Psychiatric Annals

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CME Article 

Brain-Body Interactions: The Physiological Impact of Mental Processes — The Neurobiology of the Stress Response

George I. Viamontes, MD, PhD; Charles B. Nemeroff, MD, PhD

Abstract

“My mind sent a message to my hypothalamus, told it to release the hormone CRF into the short vessels connecting my hypothalamus and my pituitary gland. The CRF inspired my pituitary gland to dump the hormone ACTH into my bloodstream. My pituitary had been making and storing ACTH for just such an occasion, and nearer and nearer the zeppelin came. And some of the ACTH in my bloodstream reached the outer shell of my adrenal gland, which had been making and storing glucocorticoids for emergencies. My adrenal gland added the glucocorticoids to my bloodstream. They went all over my body, changing glycogen into glucose. Glucose was muscle food. It would help me fight like a wildcat or run like a deer.”

Abstract

“My mind sent a message to my hypothalamus, told it to release the hormone CRF into the short vessels connecting my hypothalamus and my pituitary gland. The CRF inspired my pituitary gland to dump the hormone ACTH into my bloodstream. My pituitary had been making and storing ACTH for just such an occasion, and nearer and nearer the zeppelin came. And some of the ACTH in my bloodstream reached the outer shell of my adrenal gland, which had been making and storing glucocorticoids for emergencies. My adrenal gland added the glucocorticoids to my bloodstream. They went all over my body, changing glycogen into glucose. Glucose was muscle food. It would help me fight like a wildcat or run like a deer.”

George I. Viamontes, MD, PhD, is Regional Medical Director, OptumHealth Behavioral Solutions, St. Louis. Charles B. Nemeroff, MD, PhD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.

Dr. Viamontes has disclosed no relevant financial relationships. Dr. Nemeroff has disclosed the following relevant financial relationships: NovaDel Pharma, Mt. Cook Pharma; Member of Board of Directors; AstraZeneca, PharmaNeuroboost, and CeNeRx: Member of Scientific Advisory Board; and NovaDel Pharma, PharmaNeuroboost, 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 transferred to the publisher; used with permission.

Address correspondence to: George I. Viamontes, MD, PhD; george. viamontes@optumhealth.com.

“My mind sent a message to my hypothalamus, told it to release the hormone CRF into the short vessels connecting my hypothalamus and my pituitary gland. The CRF inspired my pituitary gland to dump the hormone ACTH into my bloodstream. My pituitary had been making and storing ACTH for just such an occasion, and nearer and nearer the zeppelin came. And some of the ACTH in my bloodstream reached the outer shell of my adrenal gland, which had been making and storing glucocorticoids for emergencies. My adrenal gland added the glucocorticoids to my bloodstream. They went all over my body, changing glycogen into glucose. Glucose was muscle food. It would help me fight like a wildcat or run like a deer.”

To state the obvious, the is a master integrator that continuously receives physiological information, analyzes it, and coordinates adjustments within the body’s organ systems to preserve homeostasis. In addition to maintaining the internal milieu, the brain identifies 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 engage adaptive neural networks eventually causes neuroplastic changes that modify the affected circuits. These adaptations essentially 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 precipitate 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 cardiac event in the next 12 months3 and increases mortality risk after acute myocardial infarction between two-and threefold in the next 3 years.4 Even relatively distant events that have affected brain development can have long-term effects on disease susceptibility. For example, the combination of childhood abuse and MDD in women is associated with heightened autonomic and adrenocorticotropic hormone (ACTH) responses to stress, which increase vulnerability to a variety of psychiatric disorders.5 This article will address the specific mechanisms by which neural processes and psychiatric illness alter the body’s physiology and change the course and outcome of medical conditions.

Mental Processes and Physiology

The brain continuously receives multiple streams of physiological and sensory data. This information is processed by a myriad of neural circuits. Physiological 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, swallowing, breathing, reflexive blinking, coughing, and sneezing.

Incoming sensory data are first transmitted to the appropriate unimodal cortices, 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 autonomic responses, and certain subsets of data prompt full emotional reactions. Even represented information that does not reach consciousness is capable of generating both autonomic and emotional responses.6 These allow this individual to deal with the object or situation that triggered the response.

