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© Med Sci Monit, 2009; 15(1): RA6-16 WWW. M ED S CI M ONIT .COM

PMID: 19114982 Review Article

Received: 2008.06.23
Neurobiological principles in the etiopathogenesis of
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Accepted: 2008.07.10
Published: 2009.01.02
disease: When diseases have a head
Boris Mravec1,2, Katarina Ondicova1, Zuzana Valaskova1, Yori Gidron3,

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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

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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)

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Summary
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There is no doubt that the nervous system is involved in the etiopathogenesis of various patholog-
O N
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-
SO

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.

key words: arthritis • atherosclerosis • cancer • diabetes mellitus • inflammation • metabolic

syndrome • neurobiology • stress
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Word count: 6586

Tables: —
Figures: —
References: 165
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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

RA6 Current Contents/Clinical Medicine • IF(2007)=1.607 • Index Medicus/MEDLINE • EMBASE/Excerpta Medica • Chemical Abstracts • Index Copernicus

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Med Sci Monit, 2009; 15(1): RA6-16
INFLUENCE OF THE BRAIN ON THE ONSET AND PROGRESSION
OF DISEASE
Experimental data and clinical observations suggest that psy-
chological (e.g. personality, hopelessness, religiosity, depres-
sion) and other factors influenced by brain activity affect the
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genesis and progression of various human diseases (e.g. cardio-
vascular, 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 dis-
ease. The field of psychoneuroimmunology extended gradually
from the traditional clinical entities of infection, autoimmuni-
ty, 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 etiopatho-
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genesis of various diseases. Furthermore, we introduce diag-
nostic and therapeutic approaches based on the interactions
between the nervous, immune, and endocrine systems and
peripheral tissues affected by pathological processes.
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A MATTER OF ARGUMENT : IS IT TIME TO EXTEND OUR
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CONCEPT OF THE NEUROBIOLOGY OF DISEASE?
N A
Current work on the neurobiology of disease focuses main-
ly on neurological and psychiatric disease. However, recent
O N
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] (“periph-
SO
eral 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 recog-
nized (see, for example, [10-13]).
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THE REASONS FOR ACCEPTING A BROADER VIEW OF THE
NEUROBIOLOGY OF DISEASE
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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 infor-
mation 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,
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lung, thyroid, liver, prostate, skin). Finally, hormones, neu-
rotransmitters, and other soluble molecules signal the neu-
roendocrine 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-
Mravec B et al –Neurobiology of disease
gens and tissue injury in the internal environment and sig-
nals 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 local-
ly 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 in-
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tersystem 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 previ-
ously not recognized or neglected (e.g. atherosclerosis, ar-
thritis, cancer, diabetes mellitus, hemorrhagic shock, isch-
emia-reperfusion injury, ileus, pancreatitis, sepsis) [18–20].
It is suggested that there is a genetic basis of neuroendo-
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crine-immune-disease interactions [21]. We hypothesize
that this genetic basis might predispose some individuals to
the development of diseases due to altered interactions be-
tween the nervous, endocrine, and immune systems. It may
also be possible that certain environmental factors (e.g. tox-
ins, stress) contribute to altering the interactions between
these three systems and in this way participate in the etio-
pathogenesis of peripheral diseases [22,23]. For example,
several studies show that exposure of an organism to stress
during early developmental periods might alter the reac-
tivity 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 un-
derstanding of the brain’s role in the etiopathogenesis and
progression of various peripheral tissue diseases is proba-
bly at its beginning.
Neuroendocrine-immune interactions: Wire and wireless
connections
To understand the mechanisms responsible for the involve-
ment of the CNS in the etiopathogenesis of peripheral tissue
diseases, it is necessary to define how the nervous system in-
teracts with the endocrine and immune system. In general,
there are two pathways enabling bidirectional communica-
tion between these three regulatory systems: wired (neuro-
nal) 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 path-
ways are fast and location-specific.
NEUROBIOLOGY OF PERIPHERAL TISSUE DISEASES
Psychoneuroimmunology: integrating the incompatible
Whereas research focusing on the involvement of the ner-
vous system in the etiopathogenesis of various diseases can
be traced back to the distant past, a description of the path-
ways enabling the brain to modulate the genesis and pro-
gression of disease was vague. A description of the mech-
anisms 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 ar-
gued 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 ac-
count the interactions of psychological and social factors
