical therapies. Indeed, deep breathing and meditation may increase vagal activity [59]. The mechanisms responsible for the positive effect of complementary and alternative medicine might include the activation of the frontal/prefrontal and limbic brain structures, indicating the positive affect and emotion-related memory processing. Activation of these brain structures induces changes in the endocrine and autonomic systems that might participate in the effects of complementary and alternative medicine [60].

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also exists in the CNS at the level of medulla oblongata. Could the brain represent another target for the treatment of arrhythmias? Could the observed beneficial effects of n3 polyunsaturated fatty acids on arrhythmias in dogs [82] as well as in humans [83] partly be due to the activation of certain brain structures as a consequence of the stimulation of the vagal ascending pathways by fat [84]? The research dealing with heart failure is preferentially orientated towards the heart itself, whereas the accumulated data indicate various changes in the brain areas and circuits responsible for the regulation of heart function [85]. Nevertheless, questions arise as to cause and effect and it is difficult to answer them unequivocally. Are the changes in the CNS only a reflection of dysfunctions accompanying heart failure, or does the altered activity in brain structures/functions influence the pathogenesis of heart failure? The role of the brain in the etiopathogenesis of heart failure is supported by experimental as well as clinical data. In animal models of heart failure, vagal nerve stimulation was found to increase the survival rate by 72% [86]. However, no study has tested whether the effects of vagal stimulation in cardiovascular disease are mediated by its anti-inflammatory effects. Interestingly, recent findings suggest that the beneficial effect of b-blockers might partially be mediated by their action in the brain [87]. According to the data above, it is not surprising that there is a tendency to establish a “heart-brain medicine”, which might substantially change our view of the mechanisms participating in the etiopathogenesis of cardiovascular disease [88]. We expect that a neurobiological view of cardiovascular disease might also elucidate the mechanisms by which the vagal nerve influences the risk for cardiovascular disease [89]. Neurobiology of metabolic diseases Researchers investigating the etiopathogenesis of metabolic diseases have primarily focused on peripheral tissues; however, data from the past decades indicate that the central nervous system is involved in these diseases as well. Neuroanatomical tracing studies showed that vast bidirectional neural communications between the CNS and peripheral organs play key roles in the control of peripheral metabolism [90,91]. It is suggested that unbalanced and arrhythmic sympatho-parasympathetic activities in different compartments of the body might participate in the development of the metabolic syndrome [92]. It is proposed that the CNS plays a major role in the hitherto unexplained regulation of body fat distribution. Moreover, it is suggested that the CNS is involved not only in the regulation of hormone production by white adipose tissue, but also in its hormonal sensitivity [93]. These findings are reflected by the introduction of a neurobiological concept of obesity [94]. Only recently, findings were published showing the links between the peripherally released sympathetic neurotransmitter neuropeptide Y, obesity, and the metabolic syndrome [95]. Recent studies on the etiopathogenesis of diabetes mellitus are increasingly focused on the role of the nervous system. Published data indicate that alterations in hypothalamic functions might participate in the pathogenesis of