There are four main types of immediate brain reactions to stimuli that, by their nature of potential threat or value, merit a response (see Figure 1, page 996):

  1. Activation of specific neural circuits, which results in release of neurotransmitters;

  2. Secretion of hypothalamic releasing factors, resulting in activation of one or more of the endocrine axes;

  3. Activation of the autonomic nervous system; and

  4. Triggering of a motor sequence in response to the stimulus.

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 Addition, the Autonomic Nervous System Is Activated, and Releasing Factors May Be Secreted to Prepare 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. Viamontes, 2009; Copyright Is Transferred to the Publisher; Used with Permission. 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. Structural Data for the Molecules Used in the Figures Were Obtained from the Research Collaboratory for Structural Informatics Protein Data Bank (RSCB PDB).39

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 Addition, the Autonomic Nervous System Is Activated, and Releasing Factors May Be Secreted to Prepare 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. Viamontes, 2009; Copyright Is Transferred to the Publisher; Used with Permission. 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. Structural Data for the Molecules Used in the Figures Were Obtained from the Research Collaboratory for Structural Informatics Protein Data Bank (RSCB PDB).39

The first three types of responses have immediate physiological consequences and, as such, these responses contribute to the effects of mental processes on medical disorders.

The Hypothalamic-Pituitary-Adrenal Axis (HPA) and Stress

Humans exist in a complex environment that includes psychosocial, physical, and physiological milieus. Stress can be broadly defined as a condition or perception that disturbs homeostasis in any of these areas. The nature, duration, and physiological demands of the disturbance determine the intensity and nature of the stress response. Humans are unique in experiencing many special stressors, including daily commuting, various types of performance situations, information overload, and the anxiety that can result from contemplating the future.

Syndromal psychiatric disorders generate considerable stress beyond the usual interpersonal and occupational challenges. This stress occurs partly because psychiatric diseases render psychosocial and occupational functioning more difficult. More specifically, mental states, such as depression, anhedonia, obsessiveness, inattentiveness, impulsivity, paranoia, anxiety, or impaired reality testing, are maladaptive and stress-provoking. Not surprisingly, psychiatric disorders are associated with neurobiological and physiological perturbations, which are known to place patients at risk for many types of medical conditions, partly because of the increased activity of stress-related systems.

In general, responses to stress involve the four processes outlined above, and they are directed at managing threat and preserving homeostasis. A hallmark of the stress response is activation of the HPA and the autonomic nervous system. A practical understanding of the components of the stress response can be developed rapidly through consideration of an imaginary situation that illustrates the brain-body reactions to a perceived external threat. The brain processes described 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 rattling sound (see Figure 2, page 997). As the noise is transduced by the ear’s sensory mechanisms into synaptic impulses, a neural representation of the sound is formed in the primary auditory cortex. The amygdala, 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 transmitted to various brain regions, including the posterior orbitofrontal cortex, which has strong, two-way connections with the amygdala.8 The amygdala and orbitofrontal cortex receive a rich, complementary selection of sensory representations, and their reciprocal processing of these inputs define the motivational significance of many perceptions.8

A Hypothetical Encounter with a Snake. (1) The Rattling Sound Activates the Amygdala, Which Induces Sympathetic Activation and Secretes CRF. (2) The Auditory Cortex Is also Activated, Along with the Orbitofrontal Cortex (3), Which Works with the Amygdala to Achieve Sympathetic Arousal (5). The Superior Colliculus (4) Coordinates Movements that Will Direct Gaze Toward the Sound. The Paraventricular Nucleus of the Hypothalamus (6) Releases Additional CRF (7). CRF Stimulates the Adrenal Cortex (8) to Release Cortisol (9). The Body’s Level of Autonomic Arousal Is Represented in the Insula (10) and Subsequently 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 I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 2. A Hypothetical Encounter with a Snake. (1) The Rattling Sound Activates the Amygdala, Which Induces Sympathetic Activation and Secretes CRF. (2) The Auditory Cortex Is also Activated, Along with the Orbitofrontal Cortex (3), Which Works with the Amygdala to Achieve Sympathetic Arousal (5). The Superior Colliculus (4) Coordinates Movements that Will Direct Gaze Toward the Sound. The Paraventricular Nucleus of the Hypothalamus (6) Releases Additional CRF (7). CRF Stimulates the Adrenal Cortex (8) to Release Cortisol (9). The Body’s Level of Autonomic Arousal Is Represented in the Insula (10) and Subsequently 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 I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