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along with biological processes [28]. Health psychology is
the domain of psychology predicated on Engel’s ‘‘biopsy-
chosocial 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 incompati-
ble” and established the scientific basis for a new discipline,
psychoneuroimmunology [29]. Psychoneuroimmunology,
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based on a bidirectional perspective of neuroimmune in-
teractions, provides the understanding of certain complex
fundamental mechanisms involved in the biopsychosocial
model [27]. Today, psychoneuroimmunology is accepted as
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a new hybrid discipline and is defined as a study of brain, be-
havior, and immune system interactions. Furthermore, psy-
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choneuroimmunology provides the framework to investigate
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the implications of neuroimmune interactions for disease
onset and progression. Psychoneuroimmunological studies
have shown that positive emotions have positive effects on
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immune functions, whereas chronic/uncontrollable stress-
ful situations and depression are associated with the sup-
pression of cellular immune functions [30]. Harmful dys-
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regulation 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, includ-
ing 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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Neurobiology of inflammatory diseases
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Cash and Wilder [32] had already proposed the idea of
neuroendocrine-immune involvement in the pathogene-
sis 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 inflamma-
tory 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], sug-
gesting a role for neuroendocrine-immune interactions in
autoimmune diseases.
The relatively recent descriptions of neural anti-inflammato-
ry mechanisms, namely that of the cholinergic anti-inflam-
matory vagal pathway [34], have significantly contributed to
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the idea of the brain’s critical role in the modulation of the
etiopathogenesis of inflammatory diseases. It was tradition-
ally 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 pe-
ripheral HPA axis-like system (e.g. CRH released from au-
tonomic nerves) is still a matter of debate [37]. However,
recent discoveries have proved that acetylcholine released
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by the vagus nerve binds to a-7 nicotinic receptors on im-
mune cells and consecutively significantly inhibits the syn-
thesis and release of pro-inflammatory cytokines [38]. In
contrast to the HPA axis, this cholinergic anti-inflammato-
ry pathway enables more complex, fast, and location-specif-
ic regulation of immune system activity by the nervous sys-
tem [34]. Research has provided evidence for the profound
effects the activated anti-inflammatory efferent pathway of
the vagus nerve has on various physiological and patholog-
ical conditions (e.g. bacterial sepsis, pancreatitis, ileus, and
rheumatoid arthritis) [20].
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Some questions regarding the cholinergic anti-inflammato-
ry 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 homeo-
stasis and neuroendocrine modulation, such as the brain-
stem and hypothalamus, can regulate the efferent vagal anti-
inflammatory response to peripheral inflammatory signals.
Future studies need to investigate this hypothesis in great-
er depth. Nevertheless, observations in laboratory animals
show impressive effects induced by chemical or electrical
stimulation of descending vagal pathways on the progres-
sion of inflammation-related pathological conditions (e.g.
hypovolemic hemorrhagic shock, ischemia-reperfusion in-
jury, pancreatitis, postoperative ileus, and sepsis [39–43]).
These effects indicate the importance of the neural regula-
tion of inflammation and its possible relevance to periph-
eral inflammatory diseases.
Inflammatory processes are also modulated by primary af-
ferent 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 gene-
related peptide [46].
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 be-
cause the central nervous system controls a wide range of
physiological functions that are crucial in maintaining ho-
meostasis and orchestrating the host response at the behav-
ioral, neuroendocrine, and autonomic levels, disturbances
in any of these adaptive functions may deleteriously influ-
ence the course of septic shock [47]. Animal experiments
show that several central pathways, namely those converg-
ing into the paraventricular hypothalamic nucleus, the cen-
tral modulator of HPA-axis activity, are activated during sep-
sis [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 con-
sequence? Similarly, since the autonomic nervous system is
involved in the regulation of immune functions, autonom-
ic 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 neu-
robiological view of inflammatory diseases? Besides elec-
trical 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 transcuta-
neous vagal mechanical stimulation [43,50]. Some studies
have reassessed the mechanisms responsible for the anti-in-
flammatory properties of polyunsaturated fatty acids (e.g.
in critically ill patients) in relation to the vagal anti-inflam-
matory pathway [51]. It is suggested that cholecystokinin
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(CCK) plays a crucial role in the activation of the vagal anti-
inflammatory 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 re-
duction 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 activa-
tion of the vagal anti-inflammatory pathway by the intake of
dietary fat might help explain why the trillions of microor-
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ganisms that reside in the intestine do not stimulate an ex-
