CM E
Brain-Body Interactions:
The Physiological Impact of Mental Processes
— The Neurobiology of the Stress Response
CM E EDUCATIONAL OBJECTIVES
1. Cite the neurobiological basis of the human stress response.
2. Review the mechanisms by which psychosocial stressors and
psychiatric illness activate stress responses and cause physi-
ological alterations that can aggravate medical conditions.
3. Explain the biological basis of inflammatory responses and
how they can be triggered by stress and psychiatric illness.
George I. Viamontes, MD, PhD, is Regional Medical Director, Op-
tumHealth Behavioral Solutions, St. Louis. Charles B. Nemeroff, MD,
PhD, Department of Psychiatry and Behavioral Sciences, Emory Uni-
versity School of Medicine, Atlanta.
Address correspondence to: George I. Viamontes, MD, PhD; george.
viamontes@optumhealth.com.
George I. Viamontes, MD, PhD and Charles B. Nemeroff, MD, PhD
PSYCHIATRIC ANNALS 39:12 | DECEMBER 2009
3912ViamontesNemeroff.indd 975
Dr. Viamontes has disclosed no relevant financial relationships.
Dr. Nemeroff has disclosed the following relevant financial rela-
tionships: NovaDel Pharma, Mt. Cook Pharma; Member of Board
of Directors; AstraZeneca, PharmaNeuroboost, and CeNeRx:
Member of Scientific Advisory Board; and NovaDel Pharma, Phar-
maNeuroboost, Corcept, and CeNeRx: Shareholder.
A note from the editors: All illustrations in this article have been
created by George I. Viamontes, MD, PhD, for specific use in this issue
of Psychiatric Annals.
Copyright G. Viamontes and C. Nemeroff 2009; copyright is trans-
ferred to the publisher; used with permission.
doi: 10.3928/00485718-20091124-03
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12/8/2009 5:16:02 PM
 T
o state the obvious, the is a mas-
ter integrator that continuously
receives physiological informa-
tion, analyzes it, and coordinates adjust-
ments within the body’s organ systems to
preserve homeostasis. In addition to main-
taining the internal milieu, the brain identi-
fies external threats and opportunities and
prepares the body for potential responses.
In moments of danger, whether internal or
external, survival depends upon the quality
of the relevant brain-body dialogue.
Chronic exposure to conditions that en-
gage adaptive neural networks eventually
causes neuroplastic changes that modify
the affected circuits. These adaptations es-
sentially reconfigure the brain to address
recurring challenges. Unfortunately, re-
configuring the brain to deal with chronic
situations can have adverse effects because
the modifications can be maladaptive when
conditions change and may be difficult or
impossible to reverse.
Many mental processes, including the
brain states induced by stress and certain
psychiatric disorders, can affect the body’s
physiology and alter medical outcomes.
For example, emotional stress can precipi-
tate severe left ventricular dysfunction in
disease-free patients1 and can inhibit the
IgG response to vaccines.2 In coronary
heart disease, major depressive disorder
(MDD) doubles the likelihood of a serious
Figure 1. Summary of general responses to stimuli whose potential threat or value merits a response.
The brain reacts by releasing regulatory neurotransmitters, which affect attention and arousal level. In cardiac event in the next 12 months3 and
addition, the autonomic nervous system is activated, and releasing factors may be secreted to prepare increases mortality risk after acute myo-
the body for the anticipated challenge. Genetically preprogrammed or learned action sequences may
be implemented automatically as a response to certain stimuli. All illustrations are copyright George I. cardial infarction between two- and three-
Viamontes, 2009; copyright is transferred to the publisher; used with permission. A note from the edi- fold in the next 3 years.4 Even relatively
tors: All illustrations in this article have been created by George I. Viamontes, MD, PhD, for specific use in
this issue of Psychiatric Annals. Structural data for the molecules used in the figures were obtained from distant events that have affected brain de-
the Research Collaboratory for Structural Informatics Protein Data Bank (RSCB PDB).39 velopment can have long-term effects on
disease susceptibility. For example, the
“My mind sent a message to my hypo- outer shell of my adrenal gland, which had combination of childhood abuse and MDD
thalamus, told it to release the hormone been making and storing glucocorticoids in women is associated with heightened
CRF into the short vessels connecting my for emergencies. My adrenal gland added autonomic and adrenocorticotropic hor-
hypothalamus and my pituitary gland. The the glucocorticoids to my bloodstream. mone (ACTH) responses to stress, which
CRF inspired my pituitary gland to dump They went all over my body, changing gly- increase vulnerability to a variety of psy-
the hormone ACTH into my bloodstream. cogen into glucose. Glucose was muscle chiatric disorders.5 This article will address
My pituitary had been making and storing food. It would help me fight like a wildcat the specific mechanisms by which neural
ACTH for just such an occasion, and nearer or run like a deer.” processes and psychiatric illness alter the
and nearer the zeppelin came. And some of — Kurt Vonnegut, Jr., Breakfast of body’s physiology and change the course
the ACTH in my bloodstream reached the Champions, 1973 and outcome of medical conditions.