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 activation of the periaqueductal gray causes the hiker to “freeze” in place, implementing an automatic defensive movement preprogrammed 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 cortex stimulate autonomic control centers in the hypothalamus.8 These, in turn, activate the intermediolateral column of the spinal cord,8 which provides sympathetic innervation to the body’s organs. Sympathetic arousal leads to tachycardia, dry mouth, pupillary dilation, blood pressure elevation, and diversion of blood flow from skin and viscera to heart and muscles. In addition, 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 facilitates 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 corticotropin-releasing factor (CRF), a 41 amino acid peptide that stimulates the locus coeruleus in the pons and causes norepinephrine 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 paraventricular nucleus of the hypothalamus. CRF is the preeminent mediator of the mammalian 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 adenohypophysis. ACTH, in turn, stimulates adrenal secretion 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 insular 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 response begins with activation of parvocellular CRF and arginine-vasopressin (AVP) neurons in the paraventricular nucleus (PVN) of the hypothalamus.14 AVP potentiates the action of CRF in eliciting ACTH release from the pituitary, although it is not an ACTH secretagogue on its own. ACTH is transcribed and translated as part of a large polypeptide prohormone called proopiomelanocortin (POMC). POMC is cleaved by specific peptides to generate ACTH, beta-endorphin, melanocyte-stimulating hormone (MSH), and corticotropin-like intermediate lobe peptide (CLIP).

The Hypothalamic-Pituitary-Adrenal (HPA) Axis. Stress Activates the Hpa Axis. This Activation Begins 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.

Figure 3. The Hypothalamic-Pituitary-Adrenal (HPA) Axis. Stress Activates the Hpa Axis. This Activation Begins 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.

In the unstressed state, CRF and AVP secretion normally occur in a circadian, pulsatile manner, with two to three secretory bursts per hour.14 The magnitude of CRF and AVP release is highest in the morning and decreases toward evening.14 This process is regulated, in part, by the suprachiasmatic nucleus, which is the circadian pacemaker in mammals. CRF secretion, in turn, facilitates the cyclical release of ACTH and cortisol. Stress disrupts the normal diurnal patterns of CRF, AVP, ACTH, and cortisol secretion by temporarily increasing the secretory pulses of CRF, which raise ACTH and cortisol concentrations in the circulation. After a CRF pulse, plasma cortisol concentrations peak in about 30 minutes and return to basal levels in about an hour.15

Cortisol exerts numerous physiological effects, including inhibition of inflammatory processes. One of the most important mechanisms by which cortisol inhibits inflammation is the inactivation of nuclear factorkappa-B(NF-kappa-B),16atranscription 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 glucocorticoid elevation also induces fluid and sodium retention, increases blood pressure, promotes muscle catabolism and osteoporosis, 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 physiological consequences that can exacerbate many medical conditions. The full stress response combines stimulation of the HPA axis with activation of the sympathetic division 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 internal organs. Modulation of the activity of the autonomic nervous system by mental processes occurs continuously. This modulation affects such medically important parameters as heart rate, volume distribution within the body, energy metabolism, and immune system function.17 The autonomic nervous system has three components: enteric, sympathetic, and parasympathetic divisions. The enteric division contains two interconnected networks of neurons and supportive cells called the myenteric plexus of Auerbach and the submucosal plexus of Meissner, which regulate the motility and secretory activity of the gastrointestinal (GI) tract. The enteric system features a complex regulatory network, which contains as many neurons as the entire spinal cord.18 Although enteric circuits function relatively independently, they are extensively innervated by sympathetic and parasympathetic neurons.