aggerated cytokine response [53].
The data discussed above related to vagal anti-inflammatory
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effects were obtained only from animal studies. Therefore
it is not surprising that there is an intensive effort to inves-
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tigate the role of the anti-inflammatory effects of the vagus
N A
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 lipopoly-
O N
saccharide-induced whole blood TNF release ex vivo in pa-
tients with severe sepsis. These data indicate that selective
activation of a-7 nicotinic receptors might provide a poten-
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tial therapeutic target to decrease cytokine release in sep-
sis [55]. The effectiveness of mechanical stimulation of the
vagus nerve, activation of cholinergic anti-inflammatory va-
gal pathways by fatty acids, and the application of a-7 nic-
otine receptor agonists on inflammation in humans need
further investigation.
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Hypnosis, imagery, relaxation, and other complementa-
ry and alternative medical therapies are suggested for the
treatment of various pathological processes, including au-
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PE
toimmune diseases [56,57]. We believe that the beneficial
effects of hypnosis on inflammatory disease support a neu-
robiological view of inflammatory processes. This assump-
tion is also supported by Oke and Tracey [58], who sug-
gest that cholinergic anti-inflammatory effects of the vagus
nerve might mediate the beneficial effects of complemen-
tary and alternative medical therapies. Indeed, deep breath-
ing and meditation may increase vagal activity [59]. The
mechanisms responsible for the positive effect of comple-
mentary and alternative medicine might include the activa-
tion of the frontal/prefrontal and limbic brain structures,
indicating the positive affect and emotion-related memo-
ry processing. Activation of these brain structures induc-
es changes in the endocrine and autonomic systems that
might participate in the effects of complementary and al-
ternative medicine [60].
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Neurobiology of cardiovascular diseases
The study of the etiopathogenesis of cardiovascular disease
(e.g. hypertension and atherosclerosis) has focused on dys-
function at the level of peripheral tissues (e.g. heart, vessels,
and kidney) as well as the level of the brain (e.g. hypotha-
lamic and brainstem structures). An increasing body of ev-
Mravec B et al –Neurobiology of disease
idence indicates that the brain’s role in the etiopathogen-
esis 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 ra-
phe nuclei [66], the central role of the brain in salt-sensi-
tive hypertension [67], and alteration of the brain’s renin-
angiotensin system in hypertension [68]. Findings related
to the role of the sympathetic nervous system in hyperten-
sion provide the basis for the hypothesis of the sympathetic
neurobiology of essential hypertension [69]. It is also sug-
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gested that alterations in the sensory innervation of car-
diovascular tissues might participate in the development
of hypertension [70]. Neuroimaging in humans recently
demonstrated correlations between stress-induced increas-
es 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 neurobiol-
ogy of hypertension might include elevated CNS activity in
regions that modulate cardiovascular activity, sympathetic
dysfunction, as well as altered sensory innervation of car-
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diovascular tissues.
While the role of the brain and the sympathetic nervous sys-
tem in the etiopathogenesis of hypertension is widely accept-
ed, research concerning atherosclerosis, arrhythmias, and
heart failure has focused almost exclusively on the role of
the heart and vascular tissues. Nevertheless, recent data sug-
gest 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 vascu-
lar 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 of-
ten been known as a vasoconstrictor. However, NPY has re-
cently emerged as a growth factor for a variety of cells, in-
cluding 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 vas-
cular smooth muscle cell proliferation [75]. On the other
hand, Gidron et al. [18] suggest that parasympathetic dys-
function is also involved in the etiopathogenesis of athero-
sclerosis. They hypothesize that the nervous system might
modulate the development and progression of atheroscle-
rosis 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 ef-
fects 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-in-
flammatory processes [78,79]. Therefore it can be suggested
that an altered balance of activities in the autonomic ner-
vous system might be a neurobiological mechanism partic-
ipating in the etiopathogenesis of atherosclerosis.
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
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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 n-
3 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
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of the vagal ascending pathways by fat [84]?
The research dealing with heart failure is preferentially
orientated towards the heart itself, whereas the accumulat-
ed data indicate various changes in the brain areas and cir-
cuits 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 accompany-
ing heart failure, or does the altered activity in brain struc-
tures/functions influence the pathogenesis of heart failure?
U
The role of the brain in the etiopathogenesis of heart fail-
ure 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,
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no study has tested whether the effects of vagal stimulation
in cardiovascular disease are mediated by its anti-inflamma-
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tory effects. Interestingly, recent findings suggest that the