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 MENTAL PROCESSES
AND PHYSIOLOGY
The brain continuously receives mul-
tiple streams of physiological and senso-
ry data. This information is processed by
a myriad of neural circuits. Physiologi-
cal data are generally processed in the
brainstem, which contains specialized
circuitry that adjusts the internal milieu
to maintain homeostasis. In addition,
the brainstem can initiate a variety of
stereotyped movements that accomplish
simple behavioral tasks automatically.
These include defensive posturing, swal-
lowing, breathing, reflexive blinking,
coughing, and sneezing.
Incoming sensory data are first trans-
mitted to the appropriate unimodal corti-
ces, and as the information is integrated
and distributed throughout the brain, its
subjective “meaning” with respect to the
organism is determined. Represented
information automatically generates au-
tonomic responses, and certain subsets
of data prompt full emotional reactions.
Figure 2. A hypothetical encounter with a snake. (1) The rattling sound activates the amygdala, which
Even represented information that does induces sympathetic activation and secretes CRF. (2) The auditory cortex is also activated, along with
not reach consciousness is capable of the orbitofrontal cortex (3), which works with the amygdala to achieve sympathetic arousal (5). The su-
perior colliculus (4) coordinates movements that will direct gaze toward the sound. The paraventricular
generating both autonomic and emo- nucleus of the hypothalamus (6) releases additional CRF (7). CRF stimulates the adrenal cortex (8) to
tional responses.6 These allow this indi- release cortisol (9). The body’s level of autonomic arousal is represented in the insula (10) and subse-
vidual to deal with the object or situation quently communicated to the cingulate gyrus, which can help to generate a motivational state that
addresses the crisis. A note from the editors: All illustrations in this article have been created by George
that triggered the response. I. Viamontes, MD, PhD, for specific use in this issue of Psychiatric Annals.
There are four main types of immedi-
ate brain reactions to stimuli that, by their THE HYPOTHALAMIC-PITUITARY- interpersonal and occupational challenges.
nature of potential threat or value, merit a ADRENAL AXIS (HPA) AND STRESS This stress occurs partly because psychi-
response (see Figure 1, page 996): Humans exist in a complex environ- atric diseases render psychosocial and
1. Activation of specific neural cir- ment that includes psychosocial, physi- occupational functioning more difficult.
cuits, which results in release of cal, and physiological milieus. Stress can More specifically, mental states, such as
neurotransmitters; be broadly defined as a condition or per- depression, anhedonia, obsessiveness, inat-
2. Secretion of hypothalamic releasing ception that disturbs homeostasis in any tentiveness, impulsivity, paranoia, anxiety,
factors, resulting in activation of of these areas. The nature, duration, and or impaired reality testing, are maladap-
one or more of the endocrine axes; physiological demands of the disturbance tive and stress-provoking. Not surprisingly,
3. Activation of the autonomic ner- determine the intensity and nature of the psychiatric disorders are associated with
vous system; and stress response. Humans are unique in neurobiological and physiological pertur-
4. Triggering of a motor sequence in experiencing many special stressors, in- bations, which are known to place patients
response to the stimulus. cluding daily commuting, various types of at risk for many types of medical condi-
The first three types of responses have performance situations, information over- tions, partly because of the increased activ-
immediate physiological consequences load, and the anxiety that can result from ity of stress-related systems.