The sympathetic system features two types of ganglia: paravertebral and prevertebral (see Figure 4, page 979). Both receive preganglionic fibers from the intermediolateral column of the spinal cord, which is located between T1 and L2 and which gives rise to the thoracolumbar projection of sympathetic fibers. Paravertebral ganglia are also known as sympathetic 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 ganglia, 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 receives direct, preganglionic sympathetic innervation is the adrenal medulla, which releases epinephrine and norepinephrine (in about a 4:1 ratio) directly into the bloodstream. Sympathetic innervation is the predominant autonomic input to the lymphoid organs, including the thymus, spleen, and lymph nodes.17

The Sympathetic Nervous System. The Diagram Shows the Thoracolumbar Projection Between T1 and L2 that Forms the Core of the Sympathetic System. Sympathetic Neurons are Located in the Intermediolateral 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 Prevertebral Ganglia Before Reaching Target Organs. SCG: Superior Cervical Ganglion; L: Lachrymal Gland; S: Salivary Gland; P: Parotid Gland; MCG: Middle Cervical Ganglion; SG: Stellate Ganglion; CG: Celiac Ganglion; Pan-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); X: Cranial Nerve X (vagus Nerve). 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.

Figure 4. The Sympathetic Nervous System. The Diagram Shows the Thoracolumbar Projection Between T1 and L2 that Forms the Core of the Sympathetic System. Sympathetic Neurons are Located in the Intermediolateral 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 Prevertebral Ganglia Before Reaching Target Organs. SCG: Superior Cervical Ganglion; L: Lachrymal Gland; S: Salivary Gland; P: Parotid Gland; MCG: Middle Cervical Ganglion; SG: Stellate Ganglion; CG: Celiac Ganglion; Pan-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); X: Cranial Nerve X (vagus Nerve). 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.

The parasympathetic system resembles the prevertebral sympathetic system in that the ganglia are located proximal to their target organs (see Figure 5, page 980). Preganglionic parasympathetic neurons are located primarily in the brainstem, with an additional set between spinal cord segments S2 to S4. Parasympathetic fibers innervate all the major organs, including the eyes, heart, lungs, GI tract, and genitals. Both pre-and postganglionic parasympathetic neurons are cholinergic.

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 Caption for Abbreviations.) 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.

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 Caption for Abbreviations.) 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.

In general, the sympathetic division of the autonomic nervous system is a major mediator of the stress response. This includes energy mobilization with catabolism of glycogen and fat, deployment of blood to the muscles, slowing of routine visceral functions, pupillary dilation, and increased heart and respiration rates. In contrast, the parasympathetic division facilitates energy conservation, as well as recuperative processes. Parasympathetic activity promotes slowing of the heartbeat and respiratory rate, digestion of food, storage of fat and glycogen, deployment of blood to the internal organs and pupillary constriction. Responses to stress, as described above, cause activation of the HPA axis, stimulation of the sympathetic nervous system, and inhibition of parasympathetic tone. The combined actions of the HPA axis and sympathetic system prepare the brain and body for responses to life threatening situations.

Physiological Effects of Stress

Stress responses can be life-saving under the right circumstances; however, they also exact a physiological cost, especially if they are chronic. At a systemic level, glucocorticoids released in response to stress inhibit the secretion of other hormones, including growth hormone, gonadotropins, and thyrotropin.14 In addition, glucocorticoids also inhibit the action of growth hormone and sex steroids on their target structures.14 These hormones normally promote lipolysis, as well as muscle and bone anabolism. As a result, the consistently high glucocorticoid levels that characterize chronic stress promote visceral adiposity, as well as decreased bone and muscle mass.14 An example of the clinical implications of this phenomenon has been reported. Women with a diagnosis of borderline personality disorder and comorbid major depressive disorder demonstrated elevated cortisol levels and decreased bone density when compared with controls who also had a diagnosis of borderline personality disorder but no current diagnosis of major depressive disorder.19 In this same study, the borderline patients with current depression also demonstrated increased levels of two inflammatory cytokines (see Figure 6, page 981): tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6).19

TNF-alpha and IL-6. The 3D Structure of Two Important Inflammatory Cytokines Is Displayed. 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 Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

Figure 6. TNF-alpha and IL-6. The 3D Structure of Two Important Inflammatory Cytokines Is Displayed. 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 Editors: All Illustrations in This Article Have Been Created by George I. Viamontes, MD, PhD, for Specific Use in This Issue of Psychiatric Annals.