N A
beneficial effect of b-blockers might partially be mediated
by their action in the brain [87].
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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
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participating in the etiopathogenesis of cardiovascular dis-
ease [88]. We expect that a neurobiological view of cardio-
vascular disease might also elucidate the mechanisms by
which the vagal nerve influences the risk for cardiovascu-
lar disease [89].
Neurobiology of metabolic diseases
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Researchers investigating the etiopathogenesis of meta-
bolic diseases have primarily focused on peripheral tis-
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sues; 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 bi-
directional neural communications between the CNS and
peripheral organs play key roles in the control of periph-
eral metabolism [90,91]. It is suggested that unbalanced
and arrhythmic sympatho-parasympathetic activities in dif-
ferent compartments of the body might participate in the
development of the metabolic syndrome [92]. It is pro-
posed that the CNS plays a major role in the hitherto un-
explained regulation of body fat distribution. Moreover, it
is suggested that the CNS is involved not only in the regu-
lation of hormone production by white adipose tissue, but
also in its hormonal sensitivity [93]. These findings are re-
flected by the introduction of a neurobiological concept of
obesity [94]. Only recently, findings were published show-
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ing the links between the peripherally released sympathet-
ic neurotransmitter neuropeptide Y, obesity, and the met-
abolic syndrome [95].
Recent studies on the etiopathogenesis of diabetes melli-
tus are increasingly focused on the role of the nervous sys-
tem. Published data indicate that alterations in hypotha-
lamic functions might participate in the pathogenesis of
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Med Sci Monit, 2009; 15(1): RA6-16
diabetes [3]. Buijs and Kreier [96] suggest that unbalanced
autonomic nervous system output may lead to a simulta-
neous occurrence of diabetes type 2, dyslipidemia, hyper-
tension, and visceral obesity, the main characteristic of the
metabolic syndrome. Razavi et al. [45] show that elimina-
tion of one subtype of pancreatic sensory neurons in non-
obese diabetes-prone (NOD) mice prevents insulitis and di-
abetes, 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 ab-
normal insulin resistance, insulitis, and diabetes for several
SE
weeks. The most parsimonious explanation unifying these
findings is a local feedback interaction between pancreat-
ic b cells and the primary sensory neurons innervating the
islets. It is suggested that nerve terminals within pancreat-
ic tissue respond to local insulin with the release of neuro-
peptides that sustain the activities of b cells within an opti-
mal 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 in-
sulin-sensitizing substance (HISS) might represent another
link between the brain and diabetes mellitus. It is suggest-
ed that HISS, released by an insulin-activated parasympa-
thetic 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 progres-
sion of diabetes.
Other studies also indicate the significance of neural regu-
lation 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 physi-
ology of food intake [101].
Based on the data above, the assumption that visceral affer-
ents and the brain itself can present targets for the treat-
ment of metabolic diseases is evident [102].
Neurobiology of gastrointestinal diseases
Gastrointestinal functions are regulated by the complex en-
teric nervous system, the activity of which is modulated by the
autonomic nervous system [103]. This anatomical arrange-
ment enables the brain to modulate the gastrointestinal sys-
tem 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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Med Sci Monit, 2009; 15(1): RA6-16
inflammation can be exacerbated by behavioral conditions
such as depression. Recently described tonic anti-inflamma-
tory influences mediated by the vagus nerve in experimen-
tal colitis provide a potential link between the brain (be-
havior) and gut inflammation [106]. Therefore, the role of
altered activities of vagal anti-inflammatory mechanisms in
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gastrointestinal inflammatory disease is intensively investi-
gated [53,107]. The involvement of neurobiological factors
in gastrointestinal diseases is also supported by observed in-
teractions 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 etiopathogene-
sis 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
U
etiopathogenesis of appendicitis. It is suggested that signifi-
cant 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 sys-
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tem, mast cells, and the etiopathogenesis of acute appendi-
citis [109,110]. The published data also indicate that ner-
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vous system dysfunction plays a role in inflammatory bowel
N A
diseases (e.g. Crohn’s disease, ulcerative colitis) [111,112].
It was found that inflammatory intestinal diseases are char-
acterized by an increased number of mast cells, alteration
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of neuropeptides, and neural innervation [113].
Interestingly, it is hypothesized that food hypersensitivi-
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ty 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 pe-
ripheral sensory signals that may, in turn, influence food
hypersensitivity. Another example of the interplay between
stress, hormones, tissue damage, immunity, and gastrointes-
tinal diseases is stress-induced ulceration and the protective
R
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
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PE