and, as such, these responses contrib- contemplating the future. In general, responses to stress involve
ute to the effects of mental processes on Syndromal psychiatric disorders gen- the four processes outlined above, and
medical disorders. erate considerable stress beyond the usual they are directed at managing threat and

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Figure 3. The hypothalamic-pituitary-adrenal (HPA) Axis. Stress activates the HPA axis. This activation be-
gins with secretion of corticotropin releasing factor (CRF) by parvocellular cells of the paraventricular
nucleus of the hypothalamus. CRF, in turn, induces secretion of adrenocorticotropic hormone (ACTH)
by the anterior pituitary. In humans, ACTH activates the adrenal cortex to produce cortisol. A note from
the editors: All illustrations in this article have been created by George I. Viamontes, MD, PhD, for specific
use in this issue of Psychiatric Annals.
preserving homeostasis. A hallmark of
the stress response is activation of the
HPA and the autonomic nervous system.
A practical understanding of the compo-
nents of the stress response can be de-
veloped rapidly through consideration of
an imaginary situation that illustrates the
brain-body reactions to a perceived exter-
nal threat. The brain processes described
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3912ViamontesNemeroff.indd 978
below are hypothetical constructs based
on current neurobiological models of risk
detection and responses to threat.7-9
Imagine a person who is hiking through
the woods when suddenly she hears a rat-
tling sound (see Figure 2, page 997). As
the noise is transduced by the ear’s sensory
mechanisms into synaptic impulses, a neu-
ral representation of the sound is formed in
the primary auditory cortex. The amygda-
la, which features a rapid, afferent pathway
for sound, receives the critical information
even before it has been fully categorized in
the auditory and heteromodal cortices.7,8
The auditory representations are trans-
mitted to various brain regions, including
the posterior orbitofrontal cortex, which
has strong, two-way connections with the
amygdala.8 The amygdala and orbitofron-
tal cortex receive a rich, complementary
selection of sensory representations, and
their reciprocal processing of these inputs
define the motivational significance of
many perceptions.8
Because the rattling sound matches a
previously learned pattern associated with
danger, the amygdala’s central nucleus
sends signals to a number of neural regions
that prepare the body for action. A signal
to the caudal reticular nucleus of the pons
begins the startle response, and activa-
tion of the periaqueductal gray causes the
hiker to “freeze” in place, implementing
an automatic defensive movement prepro-
grammed in the genes.10 Stimulation of
the parabrachial nucleus ensures efficient
blood oxygenation through the induction
of rapid respiration.10
Gaze-orienting circuits controlled by
the superior colliculus automatically direct
visual attention to the area from which the
noise came. As the snake becomes visible,
the reality of the danger is confirmed. The
activated amygdala and orbitofrontal cor-
tex stimulate autonomic control centers in
the hypothalamus.8 These, in turn, activate
the intermediolateral column of the spinal
cord,8 which provides sympathetic inner-
vation to the body’s organs. Sympathetic
arousal leads to tachycardia, dry mouth,
pupillary dilation, blood pressure eleva-
tion, and diversion of blood flow from skin
and viscera to heart and muscles. In addi-
tion, sympathetic activation of the adrenal
medulla causes release of epinephrine.
This hormone further increases heart rate,
as well as the rate and depth of breathing.
It mobilizes glycogen and its conversion to
glucose to boost energy supplies and facili-
PSYCHIATRIC ANNALS 39:12 | DECEMBER 2009
12/8/2009 5:16:09 PM
 tates muscle contraction. As sympathetic
tone increases, the arterioles in the hiker’s
skin contract, and her face seems to lose
much of its color.10
Activation of the hiker’s amygdala
leads its central nucleus to release cortico-
tropin-releasing factor (CRF), a 41 amino
acid peptide that stimulates the locus coe-
ruleus in the pons and causes norepineph-
rine release throughout the brain.11 Other
neurotransmitters, including dopamine
and acetylcholine, are also released, and
they bring the brain into a state of high
arousal.10 These emergency responses are
amplified by additional CRF release from
the parvocellular region of the paraven-
tricular nucleus of the hypothalamus. CRF
is the preeminent mediator of the mam-
malian stress response.11 It activates brain
regions that control behavioral responses
to stress,12 stimulates immune system cells
and inflammatory cytokines, and promotes
ACTH secretion from the adenohypophy-
sis. ACTH, in turn, stimulates adrenal se-
cretion of cortisol, which is the principal
mammalian glucocorticoid.11
Insular representations in the hiker’s
brain change rapidly to reflect her state of
autonomic arousal.13 As the changes in in-
sular contents are transmitted to the anterior
cingulate gyrus, they blend with conscious,
cognitive evaluations of the situation and
trigger a rapid evasive plan.