The elevation of inflammatory cytokines has been documented in a variety of patients with psychiatric disorders, including posttraumatic stress disorder (PTSD)20 and MDD.21 Psychosocial and physical stress, even in the absence of a diagnosed psychiatric disorder, can also increase circulating inflammatory cytokines.22 In elderly patients, elevation of IL-6 has been associated with a variety of active medical conditions, ranging from arthritis to lymphoma.23 Older individuals with elevated IL-6 and C-reactive protein (CRP) were 2.6 times more likely to die in the subsequent 4.6 years than individuals with low IL-6 and CRP levels.24

IL-6 is a cytokine that is produced in innate and adaptive immune responses (see Part 2 of this article, scheduled for a future issue, in the section “Brain-Immune System Interactions”). It is synthesized by a variety of cells in response to immune stimulation, 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 receptors on secreting cells.26 This mechanism facilitates the stimulation of IL-6 secretion 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 addition, IL-6 acts as a growth factor that promotes the differentiation of beta-lymphocytes into antibody-producing cells25 and is a potent inducer of CRF production.26 Although IL-6 by itself does not have perceptible 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 amplification 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 individuals 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 depression, are associated with increased baseline concentrations of IL-6.

On the surface, it may seem counterintuitive for stress-related physiological changes to lead to chronic inflammatory states because sympathetic activation and glucocorticoids inhibit systemic inflammation. The answer to this apparent paradox is that CRF and epinephrine promote immediate, or local inflammatory responses, while inhibiting systemic inflammation.28,29 These actions are consistent with the role of CRF and epinephrine as principal elements of the stress response because their first action is to prime first-line immune 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 initiated and dampen inflammatory reactions to prevent physiological damage.

Thus CRF, which activates the HPA axis, thereby increasing cortisol production, 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 Inflammation of the GI tract as a response to bacterial toxins requires the action of CRF, and inflammatory reactions of this type can be blocked by CRF receptor antagonists.30

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 Intestines, and the Skin. CRF Receptors are also Present in Many Brain Regions, and CRF Binding at These Receptors Generally Results in Activation. On a Systemic 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 Specific Use in This Issue of Psychiatric Annals.

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 Intestines, and the Skin. CRF Receptors are also Present in Many Brain Regions, and CRF Binding at These Receptors Generally Results in Activation. On a Systemic 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 Specific Use in This Issue of Psychiatric Annals.

An important experiment that clarified the role of CRF and epinephrine in inflammatory processes involved the provocation of immune responses in mice that had been adrenalectomized. In the absence of cortisol production, CRF and norepinephrine significantly increased experimentally induced inflammatory processes.32

In general, stimulation of beta-2-adrenergic receptors (beta-2-ARs) on immune cells tends to produce antiinflammatory effects, whereas stimulation of alpha-adrenergic receptors (alpha-ARs) is proinflammatory.33 For example, antigen-naïve macrophages from germ-free mice express primarily alpha-ARs, and norepinephrine stimulation of these cells induces TNF-alpha production.34 In contrast, norepinephrine reduces the responsiveness of mature, antigen-activated macrophages, which express primarily beta-2-ARs.34

A possible mechanism by which stress can be transduced into inflammatory responses has been described. Psychosocial stressors induced rapid NF-kappa-B expression in the peripheral blood mononuclear 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 production 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 requires active NF-kappa-B for transcription. Physiological concentrations of norepinephrine, 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 concatenation of experiments provides detailed evidence for a molecular pathway that leads from stress to the expression of inflammatory 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, experimental and control subjects were exposed to a standardized stressor (the Trier Social Stress Test), and both plasma IL-6 concentrations 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). However, the increases were greater in the depressed 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 respond to stress with IL-6 and NF-kappa-B elevations and that depressed men with a history of childhood abuse show a heightened stress response.

Brain Responses to Psychosocial Stressors. Psychosocial Stressors are Brain-Environment Phenomena Whose Core Defining Feature is the Interpretation of External Circumstances as Threatening. This Results in Activation of the Locus Coeruleusnorepinephrine System, Leading to Norepinephrine Release. In Addition, CRF Is Released by the Extra-Hypothalamic 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 Inflammatory 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 Specific Use in This Issue of Psychiatric Annals.

