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Review Article
Received: 2008.XX.XX
Accepted: 2008.XX.XX Neurobiological principles in the etiopathogenesis of
Published: 2008.XX.XX
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
2
Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovak Republic
3
School of Health Sciences and Social Care, Brunel University, London, United Kingdom
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 patholog-
ical 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 encour-
age us to shift our current opinion of the etiopathogenesis of disease to one of highly complex in-
teractions between peripheral tissues and the brain and in this way introduce new diagnostic and
therapeutic approaches.
Author’s address: Boris Mravec, Faculty of Medicine, Institute of Pathophysiology, Comenius University, Sasinkova 4,
811 08 Bratislava, Slovak Republic, e-mail: boris.mravec@fmed.uniba.sk
Current Contents/Clinical Medicine • IF(2007)=1.607 • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts • Index Copernicus RA1
Review Article Med Sci Monit, 2008; 14(11): RA
INFLUENCE OF THE BRAIN ON THE ONSET AND PROGRESSION gens and tissue injury in the internal environment and sig-
OF DISEASE nals their presence to the CNS during immune activation
[16]. Consequently, the neuroendocrine system modulates
Experimental data and clinical observations suggest that psy- immune functions at different levels: systematically through
chological (e.g. personality, hopelessness, religiosity, depres- the hypothalamic-pituitary-adrenocortical (HPA) axis and
sion) and other factors influenced by brain activity affect the hypothalamic-pituitary-gonadal axis, regionally through the
genesis and progression of various human diseases (e.g. cardio- release of neurotransmitters in immune organs, and local-
vascular, metabolic, inflammatory) [1]. Studies in the field of ly through nerve endings and diffuse neuroendocrine cells
neuroimmunology and psychoneuroimmunology performed at the site of different tissues. In turn, mediators released
during the last decades might provide some understanding of by immune cells (particularly cytokines) signal to the CNS
how the brain influences the genesis and progression of dis- and peripheral nervous system, enabling a bidirectional in-
ease. The field of psychoneuroimmunology extended gradually tersystem communication [15,17].
from the traditional clinical entities of infection, autoimmuni-
ty, and cancer to attain a broader relevance to inflammation, The multilevel interactions between the nervous, endocrine,
asthma, and cardiovascular and gastrointestinal disease [2]. and immune systems constitute a basis for the involvement
In the following sections we shall emphasize recent findings of the CNS in the etiopathogenesis of some pathological
that elucidate the involvement of the brain in the etiopatho- states and diseases in which the role of the CNS was previ-
genesis of various diseases. Furthermore, we introduce diag- ously not recognized or neglected (e.g. atherosclerosis, ar-
nostic and therapeutic approaches based on the interactions thritis, cancer, diabetes mellitus, hemorrhagic shock, isch-
between the nervous, immune, and endocrine systems and emia-reperfusion injury, ileus, pancreatitis, sepsis) [18–20].
peripheral tissues affected by pathological processes. It is suggested that there is a genetic basis of neuroendo-
crine-immune-disease interactions [21]. We hypothesize
A MATTER OF ARGUMENT : IS IT TIME TO EXTEND OUR that this genetic basis might predispose some individuals to
CONCEPT OF THE NEUROBIOLOGY OF DISEASE? the development of diseases due to altered interactions be-
tween the nervous, endocrine, and immune systems. It may
Current work on the neurobiology of disease focuses main- also be possible that certain environmental factors (e.g. tox-
ly on neurological and psychiatric disease. However, recent ins, stress) contribute to altering the interactions between
studies support a different view suggesting that the concept these three systems and in this way participate in the etio-
of the neurobiology of disease needs to be expanded to the pathogenesis of peripheral diseases [22,23]. For example,
neurobiology of peripheral tissue diseases [3–9] (“periph- several studies show that exposure of an organism to stress
eral tissues” are tissues outside the nervous system). These during early developmental periods might alter the reac-
assumptions are based mainly on converging data obtained tivity of the HPA axis in adulthood [24,25]. However, it is
from psychoneuroimmunological studies indicating that the necessary to note that although our knowledge about how
nervous system is involved in a much broader spectrum of the nervous system functions is expanding rapidly, our un-
pathological states and diseases than was previously recog- derstanding of the brain’s role in the etiopathogenesis and
nized (see, for example, [10-13]). progression of various peripheral tissue diseases is proba-
bly at its beginning.