As the example of the hiker illustrates,
the stress response is a complex reaction
that involves a number of neural circuits
(see Figure 3, page 978). The basic stress
Figure 4.The sympathetic nervous system.The diagram shows the thoracolumbar projection between T1 and
response begins with activation of parvo- L2 that forms the core of the sympathetic system. Sympathetic neurons are located in the intermediolateral
cellular CRF and arginine-vasopressin column of the spinal cord. Preganglionic fibers from the intermediolateral column project to paravertebral,
or sympathetic trunk ganglia. Fibers from these ganglia either innervate target organs directly or synapse on
(AVP) neurons in the paraventricular nu- prevertebral ganglia before reaching target organs. SCG: Superior cervical ganglion; L: Lachrymal gland; S:
cleus (PVN) of the hypothalamus.14 AVP Salivary gland; P: Parotid gland; MCG: Middle cervical ganglion; SG: Stellate ganglion; CG: Celiac ganglion; pan-
potentiates the action of CRF in eliciting Pancreas; SMG: Superior mesenteric ganglion; Adr: Adrenal gland; IMG: Inferior mesenteric ganglion; III: Cranial
nerve III (oculomotor nerve); VII: Cranial nerve VII (facial nerve); IX: Cranial nerve IX (glossopharyngeal nerve);
ACTH release from the pituitary, although X: Cranial nerve X (vagus nerve). A note from the editors: All illustrations in this article have been created by
it is not an ACTH secretagogue on its own. George I. Viamontes, MD, PhD, for specific use in this issue of Psychiatric Annals.
ACTH is transcribed and translated as part
of a large polypeptide prohormone called pin-like intermediate lobe peptide (CLIP). and AVP release is highest in the morning
proopiomelanocortin (POMC). POMC is In the unstressed state, CRF and AVP and decreases toward evening.14 This pro-
cleaved by specific peptides to generate secretion normally occur in a circadian, cess is regulated, in part, by the suprachias-
ACTH, beta-endorphin, melanocyte-stim- pulsatile manner, with two to three secreto- matic nucleus, which is the circadian pace-
ulating hormone (MSH), and corticotro- ry bursts per hour.14 The magnitude of CRF maker in mammals. CRF secretion, in turn,

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 tion factor required for the production of
inflammatory cytokines. In the short term,
inhibition of inflammation saves energy
and minimizes swelling, which can impede
emergency responses. However, chronic
inhibition of immune responses by high
glucocorticoid levels eventually increases
susceptibility to infection.15 Prolonged glu-
cocorticoid elevation also induces fluid and
sodium retention, increases blood pressure,
promotes muscle catabolism and osteopo-
rosis, induces hyperglycemia, and inhibits
wound healing.16
As the discussion above demonstrates,
chronic activation of the HPA axis by stress
or psychiatric illness has important physi-
ological consequences that can exacerbate
many medical conditions. The full stress
response combines stimulation of the HPA
axis with activation of the sympathetic di-
vision of the autonomic nervous system,
which is described below.

THE AUTONOMIC NERVOUS SYSTEM

The autonomic nervous system, as
briefly described in the above example, is
the major direct pathway through which
the brain modulates the function of inter-
nal organs. Modulation of the activity of
the autonomic nervous system by mental
processes occurs continuously. This modu-
lation affects such medically important pa-
rameters as heart rate, volume distribution
within the body, energy metabolism, and
immune system function.17 The autonomic
nervous system has three components: en-
teric, sympathetic, and parasympathetic
divisions. The enteric division contains
two interconnected networks of neurons
Figure 5. The parasympathetic nervous system. Preganglionic parasympathetic neurons are located
primarily in the brainstem, with an additional set between spinal cord segments S2 to S4. (See Figure 4 and supportive cells called the myenteric
caption for abbreviations. ) A note from the editors: All illustrations in this article have been created by plexus of Auerbach and the submucosal
George I. Viamontes, MD, PhD, for specific use in this issue of Psychiatric Annals.
