The Scientific Journals

By : Bettina Thraenhardt

Fortunately, it is not always necessary to eliminate the voices completely to decrease the discomfort they cause. Most people who experience acoustic hallucinations attribute a purpose to their voices. How they view their voices—wellmeaning or out to destroy them—is almost always a function of what they hear. In 2003 Mark van der Gaag, now at the Free University Amsterdam in the Netherlands, found that only two of 43 patients evaluated their hallucinations differently from what researchers expected. Some patients are convinced that critical voices are actually well-meaning. “As therapists, we need to pay more attention to how a person explains the phenomenon,” Bock concludes. Therapists who immediately talk in terms of severe mental illness often only make the problem worse, risking that the patient will withdraw. The sooner a patient begins to talk about the voices, the less power those voices tend to have.

Quiet! Some voices torment sufferers with constant insults. People who hear voices often live extremely withdrawn lives—and the hallucinations, in turn, fuel social rejection

Frequently, it is enough to reframe the voices. Even if they are overwhelmingly negative, other intentions or characteristics may be attributed to them through therapy. According to guidelines developed by Netzwerk Stimmenhoeren, a German organization dedicated to founding self-help groups and supporting the affected, their families and the psychiatric community, the main goal is to make sufferers “masters in their own house” again. Patients can sometimes regain this control not only by listening to the voices but by answering them, concentrating on positive messages and agreeing to specifi c, limited talking times.

Another mainstay of treatment involves changing a patient’s social interactions. Often a person’s relationship with his or her voices mirrors those with real people, as Mark Hayward, now at the University of Surrey in England, demonstrated in 2003. If, for example, a person usually subordinates herself to someone else, she will tend to hear dominant voices. The net effect is that the hallucinations become increasingly real. Networks of fellow sufferers may help people reduce the isolation they feel and make strides in recovery. “I got to the point where I couldn’t take it anymore,” Laurie says, explaining why she dared to “come out.” Laurie agreed to make time for her voices in the morning, and, in exchange, they agreed to leave her alone the rest of the day. The approach may seem odd, but it worked. Now, she says, “My voices simply don’t scare me anymore.

By : Bettina Thraenhardt

For those who do suffer from their inner voices, researchers are trying to fi nd ways of hushing them. Antipsychotic medications work for some but not all patients. As an alternative, Ralph E. Hoffman and his co-workers at the Yale University School of Medicine have investigated the potential of transcranial magnetic stimulation (TMS), a technique by which they can decrease brain activity in certain regions using magnetic fields. They have applied TMS to the regions involved in speech processing. In 2000 they suppressed acoustic hallucinations in 12 schizophrenic patients by decreasing the arousability of the temporoparietal cortex. In a follow-up study in 2005 they treated 50 patients for nine days with low-frequency impulses and found that verbal hallucinations decreased markedly in more than half the patients—an effect that lasted for at least three months.

The occurrence of hallucinations varies with age and race, according to a survey of the public in England and Wales. Louise C. Johns of the Institute of Psychiatry at King’s College London and her colleagues reviewed data from 2,867 whites and 5,196 members of minority ethnic groups.
Hallucinations were most common among teens in the white sample but among those in their 20s and 50s in the Caribbean group. In the South Asian sample, prevalence varied only very little by age. Overall, 4 percent of whites reported hearing or seeing things. In comparison, rates were 2.5 times higher among Caribbeans and half as much among South Asians.

Cultural Differencies

SOURCE : “OCCURRENCE OF HALLUCINATORY EXPERIENCES IN A COMMUNIT Y SAMPLE AND ETHNIC VARIATIONS,” BY L . C. JOHNS, J . Y. NAZROO, P. BEBBINGTON AND E . KUIPERS IN BRITISH JOURNAL OF PSYCHIATRY, VOL. 180; 2002

Next : Limited Talk Time

By : Bettina Thraenhardt

How do these perceptions come about in the absence of external stimuli? As Bock explains, acoustic hallucinations may arise from “too much inside” or “too little outside.” On one side of this theoretical coin, Bock suggests that, psychologically, some affected people may hold too much on the inside. Sufferers have  often experienced some kind of trauma as a child or adult, such as neglect, abuse, rape or a severe accident.  Many then suffer from unresolved confl icts or find themselves in situations that overwhelm them. In these cases, verbal hallucinations may serve as signals that they need to pay attention to their own inner voice.