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diabetes [3]. Buijs and Kreier [96] suggest that unbalanced autonomic nervous system output may lead to a simultaneous occurrence of diabetes type 2, dyslipidemia, hypertension, and visceral obesity, the main characteristic of the metabolic syndrome. Razavi et al. [45] show that elimination of one subtype of pancreatic sensory neurons in nonobese diabetes-prone (NOD) mice prevents insulitis and diabetes, despite the systemic persistence of pathogenic T-cell pools. Moreover, they found that intra-arterial injection of substance P into the NOD mouse pancreas reverses the abnormal insulin resistance, insulitis, and diabetes for several weeks. The most parsimonious explanation unifying these findings is a local feedback interaction between pancreatic b cells and the primary sensory neurons innervating the islets. It is suggested that nerve terminals within pancreatic tissue respond to local insulin with the release of neuropeptides that sustain the activities of b cells within an optimal range [45]. Tracing studies performed by Kreier et al. [97] represent further support of the role of the brain in the etiopathogenesis of type 2 diabetes mellitus. Hepatic insulin-sensitizing substance (HISS) might represent another link between the brain and diabetes mellitus. It is suggested that HISS, released by an insulin-activated parasympathetic reflex, activates glucose uptake by skeletal muscles [98]. The question is whether the vagal reflex also serves to modulate diabetes-related inflammation as a possible mechanism for influencing the pathogenesis or progression of diabetes. Other studies also indicate the significance of neural regulation of certain hormones in diabetes. For example, Ismail et al. [99] demonstrated an enhanced cholinergic control of growth-hormone responses compared with normal controls. A recent study by Dunn et al. [100] found that patients with type 1 diabetes who were unaware of their hypoglycemia had reduced activity in the amygdala and brain stem compared with similar patients with hypoglycemia awareness. These data were interpreted as reflecting greater habituation in brain regions mediating appetitive motivational behaviors in patients with hypoglycemia unawareness. Food might significantly influence the development of chronic diseases. Therefore, feedback mechanisms related to food intake (e.g. tolerance, aversion, and satiety) have to be finely tuned. Research is focused on the investigation of the role of neurobiological pathways such as endogenous opiate autoregulation or CNS reward circuits in the physiology of food intake [101]. Based on the data above, the assumption that visceral afferents and the brain itself can present targets for the treatment of metabolic diseases is evident [102]. Neurobiology of gastrointestinal diseases Gastrointestinal functions are regulated by the complex enteric nervous system, the activity of which is modulated by the autonomic nervous system [103]. This anatomical arrangement enables the brain to modulate the gastrointestinal system during physiological as well as pathological conditions [104]. The interactions between the nervous, endocrine, and immune systems in the etiopathogenesis of gastrointestinal diseases seem to be especially important [105]. For example, clinical and experimental findings indicate that intestinal

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inflammation can be exacerbated by behavioral conditions such as depression. Recently described tonic anti-inflammatory influences mediated by the vagus nerve in experimental colitis provide a potential link between the brain (behavior) and gut inflammation [106]. Therefore, the role of altered activities of vagal anti-inflammatory mechanisms in gastrointestinal inflammatory disease is intensively investigated [53,107]. The involvement of neurobiological factors in gastrointestinal diseases is also supported by observed interactions between eosinophils and nerves and changes in neuronal plasticity in rat gut-associated lymphoid tissue in response to enteric parasitism [108]. While the role of the nervous system in the etiopathogenesis of functional gastrointestinal diseases has been relatively well established [104], it has only been recently described that an alteration in innervation might participate in the etiopathogenesis of appendicitis. It is suggested that significant increases in the numbers of nerve fibers, Schwann cells, enlarged ganglia, and an increased number of mast cells represent a functional link between the enteric nervous system, mast cells, and the etiopathogenesis of acute appendicitis [109,110]. The published data also indicate that nervous system dysfunction plays a role in inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis) [111,112]. It was found that inflammatory intestinal diseases are characterized by an increased number of mast cells, alteration of neuropeptides, and neural innervation [113]. Interestingly, it is hypothesized that food hypersensitivity might be mediated by cognitive (central) sensitization [114]. In this model, the activation of extensive cognitive networks (e.g. food associations) may be triggered by peripheral sensory signals that may, in turn, influence food hypersensitivity. Another example of the interplay between stress, hormones, tissue damage, immunity, and gastrointestinal diseases is stress-induced ulceration and the protective effects of vasoactive intestinal peptide (VIP). In one study, rats exposed to cold restraint stress and either pretreated or post-treated with VIP were protected from stress-induced ulceration. VIP prevented stress-induced gastric mucosal damage and mast cell degranulation and protected gastric tissue from lipid peroxidation [115]. Neurobiology of cancer In recent years it has become clear that neuroimmune mechanisms may play a role in the defense against cancer as well as in its progression [116]. Multistage carcinogenesis is accompanied by disturbances in tissue homeostasis and perturbations in nervous and endocrine system activities which may affect anti-tumor resistance [117]. However, these processes are highly complex, and many variations are possible according to the nature of the neoplasm and its microenvironment [118]. The role of the nervous system in the etiopathogenesis of cancer is indicated by various experimental findings. Various human tumor tissues are innervated [119], and neurotransmitters might influence the apoptosis, mitogenesis, angiogenesis, and migration of cells as well as the genesis of metastasis [120]. Therefore, some researchers propose and have demonstrated the effectiveness of compounds affecting neurotransmitter receptors as a novel and promising approach to treating cancer [121].