plexus of Meissner, which regulate the
facilitates the cyclical release of ACTH about 30 minutes and return to basal lev- motility and secretory activity of the gas-
and cortisol. Stress disrupts the normal els in about an hour.15 trointestinal (GI) tract. The enteric system
diurnal patterns of CRF, AVP, ACTH, and Cortisol exerts numerous physiological features a complex regulatory network,
cortisol secretion by temporarily increas- effects, including inhibition of inflamma- which contains as many neurons as the en-
ing the secretory pulses of CRF, which tory processes. One of the most important tire spinal cord.18 Although enteric circuits
raise ACTH and cortisol concentrations mechanisms by which cortisol inhibits in- function relatively independently, they are
in the circulation. After a CRF pulse, flammation is the inactivation of nuclear extensively innervated by sympathetic and
plasma cortisol concentrations peak in factor kappa-B (NF-kappa-B),16 a transcrip- parasympathetic neurons.

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 The sympathetic system features two
types of ganglia: paravertebral and pre-
vertebral (see Figure 4, page 979). Both
receive preganglionic fibers from the in-
termediolateral column of the spinal cord,
which is located between T1 and L2 and
which gives rise to the thoracolumbar
projection of sympathetic fibers. Paraver-
tebral ganglia are also known as sympa-
thetic trunk ganglia. They are arranged in
two symmetrical chains of nervous tissue
located ventrolaterally on either side of
the spine. These chains contain 20 to 25
pairs of ganglia, which innervate the head,
thorax, trunk, and limbs. The prevertebral
sympathetic ganglia are located closer to
their targets than the paravertebral gan-
glia, and they innervate the abdominal
organs. The preganglionic sympathetic
neurons utilize acetylcholine and the
postsynaptic sympathetic neurons utilize
norepinephrine as their neurotransmitters,
respectively. The only target tissue that re-
ceives direct, preganglionic sympathetic
innervation is the adrenal medulla, which
releases epinephrine and norepinephrine
(in about a 4:1 ratio) directly into the Figure 6. TNF-alpha and IL-6. The 3D structure of two important inflammatory cytokines is displayed.
bloodstream. Sympathetic innervation is These cytokines, which can be associated with chronic inflammation, are secreted at elevated rates in
patients diagnosed with borderline personality disorder and major depressive disorder. A note from
the predominant autonomic input to the the editors: All illustrations in this article have been created by George I. Viamontes, MD, PhD, for specific
lymphoid organs, including the thymus, use in this issue of Psychiatric Annals.
spleen, and lymph nodes.17
The parasympathetic system resembles heart and respiration rates. In contrast, the also exact a physiological cost, especially
the prevertebral sympathetic system in that parasympathetic division facilitates energy if they are chronic. At a systemic level, glu-
the ganglia are located proximal to their conservation, as well as recuperative pro- cocorticoids released in response to stress
target organs (see Figure 5, page 980). Pre- cesses. Parasympathetic activity promotes inhibit the secretion of other hormones,
ganglionic parasympathetic neurons are slowing of the heartbeat and respiratory including growth hormone, gonadotropins,
located primarily in the brainstem, with rate, digestion of food, storage of fat and and thyrotropin.14 In addition, glucocor-
an additional set between spinal cord seg- glycogen, deployment of blood to the in- ticoids also inhibit the action of growth
ments S2 to S4. Parasympathetic fibers in- ternal organs and pupillary constriction. hormone and sex steroids on their target
nervate all the major organs, including the Responses to stress, as described above, structures.14 These hormones normally
eyes, heart, lungs, GI tract, and genitals. cause activation of the HPA axis, stimula- promote lipolysis, as well as muscle and
Both pre- and postganglionic parasympa- tion of the sympathetic nervous system, bone anabolism. As a result, the consis-
thetic neurons are cholinergic. and inhibition of parasympathetic tone. The tently high glucocorticoid levels that
In general, the sympathetic division of combined actions of the HPA axis and sym- characterize chronic stress promote vis-
the autonomic nervous system is a major pathetic system prepare the brain and body ceral adiposity, as well as decreased bone
mediator of the stress response. This in- for responses to life threatening situations. and muscle mass.14 An example of the
cludes energy mobilization with catabolism clinical implications of this phenomenon
of glycogen and fat, deployment of blood PHYSIOLOGICAL EFFECTS OF STRESS has been reported. Women with a diag-
to the muscles, slowing of routine visceral Stress responses can be life-saving un- nosis of borderline personality disorder
functions, pupillary dilation, and increased der the right circumstances; however, they and comorbid major depressive disorder

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Figure 7. CRF effects. CRF is the preeminent
modulator of the mammalian stress response.