Figure 8. Brain Responses to Psychosocial Stressors. Psychosocial Stressors are Brain-Environment Phenomena Whose Core Defining Feature is the Interpretation of External Circumstances as Threatening. This Results in Activation of the Locus Coeruleusnorepinephrine System, Leading to Norepinephrine Release. In Addition, CRF Is Released by the Extra-Hypothalamic 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 Inflammatory 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 Specific Use in This Issue of Psychiatric Annals.

The importance of combining activation of local or short-term inflammatory responses with inhibition of systemic inflammation is highlighted by the extreme case of sepsis. In this condition, plasma norepinephrine 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 norepinephrine release from myenteric plexus neurons in the GI tract, likely secondary to activation of tyrosine hydroxylase, the rate-limiting 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 presynaptic membrane and facilitates the release 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 norepinephrine levels spill into the hepatic portal system 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 activation and inflammatory cytokine production continues unabated, death from multiple organ failure will be the eventual 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 inflammatory influences can become dominant is the phenomenon of inadequate glucocorticoid signaling. Theoretically, such signaling could fail as a result of decreased glucocorticoid production or desensitization of glucocorticoid receptors. Evidence of inadequate glucocorticoid signaling, most likely as a result of receptor desensitization, has been found in some individuals with psychiatric disorders, more specifically depression.38 This inadequacy increases the risk of exacerbated inflammatory processes and autoimmune disorders.

Summary

The brain responds to environmental stressors by triggering rapid physiological changes that prepare the body to meet perceived challenges. These changes are primarily 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 conditions. Several syndromal psychiatric disorders also precipitate physiological changes with medical repercussions because they impair the brain’s adaptive ability and magnify the effect of environmental stressors.

Chronic stress induces the brain’s adaptive mechanisms to trigger structural and functional changes that attempt to optimize reactions to recurring conditions. Unfortunately, in a wider context or as conditions change, these neuroplastic changes can be maladaptive and difficult to reverse. One common consequence of such modifications to chronic stress is HPA axis hyperactivity. In addition, chronic stress, as well as certain psychiatric disorders, such as PTSD and MDD, promote chronic inflammatory states, which have adverse medical consequences.

The mechanisms described by which mental processes can trigger physiological changes clearly contribute to adverse effects on medical conditions. It is evident that the effective treatment of medical illness in such patients must address the significant complications posed by psychiatric disorders and chronic stress.