THE REASONS FOR ACCEPTING A BROADER VIEW OF THE
NEUROBIOLOGY OF DISEASE Neuroendocrine-immune interactions: Wire and wireless
connections
Neuroendocrine-immune interactions as a basis for the
neurobiology of peripheral tissue diseases To understand the mechanisms responsible for the involve-
ment of the CNS in the etiopathogenesis of peripheral tissue
Despite the fact that animals are made of an immense number diseases, it is necessary to define how the nervous system in-
of cells, the activities of these cells are precisely coordinated by teracts with the endocrine and immune system. In general,
three interwoven regulatory systems: the nervous, endocrine, there are two pathways enabling bidirectional communica-
and immune. It is increasingly clear that the exchange of infor- tion between these three regulatory systems: wired (neuro-
mation between these three systems plays an important role in nal) pathways and wireless (humoral) pathways [26]. These
various physiological as well as pathological states [14]. two pathways enable the brain to have a dominant role in
the modulation of peripheral tissue activity. The humoral
Neuroendocrine interactions pathways are relatively slow and less informative regarding
the location or source of signals, whereas the neural path-
The central nervous system (CNS) controls endocrine cells ways are fast and location-specific.
via the hypothalamic-pituitary axis and by efferent pathways
of the autonomic nervous system. Moreover, neuroendocrine NEUROBIOLOGY OF PERIPHERAL TISSUE DISEASES
cells are present in various peripheral organs (e.g. pancreas,
lung, thyroid, liver, prostate, skin). Finally, hormones, neu- Psychoneuroimmunology: integrating the incompatible
rotransmitters, and other soluble molecules signal the neu-
roendocrine system, exerting a feed-back control [15]. Whereas research focusing on the involvement of the ner-
vous system in the etiopathogenesis of various diseases can
Neuroimmune interactions be traced back to the distant past, a description of the path-
ways enabling the brain to modulate the genesis and pro-
There has been a growing appreciation that the immune gression of disease was vague. A description of the mech-
system can be viewed as a sensory organ that detects patho- anisms relating the “psyche” to certain disorders did not
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Med Sci Monit, 2008; 14(11): RA Mravec B et al –Neurobiology of disease
take shape until the second half of the 20th century [27]. In
his landmark article published in Science, George Engel ar-
by the vagus nerve binds to a-7 nicotinic receptors on im-
mune cells and consecutively significantly inhibits the syn-
RA
gued that biological factors such as genetics do not account thesis and release of pro-inflammatory cytokines [38]. In
for all health outcomes; rather, a proper understanding of contrast to the HPA axis, this cholinergic anti-inflammato-
the etiology and progression of disease must take into ac- ry pathway enables more complex, fast, and location-specif-
count the interactions of psychological and social factors ic regulation of immune system activity by the nervous sys-
along with biological processes [28]. Health psychology is tem [34]. Research has provided evidence for the profound
the domain of psychology predicated on Engel’s ‘‘biopsy- effects the activated anti-inflammatory efferent pathway of
chosocial model’’ and it encompasses such domains as the the vagus nerve has on various physiological and patholog-
effects of psychological and social factors on disease risk, ical conditions (e.g. bacterial sepsis, pancreatitis, ileus, and
prevention, treatment compliance, morbidity, quality of rheumatoid arthritis) [20].
life, and survival.
Some questions regarding the cholinergic anti-inflammato-
It was the experimental work of Hugo Besedovsky, George ry pathway remain unanswered. For example, the relations
Solomon, and Robert Ader who “integrated the incompati- between the afferent and efferent vagal fibers are unclear. It
ble” and established the scientific basis for a new discipline, is possible that higher CNS centers involved in body homeo-
psychoneuroimmunology [29]. Psychoneuroimmunology, stasis and neuroendocrine modulation, such as the brain-
based on a bidirectional perspective of neuroimmune in- stem and hypothalamus, can regulate the efferent vagal anti-
teractions, provides the understanding of certain complex inflammatory response to peripheral inflammatory signals.