From a neurobiological perspective, the notion of “too much inside” makes sense in that some sufferers appear to interpret their own thoughts as alien. Some researchers therefore suspect that the hallucinations involve a failure in a specifi c feedback circuit in the brain, which normally tells us that “I” am now thinking or speaking, not someone else. This hypothesis— that self-generated speech gets misattributed— seems to apply especially well to hallucinating schizophrenics, about whom researchers have the most information.

Philip K. McGuire and his colleague Louise C. Johns of the Institute of Psychiatry at King’s College London  tested the model by having several schizophrenic patients, as well as people with no psychiatric history, speak into a microphone.  At the same time, the test subjects listened to their voices, distorted by the researchers, through headphones. The participants were asked to press a button if they thought they were listening to themselves. In general, the schizophrenics had greater diffi culties identifying their own voices. Those who had active hallucinations most often attributed their speech to an external source, particularly when what they said into the microphone was disparaging or contemptuous.

Studies using brain-imaging techniques have also elucidated the physiological mechanisms that underlie verbal hallucinations. In 1993 McGuire and his colleagues scanned the brains of 12 schizophrenics while they were hearing voices and while they were not. They found that during the hallucinations the greatest increase in brain activity took place in Broca’s area, a region involved not in hearing speech but in producing it. Other speech- processing areas of the brain, including the superior temporal gyrus in the left temporal lobe, are under close scrutiny. This gyrus, or bump, is responsible for speech perception and plays a crucial role in the integration of acoustic and speech information. Various researchers, among them Thomas Dierks of the University of Bern in Switzerland, have demonstrated that it also plays a key role in verbal hallucinations.

In 1999 Dierks, who was then at the University of Frankfurt, and his co-workers used functional magnetic resonance imaging (fMRI) to observe the brains of three schizophrenic patients while they were hearing voices. In addition to the superior temporal gyrus, they found activity in the primary auditory cortex, which normally processes sounds from the outside world. No wonder these patients believed their hallucinations were real: their brains responded to them much as they did to actual speech. Several other studies have produced intriguing fi ndings, among them that the left superior temporal gyrus seems consistently smaller in patients with severe acoustic hallucinations. Exactly what this size difference signifi es is still the subject of speculation.

On the fl ip side of Bock’s theoretical coin, hearing voices is not always a consequence of neurobiological change. Sometimes the brain simply receives too few stimuli from the outside world. People who hear voices often live extremely withdrawn lives—and the hallucinations, in turn, fuel social rejection. Some sailors and hikers, for example, who have endured stimulus-poor conditions for prolonged periods have reported auditory hallucinations. Indeed, Rilke’s angel spoke only after he had lived for two months in isolation at Duino Castle. Deafness, too, can present a kind of isolation. In 1992 Detlef Koempf, a neurologist at the University Medical Center of Schleswig-Holstein, Germany, discovered that musical hallucinations are not uncommon in older peoplewho have lost some hearing. He hypothesizes that the brain stores auditory information that it has captured over an extended period. If the external output is cut off, the deposited signals may take on a life of their own.

Whether hearing voices presents a medical problem depends largely on how much a person suffers. A Dutch team headed by Marius Romme, then at the University of Maastricht in the Netherlands, found signifi can't differences in the types of auditory hallucinations experienced by schizophrenics and people who were psychiatrically normal.Both groups reported dialogues, running commentary or the vocalization of their own thoughts. The mentally ill, however, far more frequently described negative voices: “You stupid idiot!” or “As usual, you revealed our family secrets!” The other study participants usually heard benign voices that  encouraged them: “Come on, you can do it!” or “It really wasn’t your fault.” In addition, they were more likely to feel that they were in control of the voices.

Next : Hushed Voices

By : Bettina Thraenhardt

Auditory hallucinations are not always disparaging. They can also be encouraging, such as when a voice whispers, “Come on, you can do it!” or “It really wasn’t your fault.”

In fact, auditory hallucinations may not be uncommon. Because it is diffi cult to defi ne the phenomenon with true precision, data on its prevalence differ from study to study. As early as 1983, though, psychologists Thomas B. Posey and Mary E. Losch, then both at Murray State University in Kentucky, found that roughly 70 percent of the 375 college students they questioned admitted to having heard voices at least once. Subjects thought that they had heard deceased relatives, divine beings or their own thoughts. Still others had heard their names, often before falling asleep. Acoustic perceptions during waking or presleep phases—reported by 40 percent of Posey and Losch’s subjects—are generally viewed as pseudohallucinations. Thus, by including them in their tallies, these researchers may have produced a high estimate.