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 mech-
anisms may play a role in the defense against cancer as well as
in its progression [116]. Multistage carcinogenesis is accompa-
nied by disturbances in tissue homeostasis and perturbations
in nervous and endocrine system activities which may affect
anti-tumor resistance [117]. However, these processes are high-
ly 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
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cancer is indicated by various experimental findings. Various
human tumor tissues are innervated [119], and neurotrans-
mitters might influence the apoptosis, mitogenesis, angio-
genesis, and migration of cells as well as the genesis of me-
tastasis [120]. Therefore, some researchers propose and
have demonstrated the effectiveness of compounds affect-
ing neurotransmitter receptors as a novel and promising
approach to treating cancer [121].
Mravec B et al –Neurobiology of disease
Experiments in which stimulatory and lesion methods were
used showed that specific immune functions are modulat-
ed by discrete brain areas [122] Interestingly, lesion meth-
ods also showed links between tumorigenesis and the brain.
Pinealectomy is associated with an increased incidence of in-
duced breast cancer in rats, and this can be reversed by mela-
tonin administration [123]. These studies suggest that certain
CNS regions, particularly those involved in important homeo-
static and neuroendocrine functions (e.g. the median hypo-
thalamus and pineal gland) have tumor-modulatory roles.
SE
In a series of studies in humans and animals, cerebral asym-
metry (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 un-
tested issue is the relation between hemispheric lateraliza-
tion and cancer progression, given that higher left than
right frontal lobe activity is related to stronger natural-kill-
er activity [126], of potential relevance in cancer. Another
RA
study showed a significant increase in antibody titers to in-
fluenza vaccine among subjects who underwent an eight-
week training program in mindfulness meditation. These
subjects also had a significant increase in left-sided anteri-
or 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 tu-
mors. 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 hy-
pothalamic neurons [131]. It is well known that these neu-
rons are also activated by various immune challenges [132],
potentially via vagal mediation of cancer-associated inflam-
matory signals [19,76,133]. Therefore, these data might sup-
port 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 dif-
ferences 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 prog-
nostic role of depression in some cancers [135]. However,
these studies need to be viewed with caution since it is dif-
ficult 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 activi-
ty 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 peo-
ple, patients with lung cancer had higher activity in the cer-
ebellum prior to treatment and knowledge of their diagno-
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Review Article
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
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in oncology: the neurobiology of cancer. Interdisciplinary on-
cological and neuro-scientific approaches might open new av-
enues in cancer research, with a possible impact on the pre-
vention, diagnosis, and therapy of cancer.
Neurobiology of skeleton and bone marrow diseases
The existence of nerve fibers in bone is well established, al-
though the heterogeneity and extent of innervation have be-
come apparent only recently. The presence of sensory and
sympathetic fibers has been demonstrated in bone marrow,
U
mineralized bone, and periosteum [138,139]. The evidence
of neuronal innervation in skeletal tissues supports the exis-
tence of a complex and functionally significant neurotrans-
mitter-mediated signaling network in bone. It is now clear
LY L
that neurotransmitters have a profound effect on bones,
influencing the differentiation, proliferation, activity, and
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apoptosis of osteoblasts and osteoclasts [140]. Therefore it
N A
is not surprising that sympathetic denervation significantly
affects bone remodeling [141].
O N
A skeletal disease that may have an underlying neurobiolog-
ical basis is patchy osteoporosis associated with dystrophic
changes in the extremities of patients with complex regional
SO
pain syndrome type I (Sudeck’s dystrophy), which is charac-
terized 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
R
activity, and reduced bone formation, thus demonstrating
interactions between behavioral responses, the brain, and
the skeleton that lead to impaired bone structure and func-
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PE
tion. Based on all these facts it is assumed that the nervous
system is involved in bone disorders characterized by inap-
propriate 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 fac-
tors modifying tooth eruption. It has been found that sym-
pathetic denervation modifies tooth growth [141]. Neural
density in dentition increased significantly with caries. Data
suggest that caries-induced changes in neural density are im-
portant in the regulation of pulpal inflammation and heal-
ing [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
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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 frac-
ture healing needs to be investigated.
Bone marrow constitutes a complex niche for hematopoi-
etic stem cells. Published data show that sympathetic nerves
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Med Sci Monit, 2009; 15(1): RA6-16
are involved in modulating the localization of hematopoiet-
ic stem cells to the endosteal niche in bone [146]. Whether
modulation of the neural pathways innervating bone mar-
row might be used for the treatment of hematological dis-
orders (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].
SE