fundamental mechanisms involved in the biopsychosocial Future studies need to investigate this hypothesis in great-
model [27]. Today, psychoneuroimmunology is accepted as er depth. Nevertheless, observations in laboratory animals
a new hybrid discipline and is defined as a study of brain, be- show impressive effects induced by chemical or electrical
havior, and immune system interactions. Furthermore, psy- stimulation of descending vagal pathways on the progres-
choneuroimmunology provides the framework to investigate sion of inflammation-related pathological conditions (e.g.
the implications of neuroimmune interactions for disease hypovolemic hemorrhagic shock, ischemia-reperfusion in-
onset and progression. Psychoneuroimmunological studies jury, pancreatitis, postoperative ileus, and sepsis [39–43]).
have shown that positive emotions have positive effects on These effects indicate the importance of the neural regula-
immune functions, whereas chronic/uncontrollable stress- tion of inflammation and its possible relevance to periph-
ful situations and depression are associated with the sup- eral inflammatory diseases.
pression of cellular immune functions [30]. Harmful dys-
regulation of the immune system by stress is mediated by Inflammatory processes are also modulated by primary af-
the HPA axis and the sympathoadrenal medullary system. It ferent nervous fibers. It was found that these fibers play a
was shown that stress-induced immune dysregulation can be role in experimental pancreatitis as well as in a mouse model
significant enough to result in health consequences, includ- of diabetes mellitus [44,45]. These and other data indicate
ing reduced immune response to vaccines, slowed wound that the role of axonal reflexes in inflammatory processes
healing, reactivation of latent herpes viruses, and enhanced is of importance and may occur by the local secretion of
risk for more severe diseases [31]. neurotransmitters such as substance P and calcitonin gene-
related peptide [46].
Neurobiology of inflammatory diseases
Reciprocal interactions between the immune and nervous
Cash and Wilder [32] had already proposed the idea of systems are now considered to be the major components
neuroendocrine-immune involvement in the pathogene- of the host response in septic shock. It is suggested that be-
sis of inflammatory diseases. The role of these interactions cause the central nervous system controls a wide range of
in the development of autoimmune diseases is supported physiological functions that are crucial in maintaining ho-
by experimental and clinical observations. Observations in meostasis and orchestrating the host response at the behav-
patients with brain lesions showed the important role the ioral, neuroendocrine, and autonomic levels, disturbances
nervous system had in the etiopathogenesis of inflamma- in any of these adaptive functions may deleteriously influ-
tory diseases. In patients who developed scleroderma or ence the course of septic shock [47]. Animal experiments
rheumatoid arthritis after a hemiplegic stroke, the limb was show that several central pathways, namely those converg-
spared in the paretic side affected by the stroke [33], sug- ing into the paraventricular hypothalamic nucleus, the cen-
gesting a role for neuroendocrine-immune interactions in tral modulator of HPA-axis activity, are activated during sep-
autoimmune diseases. sis [48]. Disruption of the HPA-axis is a common feature in
severe sepsis [47]. Do dysfunctions of these brain structures
The relatively recent descriptions of neural anti-inflammato- play an etiological role in sepsis or do they occur as its con-
ry mechanisms, namely that of the cholinergic anti-inflam- sequence? Similarly, since the autonomic nervous system is
matory vagal pathway [34], have significantly contributed to involved in the regulation of immune functions, autonom-
the idea of the brain’s critical role in the modulation of the ic dysfunction may be a consequence of the progression of
etiopathogenesis of inflammatory diseases. It was tradition- autoimmune diseases or it may directly participate in the
ally accepted that the central nervous system modulates the etiopathogenesis of autoimmune diseases [49].