Nevertheless, in 1991 a National Institute of Mental Health survey found that nearly 5 percent of the 15,000 American adults who responded had experienced hallucinations—most of them auditory—during a one-year period; only one third of that group also met criteria for a psychiatric diagnosis. According to Thomas Bock, a psychotherapist and director of the outpatient psychosis service at the University Medical Center of  Hamburg-Eppendorf, Germany, at least 3 to 5 percent of the population in western Europe and the U.S. hear voices. Schizophrenia, in comparison, affects only about one in 100.


Next : Too much and too little

By : Bettina Thraenhardt

Not only schizophrenics experience auditory hallucinations.  Many people who are not mentally ill sometimes hear claps, whistles, buzzing, voices or even music in their heads.

Suddenly she heard someone call her name—“Laurie!”—but no one else was in the room. Feeling irritated, Laurie looked around the apartment. It was empty. Maybe someone was in the hallway? Or at the door? She found no one. Realizing that she was completely alone, Laurie felt chills run up her spine. Was she crazy?

Perhaps no other symptom is as instantly associated with insanity—some 70 percent of schizophrenics hear voices that regularly interrupt their thoughts, as do 15 percent of those who have mood disorders—but auditory hallucinations are not necessarily a sign of mental illness. They can arise as symptoms in any number
of conditions, including Alzheimer’s and Parkinson’s diseases and temporal lobe epilepsy.  In addition, episodes can occur in the absence of any physical or psychological problem.

Although such experiences are heavily stigmatized today, many famous thinkers, poets, artists and scholars of earlier times described hearing voices: a wise demon spoke to Socrates, the saints emboldened Joan of Arc, and an angel addressed Rainer Maria Rilke, inspiring his Duino Elegies. The list goes on: Carl Gustav
Jung, Andy Warhol, Galileo, Pythagoras, William Blake, Winston Churchill, Robert Schumann
and Gandhi, among others, have all reportedly heard voices.

Next : Listen Up

By : Esther M. Sternberg and Philip W. Gold

Immune Cells. Altered Genetic Activity in immune cells is an effect of cortisol. The cortisol receptors in immune cells are folded and bound to large “heat-shock” proteins. When cortisol enters a cell and binds to its receptor, the protein is displaced and the receptor unfolds. The receptor then binds to DNA in the nucleus, changing the cell’s transcription of messenger RNA (mRNA) and production of proteins. (Other molecules called c-fos and c-jun bind with the receptor and confer more specificity on its action.) The proteins leave the cell and directly affect cytokine and lymphocyte production.

For centuries, taking the cure at a mountain sanatorium or a hotsprings spa was the only available treatment for many chronic diseases. New understanding of the communication between the brain and immune system provides a physiological explanation of why such cures sometimes worked. Disruption of this communication  network leads to an increase in susceptibility to disease and can worsen the course of the illness. Restoration  of this communication system, whether through pharmacological agents or the relaxing effects of a spa, can be the first step on the road to recovery.

A corollary of these findings is that psychoactive drugs may in some cases be used to treat inflammatory  iseases, and drugs that affect the immune system may be useful in treating some psychiatric disorders. There is growing evidence that our view of ourselves and others, our style of handling stresses, as well as our genetic  makeup, can affect activities of the immune system. Similarly, there is good evidence that diseases associated with chronic inflammation significantly affect on one’s mood or level of anxiety. Finally, these findings suggest that classification of illnesses into medical and psychiatric specialties, and the boundaries that have  emarcated mind and body, are artificial.

By : Esther M. Sternberg and Philip W. Gold

In the past, the association between an inflammatory disease and stress was considered by doctors to be secondary to the chronic pain and debilitation of the disease. The recent discovery of the common  underpinning of the immune and stress responses may provide an explanation of why a patient can be  susceptibleto both inflammatory disease and depression. The hormonal dysregulation that underlies both inflammatory disease and depression can lead to either illness, depending on whether the perturbing stimulus is pro-inflammato- ry or psychologically stressful. That may explain why the waxing and waning of  depression  in arthritic patients does not always coincide with inflammatory flare-ups.

The popular belief that stress exacerbates inflammatory illness and that relaxation or removal of stress ameliorates it may indeed have a basis in fact. The interactions of the stress and immune systems and the hormonal responses they have in common could explain how conscious attempts to tone down responsivity to stress could affect immune responses.