References

  1. Wittstein IL, Thiemann DR, Lima JAC, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352(6):539–548. doi:10.1056/NEJMoa043046 [CrossRef]
  2. Glaser R, Sheridan J, Malarkey WB, MacCallum RC, Kiecolt-Glaser JK. Chronic stress modulates the immune response to a pneumococcal pneumonia vaccine. Psychosom Med. 2000;62(6):804–807.
  3. Carney RM, Rich MW, Friedland KE, et al. Major depressive disorder predicts cardiac events in patients with coronary artery disease. Psychosom Med. 1988;50(6):627–630.
  4. Carney RM, Freedland KE, Steinmeyer B, et al. History of depression and survival after acute myocardial infarction. Psychosom Med. 2009;71(3):253–259. doi:10.1097/PSY.0b013e31819b69e3 [CrossRef]
  5. Nemeroff CB. Neurobiological consequences of childhood trauma. J Clin Psychiatry. 2004;65(Suppl 1):18–28.
  6. Berridge KC, Winkielman P. What is an unconscious emotion? (The case for unconscious “liking”). Cognition and Emotion. 2003;17(2):181–211. doi:10.1080/02699930302289 [CrossRef]
  7. Bechara A, Bar-On R. Substrate of emotional and social intelligence. In: Social Neuroscience People Thinking about People. Cacciopo JT, Visser PS, Pickett CL, eds. The MIT Press, Cambridge, MA. 2006:13–40.
  8. Barbas H. Flow of information for emotions through temporal and orbitofrontal pathways. J Anat. 2007;211(2):237–249. doi:10.1111/j.1469-7580.2007.00777.x [CrossRef]
  9. Viamontes GI. An Atlas of Neurobiology: How the Brain Creates the Self. WW Norton, Inc. 2010. In press.
  10. Davis M. The role of the amygdala in fear and anxiety. Ann Rev Neurosci. 1992;15:353–375. doi:10.1146/annurev.ne.15.030192.002033 [CrossRef]
  11. Martin EI, Nemeroff CB. The role of corticotropin-releasing factor in the pathophysiology of depression: Implications for antidepressant mechanisms of action. Psychiatric Annals. 2008;38(4):260–266. doi:10.3928/00485713-20080401-02 [CrossRef]
  12. Paulus MP, Stein MB. An insular view of anxiety. Biol Psychiatry. 2006;60(4):383–387. doi:10.1016/j.biopsych.2006.03.042 [CrossRef]
  13. Tsigos C, Chrousos GP. Hypothalamic-pituitary-adrenal axis, neuroendocrine factors and stress. J Psychosom Res. 2002;53(4):865–871. doi:10.1016/S0022-3999(02)00429-4 [CrossRef]
  14. Nestler EJ, Hyman SE, Malenka RC. Molecular Neuropharmacology A Foundation for Clinical Neuroscience. 2nd ed. NewYork, NY: McGraw-Hill; 2009.
  15. Rhen T, Cidlowski JA. Antiinflammatory action of glucocorticoids--new mechanisms for old drugs. N Engl J Med. 2005;353(16):1711–23. doi:10.1056/NEJMra050541 [CrossRef]
  16. Elenkov IJ, Wilder RJ, Chrousos GP, Vizi ES. The sympathetic nerve – an integrative interface between two supersystems: the brain and the immune system. Pharmacol Rev. 2000;52:595–638.
  17. Furness JB, Costa M. Types of nerves in the enteric nervous system. Neuroscience. 1980;5(1):1–20. doi:10.1016/0306-4522(80)90067-6 [CrossRef]
  18. Kahl KH, Rudolf S, Stoeckelhuber BM, et al. Bone mineral density, markers of bone turnover, and cytokines in young women with borderline personality disorder with and without comorbid major depressive disorder. Am J Psychiatry. 2005;162(1):168–174. doi:10.1176/appi.ajp.162.1.168 [CrossRef]
  19. Maes M, Lin A, Delmeire L, et al. Elevated Serum interleukin-6 (IL-6) and IL-6 receptor concentrations in posttraumatic stress disorder following accidental man-made traumatic events. Biol Psychiatry. 1999;45(7):833–839. doi:10.1016/S0006-3223(98)00131-0 [CrossRef]
  20. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1995;9(11):853–858. doi:10.1006/cyto.1997.0238 [CrossRef]
  21. Zhou D, Kusnecov AW, Shurin MR, DePaoli M, Rabin BS. Exposure to physical and psychological stressors elevates plasma interleukin-6: relationship to activation of the hypothalamic-pituitary-adrenal axis. Endocrinology. 1993;133(6):2523–2530. doi:10.1210/en.133.6.2523 [CrossRef]
  22. Ershler W, Keller E. Age-associated increased in-terleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–270. doi:10.1146/annurev.med.51.1.245 [CrossRef]
  23. Harris T, Ferrucci L, Tracy R, et al. Associations of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly. Am J Med. 1999;106(5):506–512. doi:10.1016/S0002-9343(99)00066-2 [CrossRef]
  24. Abbas AK, Litchman AH, Pillai S. Cellular and Molecular Immunology. 6th ed. Philadelphia, PA; Elsevier: in press.
  25. Papanicolaou DA, Wilder RL, Manolagas SC, Chrousos GP. The pathophysiologic roles of in-terleukin-6 in human disease. Ann Intern Med. 1998;128(2):127–237.