activity of the immune system mainly via the HPA axis and
the sympathetic nervous system [35,36]. The role of the pe- What are the possible therapeutic consequences of a neu-
ripheral HPA axis-like system (e.g. CRH released from au- robiological view of inflammatory diseases? Besides elec-
tonomic nerves) is still a matter of debate [37]. However, trical and chemical stimulation of the vagus nerve, it was
recent discoveries have proved that acetylcholine released shown that vagal anti-inflammatory mechanisms might also
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be stimulated by high-fat enteral nutrition or by transcuta- idence indicates that the brain’s role in the etiopathogen-
neous vagal mechanical stimulation [43,50]. Some studies esis of hypertension is crucial [61–65]. This has also been
have reassessed the mechanisms responsible for the anti-in- supported by findings of increased activity in brain centers
flammatory properties of polyunsaturated fatty acids (e.g. regulating the functions of the sympathetic nervous system
in critically ill patients) in relation to the vagal anti-inflam- including the A5 noradrenergic nuclei in the pons and ra-
matory pathway [51]. It is suggested that cholecystokinin phe nuclei [66], the central role of the brain in salt-sensi-
(CCK) plays a crucial role in the activation of the vagal anti- tive hypertension [67], and alteration of the brain’s renin-
inflammatory pathway by polyunsaturated fatty acids [50]. angiotensin system in hypertension [68]. Findings related
The importance of CCK as a transduction signal between to the role of the sympathetic nervous system in hyperten-
fat and the cholinergic anti-inflammatory pathway is also sion provide the basis for the hypothesis of the sympathetic
supported by findings that the application of CCK induced neurobiology of essential hypertension [69]. It is also sug-
the anti-inflammatory reaction, as demonstrated by the re- gested that alterations in the sensory innervation of car-
duction of acetic acid-induced colitis in rats. On the other diovascular tissues might participate in the development
hand, perivagal capsaicin prevented this protective effect of hypertension [70]. Neuroimaging in humans recently
of CCK [52]. Suppression of cytokine release via the activa- demonstrated correlations between stress-induced increas-
tion of the vagal anti-inflammatory pathway by the intake of es in blood pressure and enhanced activity in the cingulate,
dietary fat might help explain why the trillions of microor- insular, and prefrontal parts of the cortex as well as in the
ganisms that reside in the intestine do not stimulate an ex- cerebellum [71]. Therefore the concept of the neurobiol-
aggerated cytokine response [53]. ogy of hypertension might include elevated CNS activity in
regions that modulate cardiovascular activity, sympathetic
The data discussed above related to vagal anti-inflammatory dysfunction, as well as altered sensory innervation of car-
effects were obtained only from animal studies. Therefore diovascular tissues.
it is not surprising that there is an intensive effort to inves-
tigate the role of the anti-inflammatory effects of the vagus While the role of the brain and the sympathetic nervous sys-
nerve in humans [54]. The possibility that nicotine can treat tem in the etiopathogenesis of hypertension is widely accept-
sepsis in humans was partially addressed by Goldstein et al. ed, research concerning atherosclerosis, arrhythmias, and
[55], who showed that cholinergic agonists inhibit lipopoly- heart failure has focused almost exclusively on the role of
saccharide-induced whole blood TNF release ex vivo in pa- the heart and vascular tissues. Nevertheless, recent data sug-
tients with severe sepsis. These data indicate that selective gest that the brain is also involved in the etiopathogenesis
activation of a-7 nicotinic receptors might provide a poten- of these diseases [72]. The nerves surrounding arteries have
tial therapeutic target to decrease cytokine release in sep- long been known to be involved in the regulation of vascu-
sis [55]. The effectiveness of mechanical stimulation of the lar tone by releasing catecholamines, acetylcholine, nitric
vagus nerve, activation of cholinergic anti-inflammatory va- oxide, and neuropeptides [73,74]. The sympathetic nerves
gal pathways by fatty acids, and the application of a-7 nic- innervating vessels release several co-transmitters, including
otine receptor agonists on inflammation in humans need neuropeptide Y (NPY). In the periphery, NPY has most of-
further investigation. ten been known as a vasoconstrictor. However, NPY has re-
cently emerged as a growth factor for a variety of cells, in-
Hypnosis, imagery, relaxation, and other complementa- cluding vascular smooth muscle cells and endothelial cells.
ry and alternative medical therapies are suggested for the It is suggested that an increase in the release of NPY from
treatment of various pathological processes, including au- sympathetic nerve endings during stressful situations (e.g.