IMMUNE SIGNALS TO THE BRAIN via the bloodstream can occur directly or indirectly. Immune cells such as monocytes, a type of white blood cell, produce a chemical messenger called interleukin- 1 (IL-1), which ordinarily will not pass through the blood-brain barrier. But certain cerebral blood vessels contain leaky junctions, which allow IL-1 molecules to pass into the brain. There they can activate the HPA axis and other neural systems. IL-1 also binds to receptors on the endothelial cells that line cerebral blood vessels. This binding can cause enzymes in the cells to produce nitric oxide or prostaglandins, which diffuse into the brain and act directly on neurons.

How much of the responsivity to stress is genetically determined and how much can be consciously controlled is not known. The set point of the stress response is to some extent genetically determined. An event that is physiologically highly stressful to one individual may be much less so to another, depending on each person’s genetic tendency to hormonal reactivity. The degree to which stress could precipitate or
exacerbate inflammatory disease would then depend both on the intensity of the stressful stimulus and on the set point of the stress system.

Psychological stress can affect an individual’s susceptibility to infectious diseases. The regulation of the immune system by the neurohormonal stress system provides a biological basis for understanding how stress might affect these diseases. There is evidence that stress does affect human immune responses to viruses and bacteria. In studies with volunteers given a standard dose of the common cold virus (rhinovirus), individuals who are simultaneously exposed to stress show more viral particles and produce more mucus than do nonstressed individuals. Medical students receiving hepatitis vaccination during their final exams do not develop full protection against hepatitis. These findings have important implications for the scheduling of vaccinations. People who are vaccinated during periods of stress might be less likely to develop full antibody protection.

Animal studies provide further evidence that stress affects the course and severity of viral illness, bacterial disease and septic shock. Stress in mice worsens the severity of influenza infection and affects both the HPA  axis and the sympathetic nervous system. Animal studies suggest that neuroendocrine mechanisms could play  a similar role in infections with other viruses, including HIV, and provide a mechanism for  understanding clinical observations that stress may exacerbate the course of AIDS. Stress increases the  susceptibility of mice to infection with mycobacteria, the bacteria that causes tuberculosis. It has been shown that an intact HPA axis protects rats against the lethal septic effects of salmonella bacteria. Finally, new understanding  of interactions of the immune and stress responses can help explain the puzzling observation that classic psychological conditioning of animals can influence their immune responses. For example, working with rats, Robert Ader and Nicholas Cohen of the University of Rochester paired saccharinflavored water with an  immunosuppressive drug. Eventually the saccharin alone produced a decrease in immune function similar to  that of the drug.

Stress is not only personal but is perceived through the prism of interactions with other persons. Social  interactions can either add to or lessen psychological stress and similarly affect our hormonal responses to it,  which in turn can alter immune responses. Thus, the social psychological stresses that we experience can  affect our susceptibility to inflammatory and infectious diseases and the course of a disease. For instance, studies have shown that persons exposed to chronic social stresses for more than two months have increased  susceptibility to the common cold.

Other studies have shown that the immune responses of long-term caregivers, such as spouses of Alzheimer’s patients, become blunted. Immune responses in unhappily married and divorcing couples are also blunted.  Often the wife has a feeling of helplessness and experiences the greatest amount of stress. In such a scenario,  studies have found that the levels of stress hormones are elevated and immune responses usually are lowered  in the wife but not in the husband.

On the other hand, a positive supportive environment of extensive social networks or group psychotherapy  can enhance immune response and resistance to disease—even cancer. Women with breast cancer, for  instance, who receive strong, positive social support during their illness have significantly longer life spans than women without such support.

Next : New Approaches to Treatment

By : Esther M. Sternberg and Philip W. Gold

Although the role of the stress response in inflammatory disease in humans is more difficult to prove, there is a growing amount of evidence that a wide variety of such diseases are associated with impairment of the HPA axis and lower levels of CRH secretion, which ultimately results in a hyperactive immune system.  Furthermore, patients with a mood disorder called atypical depression also have a blunted stress response and impaired CRH function, which leads to lethargy, fatigue, increased sleep and increased feeding that often produces weight gain.

Patients with other illnesses characterized by lethargy and fatigue, such as chronic fatigue syndrome, fibromyalgia and seasonal affective disorder (SAD), exhibit features of both depression and a hyperactive immune system. A person with chronic fatigue syndrome classically manifests debilitating lethargy or fatigue lasting six months or longer with no demonstrable medical cause, as well as feverishness, aches in joints and muscles, allergic symptoms and higher levels of antibodies to a variety of viral antigens (including Epstein-Barr virus).

Patients with fibromyalgia suffer from muscle aches, joint pains and sleep abnormalities, symptoms similar to  early, mild rheumatoid arthritis. Both these illnesses are associated with a profound fatigue like that in atypical depression. SAD, which usually occurs in winter, is typified by lethargy, fatigue, increased food intake and  increased sleep. Many of its symptoms are similar to those of atypical depression.