It activates both mast cells and mononuclear
phagocytes and can generate local inflammatory
responses in organs such as the lungs, the intes-
tines, and the skin. CRF receptors are also present
in many brain regions, and CRF binding at these
receptors generally results in activation. On a sys-
temic basis, CRF induces release of ACTH by the
anterior pituitary, which in turn promotes release
of cortisol by the adrenal cortex. A note from the
editors: All illustrations in this article have been
created by George I. Viamontes, MD, PhD, for spe-
cific use in this issue of Psychiatric Annals.
Figure 8. Brain responses to psychosocial stressors.
Psychosocial stressors are brain-environment phe-
nomena whose core defining feature is the inter-
pretation of external circumstances as threatening.
This results in activation of the locus coeruleus-
norepinephrine system, leading to norepinephrine
release. In addition, CRF is released by the extra-hy-
pothalamic corticotropin-releasing factor system,
which includes the central nucleus of the amygdala.
CRF, in turn, leads to activation of NF-kappa-B, and
subsequent synthesis and secretion of inflammato-
ry cytokines such as IL-6. Activation of the HPA axis
results in the secretion of cortisol. A note from the
editors: All illustrations in this article have been
created by George I. Viamontes, MD, PhD, for spe-
cific use in this issue of Psychiatric Annals.
demonstrated elevated cortisol levels and
decreased bone density when compared
with controls who also had a diagnosis
of borderline personality disorder but
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3912ViamontesNemeroff.indd 982
no current diagnosis of major depressive
disorder.19 In this same study, the border-
line patients with current depression also
demonstrated increased levels of two in-
flammatory cytokines (see Figure 6, page
981): tumor necrosis factor-alpha (TNF-
alpha) and interleukin-6 (IL-6).19
The elevation of inflammatory cyto-
kines has been documented in a variety of
patients with psychiatric disorders, includ-
ing posttraumatic stress disorder (PTSD)20
and MDD.21 Psychosocial and physical
stress, even in the absence of a diagnosed
psychiatric disorder, can also increase cir-
culating inflammatory cytokines.22 In el-
derly patients, elevation of IL-6 has been
associated with a variety of active medical
conditions, ranging from arthritis to lym-
phoma.23 Older individuals with elevated
IL-6 and C-reactive protein (CRP) were
2.6 times more likely to die in the subse-
quent 4.6 years than individuals with low
IL-6 and CRP levels.24
IL-6 is a cytokine that is produced in in-
nate and adaptive immune responses (see
Part 2 of this article, scheduled for a future
issue, in the section “Brain-Immune Sys-
tem Interactions”). It is synthesized by a va-
riety of cells in response to immune stimu-
lation, including mononuclear phagocytes,
fibroblasts, endothelial cells, and activated
T cells.25 In addition, IL-6 release can be
triggered by increased epinephrine levels,
via activation of beta-2 adrenergic recep-
tors on secreting cells.26 This mechanism
facilitates the stimulation of IL-6 secre-
tion by stress. IL-6 stimulates hepatocytes
to synthesize the acute-phase proteins that
characterize early responses to infection.24
These include fibrinogen, whose elevation
increases the risk of thrombosis.25 In addi-
tion, IL-6 acts as a growth factor that pro-
motes the differentiation of beta-lympho-
cytes into antibody-producing cells25 and
is a potent inducer of CRF production.26
Although IL-6 by itself does not have per-
ceptible behavioral effects in experimental
animals other than production of fever, it
increases the observed sickness behavior
of animals injected intraperitoneally with
bacterial endotoxin.27 The mechanism for
this phenomenon appears to be amplifi-
cation of other inflammatory cytokines,
specifically interleukin-1-beta (IL-1beta)
and tumor necrosis factor-alpha (TNF-
alpha) within the brain.27 IL-6 deficient
mice have lower levels of inflammatory
cytokines within the brain during active
immune reactions and show diminished
sickness responses in comparison with
normal controls.27 IL-6 and TNF-alpha are
normally secreted in a regulated manner
by adipose tissue.28 Plasma levels of these
cytokines are directly proportional to body
mass index and are elevated in individu-
als with visceral obesity.28 The secretion
of these cytokines has a circadian pattern,
and levels are highest in late evening and
early morning.28 Stress and psychiatric
disorders, most prominently major depres-
sion, are associated with increased baseline
concentrations of IL-6.