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Experiments in which stimulatory and lesion methods were used showed that specific immune functions are modulated by discrete brain areas [122] Interestingly, lesion methods also showed links between tumorigenesis and the brain. Pinealectomy is associated with an increased incidence of induced breast cancer in rats, and this can be reversed by melatonin administration [123]. These studies suggest that certain CNS regions, particularly those involved in important homeostatic and neuroendocrine functions (e.g. the median hypothalamus and pineal gland) have tumor-modulatory roles. In a series of studies in humans and animals, cerebral asymmetry (i.e. greater left than right hemisphere activity) was found to be associated with enhanced immunity [124]. The sympathetic nervous system partly mediates the effects of brain asymmetry on immunity [125]. Thus higher-order cerebral functions also affect immune functions. One untested issue is the relation between hemispheric lateralization and cancer progression, given that higher left than right frontal lobe activity is related to stronger natural-killer activity [126], of potential relevance in cancer. Another study showed a significant increase in antibody titers to influenza vaccine among subjects who underwent an eightweek training program in mindfulness meditation. These subjects also had a significant increase in left-sided anterior brain electrical activity. The magnitude of the increase in left-sided brain activation predicted the magnitude of the antibody titer rise to the vaccine [127]. Surprisingly, there are only scattered data describing the changes in neuronal activity in the CNS in animals with tumors. Immunohistochemical investigation of the CNS in tumor-bearing rats showed an increased activity of spinal cord as well as brainstem and forebrain neurons [128–130]. Recently we found that the advanced stage of tumorigenesis is accompanied by an increased activity of brainstem and hypothalamic neurons [131]. It is well known that these neurons are also activated by various immune challenges [132], potentially via vagal mediation of cancer-associated inflammatory signals [19,76,133]. Therefore, these data might support the assumption that the CNS receives signals related to tumorigenesis [133]. It remains to be determined whether the processing of tumor-related signals in the brain might consequently activate descending nervous pathways with a potential defense against cancer. Finally, some studies in humans have found interesting differences between cancer patients and controls in the activity of various brain regions. Tashiro et al. [134] found reduced prefrontal activation in cancer patients versus controls and suggested that the brain’s response to a tumor resembles that of a depressive state. This is important considering the prognostic role of depression in some cancers [135]. However, these studies need to be viewed with caution since it is difficult to distinguish the effects of the cancer per se from the effects of cancer treatments (radiation, chemotherapy) on the brain. In addition, the patients knew they had cancer; therefore it is difficult to conclude whether these findings reflect any relationships between pre-cancer brain activity or the effects of knowing one has cancer on the CNS. Addressing these methodological limitations, a recent, yet unpublished study found that, compared with healthy people, patients with lung cancer had higher activity in the cerebellum prior to treatment and knowledge of their diagno-

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sis [136]. Given the vast homeostatic roles of the cerebellum [137], this response could reflect the brain’s initial attempts to modulate tumor growth or its somatic effects. We expect that focusing on the interactions between the brain and cancer might constitute the basis for forming a new branch in oncology: the neurobiology of cancer. Interdisciplinary oncological and neuro-scientific approaches might open new avenues in cancer research, with a possible impact on the prevention, diagnosis, and therapy of cancer. Neurobiology of skeleton and bone marrow diseases The existence of nerve fibers in bone is well established, although the heterogeneity and extent of innervation have become apparent only recently. The presence of sensory and sympathetic fibers has been demonstrated in bone marrow, mineralized bone, and periosteum [138,139]. The evidence of neuronal innervation in skeletal tissues supports the existence of a complex and functionally significant neurotransmitter-mediated signaling network in bone. It is now clear that neurotransmitters have a profound effect on bones, influencing the differentiation, proliferation, activity, and apoptosis of osteoblasts and osteoclasts [140]. Therefore it is not surprising that sympathetic denervation significantly affects bone remodeling [141]. A skeletal disease that may have an underlying neurobiological basis is patchy osteoporosis associated with dystrophic changes in the extremities of patients with complex regional pain syndrome type I (Sudeck’s dystrophy), which is characterized by altered activity of the sympathetic nervous system [142]. Another example is the loss of bone mass observed in patients with depression. It has recently been shown that the sympathetic nervous system mediates the skeletal effects of stress-induced depression. Results of Yirmiya et al. [143] define a linkage between depression, excessive adrenergic activity, and reduced bone formation, thus demonstrating interactions between behavioral responses, the brain, and the skeleton that lead to impaired bone structure and function. Based on all these facts it is assumed that the nervous system is involved in bone disorders characterized by inappropriate and extensive changes in bone formation and/or bone reabsorption (e.g. osteoporosis). Bone innervation also participates in the modulation of tooth growth. The autonomic nervous system is one of the factors modifying tooth eruption. It has been found that sympathetic denervation modifies tooth growth [141]. Neural density in dentition increased significantly with caries. Data suggest that caries-induced changes in neural density are important in the regulation of pulpal inflammation and healing [144]. In another study, restraint stress led to increased IL-6 mRNA in the calvaria of mice, and this was mediated by sympathetic b-adrenergic transmission, as it was blocked by the b-blocker propranolol [145]. Since IL-6 modulates the development of osteoblasts and osteoclasts, these data demonstrate that psychological stress could influence bone metabolism via neuroimmune pathways. The relevance of these findings for the prognosis of bone diseases and fracture healing needs to be investigated. Bone marrow constitutes a complex niche for hematopoietic stem cells. Published data show that sympathetic nerves