This “neurochemical signature” of bone cancer pain ap-
pears 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 trans-
mission of nociceptive information. Under such conditions,
normally non-noxious input is amplified and perceived as a
noxious stimulus [147]. One could speculate that such sen-
sitization may exist to alert the brain, and hence the per-
son, to take actions in relation to cancer.
Neurobiology of skin diseases
The skin is a prominent target organ for numerous neuroen-
docrine, neurotrophic, and neurotransmitter signals which
have a profound impact on skin biology in health and dis-
ease. 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 joint-
ly exploit the immune system to provide additional signal-
ing 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 re-
duced production of IL-1 and IL-8 at the wound site [152].
Nitric oxide may also play a role in stress-related skin dis-
eases. Small quantities of NO produced by constitutive en-
zymes 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 bal-
ance between both properties is crucial. It is suggested that
the involvement of nitric oxide in stress-related diseases rep-
resents a common pathway, with various pathophysiological
analogies, that may be accessible when using stress manage-
ment 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 interfol-
licular innervation and neuroimmune crosstalk [154,155].
Substance P and nerve growth factor are recruited as key
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Med Sci Monit, 2009; 15(1): RA6-16
mediators of stress-induced hair growth-inhibitory effects
[156]. The role of stress in atopic dermatitis is also consid-
ered [157].
METHODS FOR STUDYING THE NEUROBIOLOGY OF DISEASE
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The studies cited above revealed not only important infor-
mation 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 ac-
tivity (EEG) and hemispheric lateralization with immune-
U
competence 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
LY L
in peripheral tissue diseases. Finally, future studies need to
test the effects of various “brain training” techniques (e.g.
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neurofeedback) on disease progression using randomized
N A
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.
O N
FUTURE DIRECTIONS
SO
The evidence for multiple interactions between the brain,
endocrine, and immune systems leads to a scientifically
based reorientation of modern medicine towards the holis-
tic 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 exper-
imental and clinical data reviewed here indicate that the
R
brain is involved in the etiopathogenesis of a wide spectrum
of peripheral tissue diseases, including cardiovascular, in-
flammatory, and metabolic diseases and cancer. We suggest
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PE
that the spectrum of diseases in which the brain participates
will be significantly widened in the future. The use of ade-
quate 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 under-
stood, studies in humans can focus on longitudinal designs
examining correlations between brain functioning and dis-
ease onset and prognosis. Finally, studies should test wheth-
er 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, indi-
viduals differ in the structures, functioning, and integration
of their nervous system. We suggest that individual differ-
py is for personal use only - distribution prohibited.
ences 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 individu-
als to some diseases or protect them from them (e.g. meta-
bolic 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
Mravec B et al –Neurobiology of disease
with autoimmune diseases in chronically inflamed tissues,
while substance P-positive fibers sprout into the inflamed
area [162]. Hence neuroimmune pathways and signals in-
fluence and are influenced by disease.
CONCLUSIONS
Living systems are capable of mounting appropriate respons-
es to unpredictable changes in their internal and external
environment. This kind of self-organization seems to oper-
ate as a self-programming machine, i.e. an organization able
SE
to modify itself [163]. The brain, a prominent structure par-
ticipating in this process, may precisely coordinate the activ-
ities of all the cells in the body, either directly or via modu-
lation of the activity of the endocrine and immune systems.
This assumption is supported by modern molecular biolog-
ical techniques which unequivocally demonstrate that the
nervous, endocrine, and immune systems “speak” common
languages by sharing common signal mediators and recep-
tors. We suggest that the dense interaction between the ner-
vous, endocrine, and immune systems enables the brain to
RA
be involved in the etiopathogenesis of a much wider spec-
trum of diseases than previously expected.
Some scientists refer to the last decade of the 20th centu-
ry as the “decade of the brain” [164]. However, we suggest
that the shift of attention to the role of the brain in the etio-
pathogenesis 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 con-
stitute the basis for extending the field of the neurobiol-
ogy of diseases. Such an expansion might change our un-
derstanding of the etiopathogenesis of various diseases and
facilitate a better understanding of many complex phenom-
ena connected with mind and body interactions (e.g. the
effects of stress on the development of diseases, the place-
bo effect). We expect that in the next decades a new field
in health sciences will be created, namely mind-body med-
icine, which will make the diagnosis of diseases more pre-
cise 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 appropri-
ate 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. salicy-
lates, b-blockers) [87,165]. We hope that further research
into the roles of the nervous, endocrine, and immune sys-
tems in disease onset and progression will enhance our sci-
entific understanding and treatment of disease.
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