toimmune diseases [56,57]. We believe that the beneficial ischemia) might promote atherosclerosis by stimulating vas-
effects of hypnosis on inflammatory disease support a neu- cular smooth muscle cell proliferation [75]. On the other
robiological view of inflammatory processes. This assump- hand, Gidron et al. [18] suggest that parasympathetic dys-
tion is also supported by Oke and Tracey [58], who sug- function is also involved in the etiopathogenesis of athero-
gest that cholinergic anti-inflammatory effects of the vagus sclerosis. They hypothesize that the nervous system might
nerve might mediate the beneficial effects of complemen- modulate the development and progression of atheroscle-
tary and alternative medical therapies. Indeed, deep breath- rosis via the vagus nerve. This is based on the role of the
ing and meditation may increase vagal activity [59]. The vagus nerve in transmitting information about peripheral
mechanisms responsible for the positive effect of comple- inflammation to the CNS [76] and the anti-inflammatory ef-
mentary and alternative medicine might include the activa- fects of vagal stimulation on pro-inflammatory cytokines in
tion of the frontal/prefrontal and limbic brain structures, the heart [42]. Vagal effects on inflammation are important
indicating the positive affect and emotion-related memo- since they affect the onset and prognosis of coronary artery
ry processing. Activation of these brain structures induc- disease [77]. On the other hand, stress-induced activation of
es changes in the endocrine and autonomic systems that the sympathetic nervous system might locally induce pro-in-
might participate in the effects of complementary and al- flammatory processes [78,79]. Therefore it can be suggested
ternative medicine [60]. that an altered balance of activities in the autonomic ner-
vous system might be a neurobiological mechanism partic-
Neurobiology of cardiovascular diseases ipating in the etiopathogenesis of atherosclerosis.
The study of the etiopathogenesis of cardiovascular disease Recent stimulation experiments and clinical lesion studies
(e.g. hypertension and atherosclerosis) has focused on dys- indicate that the brain (e.g. insular cortex) is also involved
function at the level of peripheral tissues (e.g. heart, vessels, in the development of arrhythmias [80]. Interestingly,
and kidney) as well as the level of the brain (e.g. hypotha- Pokorovskij [81] suggests that along with the existence of the
lamic and brainstem structures). An increasing body of ev- intracardiac pacemaker, a generator of the cardiac rhythm
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inflammation can be exacerbated by behavioral conditions Experiments in which stimulatory and lesion methods were
such as depression. Recently described tonic anti-inflamma- used showed that specific immune functions are modulat-
tory influences mediated by the vagus nerve in experimen- ed by discrete brain areas [122] Interestingly, lesion meth-
tal colitis provide a potential link between the brain (be- ods also showed links between tumorigenesis and the brain.
havior) and gut inflammation [106]. Therefore, the role of Pinealectomy is associated with an increased incidence of in-
altered activities of vagal anti-inflammatory mechanisms in duced breast cancer in rats, and this can be reversed by mela-
gastrointestinal inflammatory disease is intensively investi- tonin administration [123]. These studies suggest that certain
gated [53,107]. The involvement of neurobiological factors CNS regions, particularly those involved in important homeo-
in gastrointestinal diseases is also supported by observed in- static and neuroendocrine functions (e.g. the median hypo-
teractions between eosinophils and nerves and changes in thalamus and pineal gland) have tumor-modulatory roles.
neuronal plasticity in rat gut-associated lymphoid tissue in
response to enteric parasitism [108]. In a series of studies in humans and animals, cerebral asym-
metry (i.e. greater left than right hemisphere activity) was
While the role of the nervous system in the etiopathogene- found to be associated with enhanced immunity [124]. The
sis of functional gastrointestinal diseases has been relatively sympathetic nervous system partly mediates the effects of
well established [104], it has only been recently described brain asymmetry on immunity [125]. Thus higher-order
that an alteration in innervation might participate in the cerebral functions also affect immune functions. One un-
etiopathogenesis of appendicitis. It is suggested that signifi- tested issue is the relation between hemispheric lateraliza-
cant increases in the numbers of nerve fibers, Schwann cells, tion and cancer progression, given that higher left than
enlarged ganglia, and an increased number of mast cells right frontal lobe activity is related to stronger natural-kill-
represent a functional link between the enteric nervous sys- er activity [126], of potential relevance in cancer. Another
tem, mast cells, and the etiopathogenesis of acute appendi- study showed a significant increase in antibody titers to in-
citis [109,110]. The published data also indicate that ner- fluenza vaccine among subjects who underwent an eight-
vous system dysfunction plays a role in inflammatory bowel week training program in mindfulness meditation. These
diseases (e.g. Crohn’s disease, ulcerative colitis) [111,112]. subjects also had a significant increase in left-sided anteri-
It was found that inflammatory intestinal diseases are char- or brain electrical activity. The magnitude of the increase
acterized by an increased number of mast cells, alteration in left-sided brain activation predicted the magnitude of
of neuropeptides, and neural innervation [113]. the antibody titer rise to the vaccine [127].