On the surface, it may seem counter-
intuitive for stress-related physiological
changes to lead to chronic inflammatory
states because sympathetic activation and
glucocorticoids inhibit systemic inflam-
mation. The answer to this apparent para-
dox is that CRF and epinephrine promote
immediate, or local inflammatory respons-
es, while inhibiting systemic inflamma-
tion.28,29 These actions are consistent with
the role of CRF and epinephrine as princi-
pal elements of the stress response because
their first action is to prime first-line im-
mune cells to address potential, localized
invasion by pathogens. At the same time,
later systemic antiinflammatory effects
conserve energy by preventing expansion
of any immune response that may be initi-
ated and dampen inflammatory reactions
to prevent physiological damage.
Thus CRF, which activates the HPA
axis, thereby increasing cortisol produc-
tion, also stimulates mast cells,30 which
can promote local inflammatory responses
in the skin and GI tract30 (see Figure 7).
In addition, CRF induces IL-6 production
by human mononuclear cells.31 Inflamma-
tion of the GI tract as a response to bacte-
PSYCHIATRIC ANNALS 39:12 | DECEMBER 2009
12/8/2009 5:16:27 PM
 rial toxins requires the action of CRF, and
inflammatory reactions of this type can be
blocked by CRF receptor antagonists.30
An important experiment that clarified
the role of CRF and epinephrine in inflam-
matory processes involved the provocation
of immune responses in mice that had been
adrenalectomized. In the absence of corti-
sol production, CRF and norepinephrine
significantly increased experimentally in-
duced inflammatory processes.32
In general, stimulation of beta-2-adren-
ergic receptors (beta-2-ARs) on immune
cells tends to produce antiinflammatory
effects, whereas stimulation of alpha-ad-
renergic receptors (alpha-ARs) is pro-in-
flammatory.33 For example, antigen-naïve
macrophages from germ-free mice express
primarily alpha-ARs, and norepinephrine
stimulation of these cells induces TNF-al-
pha production.34 In contrast, norepineph-
rine reduces the responsiveness of mature,
antigen-activated macrophages, which ex-
press primarily beta-2-ARs.34
A possible mechanism by which stress
can be transduced into inflammatory re-
sponses has been described. Psychosocial
stressors induced rapid NF-kappa-B ex-
pression in the peripheral blood mono-
nuclear cells of 17 out of 19 volunteers,
with levels returning to normal 60 minutes
after stress exposure.35 Moreover, using
transgenic mice that require NF-kappa-
B to transcribe an inserted beta-globin
gene, beta-globin was produced by blood
mononuclear cells after immobilization
stress. This is indicative of stress-induced
activation of NF-kappaB. Beta-globin pro-
duction could be reduced by the alpha-1
adrenergic inhibitor prasozin.35 Finally, a
human monocyte line, THP-1, was treated
with epinephrine and norepinephrine and
assayed for production of IL-6, which re-
quires active NF-kappa-B for transcription.
Physiological concentrations of norepi-
nephrine, but not epinephrine, induced IL-
6 production in a dose-dependent manner.
IL-6 production was inhibited by alpha-1
and beta-2 antagonists.35 This concatena-
tion of experiments provides detailed evi-
PSYCHIATRIC ANNALS 39:12 | DECEMBER 2009
3912ViamontesNemeroff.indd 983
dence for a molecular pathway that leads
from stress to the expression of inflamma-
tory cytokines.