CRH, the Locus Ceruleus and Sympathetic Nervous System HYPOTHALAMIC CRH produces changes important to stress and inflammation adaptation in ways other than inducing cortisol release from the adrenal glands. Pathways from CRH-secreting neurons in the hypothalamus extend to the locus ceruleus in the brain stem. Separate pathways from other hypothalamic neurons to the brain stem influence sympathetic nervous system activity, which modulates inflammatory responses as well as regulating metabolic and cardiovascular activities. Stimulation by CRH of the locus ceruleus produces protective behaviors such as arousal and fear (red indicates stimulation, blue inhibition). The locus ceruleus, in turn, provides feedback to the hypothalamus for continued production of CRH and also acts on the sympathetic nervous system. Self-inhibitory feedback keeps the activities of CRH and the locus ceruleus under control.

A deficiency of CRH could contribute to lethargy in patients with chronic fatigue syndrome. Injection of CRH into patients with fatigue syndrome causes a delayed and blunted ACTH secretion by the HPA axis. That same response is also seen in patients whose hypothalamus has been injured or who have a tumor. Also, fatigue and hyperactivity of the immune response are associated with cortisol deficiency, which occurs when CRH secretion decreases. The hormone levels and responses in patients with fatigue syndromes suggest— but do not prove—that their HPA-axis functions are impaired, resulting in a decrease in CRH and cortisol secretion and an increase in immune system activity. Together these findings suggest that human illness  characterized by fatigue and hyperimmunity could possibly be treated by drugs that mimic CRH actions in the brain.

In contrast, the classic form of depression, melancholia, actually is not a state of inactivation and suppression of thought and feeling; rather it presents as an organized state of anxiety. The anxiety of melancholia is chiefly about the self. Melancholic patients feel impoverished and defective and often express hopelessness about the prospects for their unworthy selves in either love or work. The anxious hyperarousal of melancholic patients also manifests as a pervasive sense of vulnerability, and melancholic patients often interpret relatively neutral cues as harbingers of abandonment or embarrassment.

Melancholic patients also show behavioral alterations suggestive of physiological hyperarousal. They characteristically suffer from insomnia (usually early-morning awakening) and experience inhibition of eating,  sexual activity and menstruation. One of the most widely found biological abnormalities in patients with melancholia is that of sustained hypersecretion of cortisol.

Many studies have been conducted on patients  with major depression to determine whether the excessive level of cortisol associated with depression correlates with suppressed immune responses. Some have found  a correlation between hypercortisolism and immunosuppression; others have not. Because depression can have a variety of mental and biochemical causes only some depressed patients may be immunosuppressed.

The excessive secretion of cortisol in melancholic patients is the result predominantly of hypersecretion of  CRH, caused by a defect in or above the hypothalamus. Thus, the clinical and biochemical manifestations of  melancholia reflect a generalized stress response that has escaped the usual counterregulation, remaining, as it were, stuck in the “on” position.

The effects of tricyclic antidepressant drugs on components of the stress response support the concept that melancholia is associated with a chronic stress response. In rats, regular, but not acute, administration of the  tricyclic antidepressant imipramine significantly lowers the levels of CRH precursors in the hypothalamus. Imipramine given for two months to healthy persons with normal cortisol levels causes a gradual and sustained decrease in CRH secretion and other HPA-axis functions, indicating that down-regulation of important components of the stress response is an intrinsic effect of imipramine.

Depression is also associated with inflammatory disease. About 20 percent of patients with rheumatoid arthritis develop clinical depression at some point during the course of their arthritic disease. A questionnaire commonly used by clinicians to diagnose depression contains about a dozen questions that are almost always  answered affirmatively by patients with arthritis.

Next : Stress and Illness

By : Esther M. Sternberg and Philip W. Gold

The immune response is an elegant and finely tuned cascade of cellular events aimed at ridding the body of foreign substances, bacteria and viruses.

One of the major discoveries of contemporary immunology is that white blood cells produce small proteins that indirectly coordinate the responses of other parts of the immune system to pathogens. For example, the protein interleukin-1 (IL-1) is made by a type of white blood cell called a monocyte or macrophage. IL-1 stimulates another type of white blood cell, the lymphocyte, to produce interleukin-2 (IL-2), which in turn induces lymphocytes to develop into mature immune cells. Some mature lymphocytes, called plasma cells, make antibodies that fight infection, whereas others, the cytotoxic lymphocytes, kill viruses directly. Other interleukins mediate the activation of immune cells that are involved in allergic reactions.