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are involved in modulating the localization of hematopoietic stem cells to the endosteal niche in bone [146]. Whether modulation of the neural pathways innervating bone marrow might be used for the treatment of hematological disorders (e.g. anemia) remains to be elucidated. A neurobiological view of bone diseases can also be traced to bone cancer. It has been observed that alterations in the neurochemistry of the spinal cord and the sensitization of primary afferents positively correlated with the extent of bone destruction and the growth of the tumor [147–149]. This “neurochemical signature” of bone cancer pain appears unique when compared with changes that occur in persistent inflammatory or neuropathic pain. Even cancer pain induces, and is at least partially maintained by, a state of central sensitization, in which neurochemical changes in the spinal cord and forebrain promote an increased transmission of nociceptive information. Under such conditions, normally non-noxious input is amplified and perceived as a noxious stimulus [147]. One could speculate that such sensitization may exist to alert the brain, and hence the person, to take actions in relation to cancer. Neurobiology of skin diseases The skin is a prominent target organ for numerous neuroendocrine, neurotrophic, and neurotransmitter signals which have a profound impact on skin biology in health and disease. Furthermore, the skin is a potent “factor” for the same signals. These, as well as the recognition that the skin and nervous system share a common molecular syntax and jointly exploit the immune system to provide additional signaling and regulatory input, are beginning to revolutionize our perception of the skin. As a consequence, a new specialty, i.e. cutaneous neuroendocrinology, has emerged to explore the “brain-skin connection”, which includes the inseparable fields of skin neurobiology, namely neuroimmunology and neuropharmacology [150]. Neuro-cutaneous interactions are mediated by a wide variety of signaling molecules which exhibit important influences on the skin in health as well as in disease (e.g. serotonin, substance P) [151]. One example of the psychoneuroimmunology of the skin is the accumulating evidence that psychological stress (e.g. chronic stress due to caring for an ill person) delays wound healing. The underlying mechanism appears to be via reduced production of IL-1 and IL-8 at the wound site [152]. Nitric oxide may also play a role in stress-related skin diseases. Small quantities of NO produced by constitutive enzymes may predominantly mediate physiological effects. In contrast, the expression of inducible NO synthases may lead to larger quantities of NO, a situation that may be associated with the cytotoxic and detrimental effects of NO. The balance between both properties is crucial. It is suggested that the involvement of nitric oxide in stress-related diseases represents a common pathway, with various pathophysiological analogies, that may be accessible when using stress management and relaxation response techniques [74,153]. Stress has long been discussed as a cause of hair loss. Data suggest that stress triggers a cascade of molecular events including plasticity of the peptidergic peri- and interfollicular innervation and neuroimmune crosstalk [154,155]. Substance P and nerve growth factor are recruited as key

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mediators of stress-induced hair growth-inhibitory effects [156]. The role of stress in atopic dermatitis is also considered [157].