Interestingly, it is hypothesized that food hypersensitivi- Surprisingly, there are only scattered data describing the
ty might be mediated by cognitive (central) sensitization changes in neuronal activity in the CNS in animals with tu-
[114]. In this model, the activation of extensive cognitive mors. Immunohistochemical investigation of the CNS in
networks (e.g. food associations) may be triggered by pe- tumor-bearing rats showed an increased activity of spinal
ripheral sensory signals that may, in turn, influence food cord as well as brainstem and forebrain neurons [128–130].
hypersensitivity. Another example of the interplay between Recently we found that the advanced stage of tumorigenesis
stress, hormones, tissue damage, immunity, and gastrointes- is accompanied by an increased activity of brainstem and hy-
tinal diseases is stress-induced ulceration and the protective pothalamic neurons [131]. It is well known that these neu-
effects of vasoactive intestinal peptide (VIP). In one study, rons are also activated by various immune challenges [132],
rats exposed to cold restraint stress and either pretreated potentially via vagal mediation of cancer-associated inflam-
or post-treated with VIP were protected from stress-induced matory signals [19,76,133]. Therefore, these data might sup-
ulceration. VIP prevented stress-induced gastric mucosal port the assumption that the CNS receives signals related to
damage and mast cell degranulation and protected gastric tumorigenesis [133]. It remains to be determined whether
tissue from lipid peroxidation [115]. the processing of tumor-related signals in the brain might
consequently activate descending nervous pathways with a
Neurobiology of cancer potential defense against cancer.
In recent years it has become clear that neuroimmune mech- Finally, some studies in humans have found interesting dif-
anisms may play a role in the defense against cancer as well as ferences between cancer patients and controls in the activity
in its progression [116]. Multistage carcinogenesis is accompa- of various brain regions. Tashiro et al. [134] found reduced
nied by disturbances in tissue homeostasis and perturbations prefrontal activation in cancer patients versus controls and
in nervous and endocrine system activities which may affect suggested that the brain’s response to a tumor resembles that
anti-tumor resistance [117]. However, these processes are high- of a depressive state. This is important considering the prog-
ly complex, and many variations are possible according to the nostic role of depression in some cancers [135]. However,
nature of the neoplasm and its microenvironment [118]. these studies need to be viewed with caution since it is dif-
ficult to distinguish the effects of the cancer per se from the
The role of the nervous system in the etiopathogenesis of effects of cancer treatments (radiation, chemotherapy) on
cancer is indicated by various experimental findings. Various the brain. In addition, the patients knew they had cancer;
human tumor tissues are innervated [119], and neurotrans- therefore it is difficult to conclude whether these findings
mitters might influence the apoptosis, mitogenesis, angio- reflect any relationships between pre-cancer brain activi-
genesis, and migration of cells as well as the genesis of me- ty or the effects of knowing one has cancer on the CNS.
tastasis [120]. Therefore, some researchers propose and Addressing these methodological limitations, a recent, yet
have demonstrated the effectiveness of compounds affect- unpublished study found that, compared with healthy peo-
ing neurotransmitter receptors as a novel and promising ple, patients with lung cancer had higher activity in the cer-
approach to treating cancer [121]. ebellum prior to treatment and knowledge of their diagno-
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mediators of stress-induced hair growth-inhibitory effects with autoimmune diseases in chronically inflamed tissues,
[156]. The role of stress in atopic dermatitis is also consid- while substance P-positive fibers sprout into the inflamed
ered [157]. area [162]. Hence neuroimmune pathways and signals in-
fluence and are influenced by disease.