The interleukins were originally named to reflect what was considered to be their primary function: communication between (“inter-”) the white blood cells (“leukins”). But it is now known that interleukins also act as chemical signals between immune cells and many other types of cells and organs, including parts of the brain, and so a new name—“cytokine”—has been coined. Cytokines are biological molecules that cells use to communicate.  Each cytokine is a distinct protein molecule, encoded by a separate gene, that targets a particular cell type. A cytokine can either stimulate or inhibit a response depending on the presence of other cytokines or other stimuli and the current state of metabolic activity. This flexibility allows the immune system to take the most appropriate actions to stabilize the local cellular environment and to maintain homeostasis.

Cytokines from the body’s immune system can send signals to the brain in several ways. Ordinarily, a  “bloodbrain barrier” shields the central nervous system from potentially dangerous molecules in the bloodstream. During inflammation or illness, however, this barrier becomes more permeable, and cytokines may be carried across into the brain with nutrients from the blood. Certain cytokines, on the other hand, readily pass through at any time. But cytokines do not have to cross the blood-brain barrier to exert their effects. Cytokines made in the lining of blood vessels in the brain can stimulate the release of secondary chemical signals in the brain tissue around the blood vessels.

Cytokines can also signal the brain via direct nerve routes, such as the vagus nerve, which innervates the heart, stomach, small intestine and other organs of the abdominal cavity. Injection of IL-1 into the abdominal cavity activates the nucleus of the tractus solitarius, the principal region of the brain stem for receipt of visceral sensory signals. Cutting the vagus nerve blocks activation of the tractus nucleus by IL-1. Sending signals along nerve routes is the most rapid mechanism—on the order of milliseconds—by which cytokines signal the brain.

Activation of the brain by cytokines from the peripheral parts of the body induces behaviors of the stress response, such as anxiety and cautious avoidance, that keep the affected individual out of harm’s way until full healing occurs. Anyone who has experienced lethargy and excess sleepiness during an illness will recognize this set of characteristic responses as “sickness behavior.”

Hypothalamus-Pituitary-Adrenal (HPA) Axis HPA AXIS is a central component of the brain’s neuroendocrine response to stress. The hypothalamus, when stimulated, secretes corticotropin-releasing hormone (CRH) into the hypophyseal portal system, which supplies blood to the anterior pituitary. CRH stimulates the pituitary (red arrows show stimulatory pathways) to secrete adrenocorticotropin hormone (ACTH) into the bloodstream. ACTH causes the adrenal glands to release cortisol, the classic stress hormone that arouses the body to meet a challenging situation. But cortisol then modulates the stress response (blue arrows indicate inhibitory effects) by acting on the hypothalamus to inhibit the continued release of CRH. Also a potent immunoregulator, cortisol acts on many parts of the immune system to prevent it from overreacting and harming healthy cells and tissue.

Neurons and nonneuronal brain cells also produce cytokines of their own. Cytokines in the brain regulate  nerve cell growth and death, and they also can be recruited by the immune system to stimulate the release of CRH. The IL-1 cytokine system in the brain is currently the best understood—all its components have been identified, including receptors and a naturally occurring antagonist that binds to IL-1 receptors without activating them. The anatomical and cellular locations of this IL-1 circuitry are being mapped out in detail, and this new knowledge will aid researchers in designing drugs that block or enhance the actions of such circuits and the functions they regulate.

Excessive amounts of cytokines in the brain can be toxic to nerves. In genetically engineered mice, transplanted genes that overexpress cytokines produce neurotoxic effects. Some of the neurological symptoms of AIDS in humans also may be caused by overexpression of certain cytokines in the brain. High levels of IL-1 and other cytokines have been found in the brain tissue of patients living with AIDS, concentrated in areas around the giant macrophages that invade the patients’ brain tissue.

Any disruption of communication between the brain and the immune system leads to greater susceptibility to inflammatory disease and, frequently, to increased severity of the immune complications. For instance, animals whose brain-immune communications have been disrupted (through surgery or drugs) are highly liable to lethal complications of inflammatory diseases and infectious diseases.

INTERACTION BRAIN AND IMMUNE SYSTEM Brain and immune system can either stimulate (red arrows) or inhibit (blue arrows) each other. Immune cells produce cytokines (chemical signals) that stimulate the hypothalamus through the bloodstream or via nerves elsewhere in the body. The hormone CRH, produced in the hypothalamus, activates the HPA axis. The release of cortisol tunes down the immune system. CRH, acting on the brain stem, stimulates the sympathetic nervous system, which innervates immune organs and regulates inflammatory responses throughout the body. Disruption of these communications in any way leads to greater susceptibility to disease and immune complications.