METHODS FOR STUDYING THE NEUROBIOLOGY OF DISEASE The studies cited above revealed not only important information concerning neuroimmune effects on disease, but also introduced some methods for investigating whether the CNS may modulate the progression of disease. Lesion studies have been tested on animals to examine the role of brain regions in peripheral diseases [158], the effect of stimulation of various nerves (e.g. vagal nerves) in relation to heart failure [86], and chemical vagotomy in mice with cancer were also investigated [159]. In humans, correlation studies have demonstrated associations between brain activity (EEG) and hemispheric lateralization with immunecompetence in HIV [160]. Other methods in humans may also include the comparison of brain activity in patients with diseases and healthy controls [134]. Future studies need to examine prospectively the prognostic role of brain activity in peripheral tissue diseases. Finally, future studies need to test the effects of various “brain training” techniques (e.g. neurofeedback) on disease progression using randomized controlled designs. Using such experimental designs may shed light on the causality of such relationships and on the clinical and therapeutic significance of these associations.

FUTURE DIRECTIONS The evidence for multiple interactions between the brain, endocrine, and immune systems leads to a scientifically based reorientation of modern medicine towards the holistic view. Such an approach has shown that the slogan mens sana in corpore sano is valid as well as the other way around, i.e. corpus sanum per mentem sanam [161]. The various experimental and clinical data reviewed here indicate that the brain is involved in the etiopathogenesis of a wide spectrum of peripheral tissue diseases, including cardiovascular, inflammatory, and metabolic diseases and cancer. We suggest that the spectrum of diseases in which the brain participates will be significantly widened in the future. The use of adequate animal models might help us in understanding the role of the brain and the pathways that are involved in the etiopathogenesis of various diseases. Once these are understood, studies in humans can focus on longitudinal designs examining correlations between brain functioning and disease onset and prognosis. Finally, studies should test whether manipulating brain activity (e.g. enhancing left frontal cortical activity) may prevent or slow down diseases whose pathogenesis depends on immune system activity. The development of the nervous system represents one of the most complex ontogenetic processes. Therefore, individuals differ in the structures, functioning, and integration of their nervous system. We suggest that individual differences in the anatomy of the brain and peripheral nervous system (e.g. increased or decreased sensory innervation of the gut) are factors that might predispose certain individuals to some diseases or protect them from them (e.g. metabolic disorders, cancer). Future studies need to investigate such possibilities. However, the opposite is also possible, i.e. diseases might alter structures of the nervous system. It has been found that sympathetic nerve fibers are lost in patients

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with autoimmune diseases in chronically inflamed tissues, while substance P-positive fibers sprout into the inflamed area [162]. Hence neuroimmune pathways and signals influence and are influenced by disease.

CONCLUSIONS Living systems are capable of mounting appropriate responses to unpredictable changes in their internal and external environment. This kind of self-organization seems to operate as a self-programming machine, i.e. an organization able to modify itself [163]. The brain, a prominent structure participating in this process, may precisely coordinate the activities of all the cells in the body, either directly or via modulation of the activity of the endocrine and immune systems. This assumption is supported by modern molecular biological techniques which unequivocally demonstrate that the nervous, endocrine, and immune systems “speak” common languages by sharing common signal mediators and receptors. We suggest that the dense interaction between the nervous, endocrine, and immune systems enables the brain to be involved in the etiopathogenesis of a much wider spectrum of diseases than previously expected. Some scientists refer to the last decade of the 20th century as the “decade of the brain” [164]. However, we suggest that the shift of attention to the role of the brain in the etiopathogenesis of peripheral diseases will provide new avenues in neuroscience research and in clinical practice in the 21st century. The extension of the psychoneuroimmunological view of neuroendocrine-immune interactions might constitute the basis for extending the field of the neurobiology of diseases. Such an expansion might change our understanding of the etiopathogenesis of various diseases and facilitate a better understanding of many complex phenomena connected with mind and body interactions (e.g. the effects of stress on the development of diseases, the placebo effect). We expect that in the next decades a new field in health sciences will be created, namely mind-body medicine, which will make the diagnosis of diseases more precise by monitoring the changes in the brain that reflect or predict the progression of peripheral diseases. Moreover, it is possible that therapeutic interventions will shift from the periphery to the brain, since modulation of appropriate brain circuits might represent a new form of treating peripheral diseases. It is possible that even some of today’s drugs, thought to elicit their beneficial effects directly in injured tissues, might influence a disease’s progression by modifying the activity of some brain structures (e.g. salicylates, b-blockers) [87,165]. We hope that further research into the roles of the nervous, endocrine, and immune systems in disease onset and progression will enhance our scientific understanding and treatment of disease.

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