METHODS FOR STUDYING THE NEUROBIOLOGY OF DISEASE
CONCLUSIONS
The studies cited above revealed not only important infor-
mation concerning neuroimmune effects on disease, but Living systems are capable of mounting appropriate respons-
also introduced some methods for investigating whether es to unpredictable changes in their internal and external
the CNS may modulate the progression of disease. Lesion environment. This kind of self-organization seems to oper-
studies have been tested on animals to examine the role ate as a self-programming machine, i.e. an organization able
of brain regions in peripheral diseases [158], the effect of to modify itself [163]. The brain, a prominent structure par-
stimulation of various nerves (e.g. vagal nerves) in relation ticipating in this process, may precisely coordinate the activ-
to heart failure [86], and chemical vagotomy in mice with ities of all the cells in the body, either directly or via modu-
cancer were also investigated [159]. In humans, correlation lation of the activity of the endocrine and immune systems.
studies have demonstrated associations between brain ac- This assumption is supported by modern molecular biolog-
tivity (EEG) and hemispheric lateralization with immune- ical techniques which unequivocally demonstrate that the
competence in HIV [160]. Other methods in humans may nervous, endocrine, and immune systems “speak” common
also include the comparison of brain activity in patients with languages by sharing common signal mediators and recep-
diseases and healthy controls [134]. Future studies need to tors. We suggest that the dense interaction between the ner-
examine prospectively the prognostic role of brain activity vous, endocrine, and immune systems enables the brain to
in peripheral tissue diseases. Finally, future studies need to be involved in the etiopathogenesis of a much wider spec-
test the effects of various “brain training” techniques (e.g. trum of diseases than previously expected.
neurofeedback) on disease progression using randomized
controlled designs. Using such experimental designs may Some scientists refer to the last decade of the 20th centu-
shed light on the causality of such relationships and on the ry as the “decade of the brain” [164]. However, we suggest
clinical and therapeutic significance of these associations. that the shift of attention to the role of the brain in the etio-
pathogenesis of peripheral diseases will provide new avenues
FUTURE DIRECTIONS in neuroscience research and in clinical practice in the 21st
century. The extension of the psychoneuroimmunological
The evidence for multiple interactions between the brain, view of neuroendocrine-immune interactions might con-
endocrine, and immune systems leads to a scientifically stitute the basis for extending the field of the neurobiol-
based reorientation of modern medicine towards the holis- ogy of diseases. Such an expansion might change our un-
tic view. Such an approach has shown that the slogan mens derstanding of the etiopathogenesis of various diseases and
sana in corpore sano is valid as well as the other way around, facilitate a better understanding of many complex phenom-
i.e. corpus sanum per mentem sanam [161]. The various exper- ena connected with mind and body interactions (e.g. the
imental and clinical data reviewed here indicate that the effects of stress on the development of diseases, the place-
brain is involved in the etiopathogenesis of a wide spectrum bo effect). We expect that in the next decades a new field
of peripheral tissue diseases, including cardiovascular, in- in health sciences will be created, namely mind-body med-
flammatory, and metabolic diseases and cancer. We suggest icine, which will make the diagnosis of diseases more pre-
that the spectrum of diseases in which the brain participates cise by monitoring the changes in the brain that reflect or
will be significantly widened in the future. The use of ade- predict the progression of peripheral diseases. Moreover,
quate animal models might help us in understanding the it is possible that therapeutic interventions will shift from
role of the brain and the pathways that are involved in the the periphery to the brain, since modulation of appropri-
etiopathogenesis of various diseases. Once these are under- ate brain circuits might represent a new form of treating
stood, studies in humans can focus on longitudinal designs peripheral diseases. It is possible that even some of today’s
examining correlations between brain functioning and dis- drugs, thought to elicit their beneficial effects directly in
ease onset and prognosis. Finally, studies should test wheth- injured tissues, might influence a disease’s progression by
er manipulating brain activity (e.g. enhancing left frontal modifying the activity of some brain structures (e.g. salicy-
cortical activity) may prevent or slow down diseases whose lates, b-blockers) [87,165]. We hope that further research
pathogenesis depends on immune system activity. into the roles of the nervous, endocrine, and immune sys-
tems in disease onset and progression will enhance our sci-
The development of the nervous system represents one of entific understanding and treatment of disease.
the most complex ontogenetic processes. Therefore, indi-
viduals differ in the structures, functioning, and integration REFERENCES:
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