Susceptibility to inflammatory disease that is associated with genetically impaired stress response can be found across species—in rats, mice, chickens and, though the evidence is less direct, humans. For instance, the Lewis strain of rat is naturally prone to many inflammatory diseases because of a severe impairment of its HPA axis, which greatly diminishes CRH secretion in response to stress. In contrast, the hyperresponsive HPA-axis in the Fischer strain of rat provides it with a strong resistance to inflammatory disease.

Evidence of a causal link between an impaired stress response and susceptibility to inflammatory disease comes from pharmacological and surgical studies. Pharmacological intervention such as treatment with a drug that blocks cortisol receptors enhances autoimmune inflammatory disease. Injecting low doses of cortisol into disease-susceptible rats enhances their resistance to inflammation. Strong evidence comes from surgical intervention. Removal of the pituitary gland or the adrenal glands from rats that normally are resistant to inflammatory disease renders them highly susceptible. Further proof comes from studies in which the  transplantation of hypothalamic tissue from disease-resistant rats into the brain of susceptible rats dramatically improves their resistance to peripheral inflammation.

These animal studies demonstrate that disruption of the brain’s stress response enhances the body’s response to inflammatory disease, and reconstitution of the stress response reduces susceptibility to inflammation. One implication of these findings is that disruption of the brain-immune communication system by inflammatory, toxic or infectious agents could contribute to some of the variations in the course of the immune system’s inflammatory response.

Next : CRH and Depression

By : Esther M. Sternberg and Philip W. Gold

Both systems also rely on chemical mediators for communication. Electrical signals along nerve pathways, for instance, are converted to chemical signals at the synapses between neurons. The chemical messengers produced by immune cells communicate not only with other parts of the immune system but also with the  brain and nerves, and chemicals released by nerve cells can act as signals to immune cells. Hormones from the body travel to the brain in the bloodstream, and the brain itself makes hormones. Indeed, the brain is  perhaps the most prolific endocrine organ in the body and produces many hormones that act both on the   brain and on tissues throughout the body.

A key hormone shared by the central nervous and immune systems is corticotropin- releasing hormone (CRH); produced in the hypothalamus and several other brain regions, it unites the stress and immune responses. The hypothalamus releases CRH into a specialized bloodstream circuit that conveys the hormone  to the pituitary gland, which is just beneath the brain. CRH causes the pituitary to release adrenocorticotropin
hormone (ACTH) into the bloodstream, which in turn stimulates the adrenal glands to produce cortisol, the  best-known hormone of the stress response.

Cortisol is a steroid hormone that increases the rate and strength of heart contractions, sensitizes blood vessels to the actions of norepinephrine (an adrenalinelike hormone) and affects many metabolic functions —actions that help to prepare the body to meet a stressful situation. In addition, cortisol is a potent  immunoregulator and antiinflammatory agent. It plays a crucial role in preventing the immune system from overreacting to injuries and damaging tissues. Furthermore, cortisol inhibits the release of CRH by the  hypothalamus—a simple feedback loop that keeps this component of the stress response under control. Thus, CRH and cortisol directly link the body’s brainregulated stress response and its immune response.

CRH-secreting neurons of the hypothalamus send fibers to regions in the brain stem that help to regulate the sympathetic nervous system, as well as to another brain stem area called the locus ceruleus. The sympathetic nervous system, which mobilizes the body during stress, also innervates immune organs, such as the thymus,  lymph nodes and spleen, and helps to control inflammatory responses throughout the body. Stimulation of the  locus ceruleus leads to behavioral arousal, fear and enhanced vigilance.

Perhaps even more important for the induction of fear-related behaviors is the amygdala, where inputs from  the sensory regions of the brain are charged as stressful or not. CRH-secreting neurons in the central nucleus  of the amygdala send fibers to the hypothalamus and the locus ceruleus, as well as to other parts of the brain  stem. These CRH-secreting neurons are targets of messengers released by immune cells during an immune response. By recruiting the CRH-secreting neurons, the immune signals not only activate cortisolmediated restraint of the immune response but also induce behaviors that assist in recovery from illness or injury. CRH-secreting neurons also have connections with hypothalamic regions that regulate food intake and  reproductive behavior. In addition, there are other hormonal and nerve systems, such as the thyroid, growth and female sex hormones, and the sympathomedullary pathways, that influence brain–immune system  interactions.