The above results have been extended
by our study of men with a history of MDD
and early life stress.36 In this study, experi-
mental and control subjects were exposed
to a standardized stressor (the Trier Social
Stress Test), and both plasma IL-6 con-
centrations and NF-kappaB in peripheral
blood mononuclear cells were measured.
In both control and experimental groups,
IL-6 and NF-kappa-B levels increased
with stress (see Figure 8, page 982). How-
ever, the increases were greater in the de-
pressed men with a history of child abuse
and positively correlated with depression
severity, as assessed with the Hamilton
Depression Rating Scale, but not related
to childhood abuse severity, as measured
by the Childhood Trauma Questionnaire.36
This study indicates that normal men re-
spond to stress with IL-6 and NF-kappa-B
elevations and that depressed men with a
history of childhood abuse show a height-
ened stress response.
The importance of combining activa-
tion of local or short-term inflammatory re-
sponses with inhibition of systemic inflam-
mation is highlighted by the extreme case
of sepsis. In this condition, plasma norepi-
nephrine levels increase significantly, and
this increase is paralleled by proportional
increases in the inflammatory cytokines
TNF-alpha, IL-6, and IL-1beta.37 The rise
in plasma norepinephrine concentrations is,
in part, the result of increased norepineph-
rine release from myenteric plexus neurons
in the GI tract, likely secondary to activa-
tion of tyrosine hydroxylase, the rate-lim-
iting enzyme in norepinephrine synthesis.
In addition, there is increased synthesis of
Syntaxin 1A in myenteric plexus neurons
in sepsis.37 Syntaxin 1A is a protein that
promotes attachment of norepinephrine
vesicles to the internal surface of the pre-
synaptic membrane and facilitates the re-
lease of vesicle contents.37 Syntaxin 1A not
only promotes norepinephrine release but
also blocks the norepinephrine transporter,
which normally recycles norepinephrine.37
The resultant extremely high norepineph-
rine levels spill into the hepatic portal sys-
tem and result in activation of Kupffer cells
in the liver, which are tissue macrophages
that produce inflammatory cytokines.37 If
the cascade of intense noradrenergic ac-
tivation and inflammatory cytokine pro-
duction continues unabated, death from
multiple organ failure will be the even-
tual outcome. This extreme, yet common
clinical example illustrates the serious risk
posed by inflammatory processes. Without
the systemic inhibition of inflammation
that is normally in place, even relatively
small, inflammatory reactions may have
disastrous systemic effects.
Another mechanism by which inflam-
matory influences can become dominant is
the phenomenon of inadequate glucocorti-
coid signaling. Theoretically, such signal-
ing could fail as a result of decreased glu-
cocorticoid production or desensitization
of glucocorticoid receptors. Evidence of
inadequate glucocorticoid signaling, most
likely as a result of receptor desensitiza-
tion, has been found in some individuals
with psychiatric disorders, more specifical-
ly depression.38 This inadequacy increases
the risk of exacerbated inflammatory pro-
cesses and autoimmune disorders.
SUMMARY
The brain responds to environmental
stressors by triggering rapid physiological
changes that prepare the body to meet per-
ceived challenges. These changes are pri-
marily mediated by the actions of the HPA
axis and the autonomic nervous system.
Every major body system is affected by
stress, with measurable repercussions on
the course and outcome of medical condi-
tions. Several syndromal psychiatric disor-
ders also precipitate physiological changes
with medical repercussions because they
impair the brain’s adaptive ability and mag-
nify the effect of environmental stressors.
Chronic stress induces the brain’s adap-
tive mechanisms to trigger structural and
functional changes that attempt to optimize
PsychiatricAnnalsOnline.com | 983
12/8/2009 5:16:30 PM
 reactions to recurring conditions. Unfortu-
nately, in a wider context or as conditions
change, these neuroplastic changes can be
maladaptive and difficult to reverse. One
common consequence of such modifica-
tions to chronic stress is HPA axis hyper-
activity. In addition, chronic stress, as well
as certain psychiatric disorders, such as
PTSD and MDD, promote chronic inflam-
matory states, which have adverse medical
consequences.
The mechanisms described by which
mental processes can trigger physiologi-
cal changes clearly contribute to adverse
effects on medical conditions. It is evident
that the effective treatment of medical ill-
ness in such patients must address the sig-
nificant complications posed by psychiatric
disorders and chronic stress.
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