  26. Sparkman NL, Buchanan JB, Heyen JR, Chen J, Beverly JL, Johnson RW. Interleukin–6 facilitates lipopolysaccharide-induced disruption in working memory and expression of other proinflammatory cytokines in hippocampal neuronal cell layers. J Neurosci. 2006;26(42):10709–10716. doi:10.1523/JNEUROSCI.3376-06.2006 [CrossRef]
  27. Elenkov IJ. Neurohormonal-cytokine interactions: Implications for inflammation, common human diseases and well-being. Neurochem Int. 2008;52(1–2):40–51. doi:10.1016/j.neuint.2007.06.037 [CrossRef]
  28. Mastorakos G, Karoutsou EI, Mizamtsidi M. Corticotropin releasing hormone and the immune/inflammatory response. European Journal of Endocrinology. 2006;155:S77–S84. doi:10.1530/eje.1.02243 [CrossRef]
  29. Black PH. Stress and the inflammatory response: A review of neurogenic inflammation. Brain Behav Immun. 2002;16(6):622–653. doi:10.1016/S0889-1591(02)00021-1 [CrossRef]
  30. Angioni S, Petraglia F, Gallinelli A, et al. Corticotropin-releasing hormone modulates cytokine release in cultured human peripheral blood mononuclear cells. Life Sci. 1993;53(23):1735–1742. doi:10.1016/0024-3205(93)90160-5 [CrossRef]
  31. Karalis KP, Kontopoulos E, Muglia LJ, Majzoub JA. Corticotropin-releasing hormone deficiency unmasks the proinflammatory effect of epinephrine. Proc Nat Acad Sci USA. 1999;96(12):7093–7097. doi:10.1073/pnas.96.12.7093 [CrossRef]
  32. Molina PE. Neurobiology of the stress response: contribution of the sympathetic nervous system to the neuroimmune axis in traumatic injury. Shock. 2005;24(1):3–10. doi:10.1097/01.shk.0000167112.18871.5c [CrossRef]
  33. Spengler RN, Allen RM, Remick DG, Strieter RM, Kunkel SL. Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. J Immunol. 1990;145(5):1430–1434.
  34. Bierhaus A, Wolf J, Andrassy M, et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA. 2003;100(4):1920–1925. doi:10.1073/pnas.0438019100 [CrossRef]
  35. Pace TWW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163(9):1630–1633. doi:10.1176/appi.ajp.163.9.1630 [CrossRef]
  36. Miksa M, Ronquian W, Wang P. Sympathetic excitotoxicity in sepsis: proinflammatory priming of macrophages by norepinephrine. Frontiers in Bioscience. 2005;10:2217–2229. doi:10.2741/1691 [CrossRef]
  37. Raison CL, Miller AH. When not enough is too much: The role of insufficient glucocorticoid signaling in the pathophysiology of stress-related disorders. Am J Psychiatry. 2003;160(7):1554–1565. doi:10.1176/appi.ajp.160.9.1554 [CrossRef]
  38. Molecular structures were obtained from the Research Collaboratory for Structural Informatics Protein Data Bank (RSCB PDB) as follows: doi:10.1093/emboj/16.5.989 [CrossRef] Somers W, Stahl M, Seerah JSa. Interleukin-6: . A crystal structure for interleukin 6: implications for a novel mode of receptor dimerization and signaling. Embo J. 1997;16:989. DOI: 10.1093/EM-BOJ/16.5.989.Eck MJ, Sprang RJb. Tumor Necrosis Factor – Alpha: . The structure of tumor necrosis factor-alpha at 2.6 a resolution. Implications for receptor binding. J Biol Chem. 1988;263:1218. DOI: 10.1074/JBC.272.4.2153.Ghosh G, Van Duyne G, Sigler PBc. Nuclear Factor Kappa-B: . Structure of NF-Kappa B P50 homodimer bound to a Kappa B site. Nature. 1995;373(6512):303. DOI: 10.1038/373303A0.Pioszak AA, Parker NR, Suino-Powell K, Xu HEd. Corticotropin-Releasing Factor (CRF): . Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1. J Biol Chem. 2008;283(47):32900. DOI: 10.1074/JBC.M805749200.

CME 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 physiological 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.

Authors

George I. Viamontes, MD, PhD, is Regional Medical Director, OptumHealth Behavioral Solutions, St. Louis. Charles B. Nemeroff, MD, PhD, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.

Dr. Viamontes has disclosed no relevant financial relationships. Dr. Nemeroff has disclosed the following relevant financial relationships: NovaDel Pharma, Mt. Cook Pharma; Member of Board of Directors; AstraZeneca, PharmaNeuroboost, and CeNeRx: Member of Scientific Advisory Board; and NovaDel Pharma, PharmaNeuroboost, 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 transferred to the publisher; used with permission.

Address correspondence to: George I. Viamontes, MD, PhD; george. .viamontes@optumhealth.com

10.3928/00485718-20091124-03

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