Next : The Immune System’s Signals

by : Esther M. Sternberg and Philip W. Gold


When homeostasis is disturbed or threatened, a repertoire of molecular, cellular and behavioral responses comes into play. These responses attempt to counteract the disturbing forces in order to reestablish a steady state. They can be specific to the foreign invader or a particular stress, or they can be generalized and  nonspecific when the threat to homeostasis exceeds a certain threshold. The adaptive responses may themselves turn into stressors capable of producing disease. We are just beginning to understand the many ways in which the brain and the immune system are interdependent, how they help to regulate and counterregulate each other and how they themselves can malfunction and produce disease.

The stress response promotes physiological and behavioral changes that enhance survival in threatening or  taxing situations. For instance, when we are facing a potentially life-threatening situation, the brain’s stress response goes into action to enhance our focused attention, our fear and our fight-or-flight response, while simultaneously inhibiting behaviors, such as feeding, sex and sleep, that might lessen the chance of immediate  survival. The stress response, however, must be regulated to be neither excessive nor suboptimal; otherwise, disorders of arousal, thought and feeling emerge.

The immune system’s job is to bar foreign pathogens from  the body and to recognize and destroy those that penetrate its shield. The immune system also must neutralize potentially dangerous toxins, facilitate repair of damaged or worn tissues, and dispose of abnormal cells. Its responses are so powerful that they require constant regulation to ensure that they are neither excessive nor indiscriminate and yet remain effective. When the immune system escapes regulation, autoimmune and  inflammatory diseases or immune deficiency syndromes result.

The immune and central nervous systems appear, at first glance, to be organized in very different ways. The  brain is usually regarded as a centralized command center, sending and receiving electrical signals along fixed  pathways, much like a telephone network. In contrast, the immune system is decentralized, and its organs (spleen, lymph nodes, thymus and bone marrow) are located throughout the body. The classical view is that  the immune system communicates by releasing immune cells into the bloodstream that float, like boats, to new locations to deliver their messages or to perform other functions. The central nervous and immune systems, however, are in fact more similar than different in their modes of receiving, recognizing and integrating signals from the external environment and in their structural design for accomplishing these tasks. Both the central
nervous system and the immune system possess “sensory” elements, which receive information from the  nvironment and other parts of the body, and “motor” elements, which carry out an appropriate response.

Next : Cross Communication

By : Esther M. Sternberg and Philip W. Gold

The belief that the mind plays an important role in physical illness goes back to the earliest days of medicine. From the time of the ancient Greeks to the beginning of the 20th century, it was generally accepted by both
physician and patient that the mind can affect the course of illness, and it seemed natural to apply this concept in medical treatments of disease. After the discovery of antibiotics, a new assumption arose that treatment of infectious or inflammatory disease requires only the elimination of the foreign organism or agent that triggers the illness. In the rush to discover new antibiotics and drugs that cure specific infections and diseases, the fact that the body’s own responses can influence susceptibility to disease and its course was largely ignored by medical researchers.

It is ironic that research into infectious and inflammatory disease first led 20th-century medicine to reject the idea that the mind influences physical illness, and now research in the same field—including the work of our laboratory and of our collaborators at the National Institutes of Health—is proving the contrary. New molecular and pharmacological tools have made it possible for us to identify the intricate network that exists between the immune system and the brain, a network that allows the two systems to signal  each other continuously and rapidly. Chemicals produced by immune cells signal the brain, and the rain in turn sends chemical signals to restrain the immune system. These same chemical signals also affect behavior and the response to stress. Disruption of this communication network in any way, whether inherited or through drugs, toxic substances or surgery, exacerbates the diseases that these systems guard against: infectious, inflammatory, autoimmune and associated mood disorders.

The clinical significance of these findings is likely to prove profound. They hold the
promise of extending the range of therapeutic treatments available for various disorders,
as drugs previously known to work primarily for nervous system problems
are shown to be effective against immune maladies, and vice versa. They also help
to substantiate the popularly held impression (still discounted in some medical circles)
that our state of mind can influence how well we resist or recover from infectious
or inflammatory diseases.

Immune response can be altered at the cellular level by stress hormones.

The brain’s stress response system is activated in threatening situations. The immune system responds automatically to pathogens and foreign molecules. These two response systems are the body’s principal means for maintaining an internal steady state called homeostasis. A substantial proportion of human cellular machinery is dedicated to maintaining it.

Next : Anatomy of the Stress and Immune Systems