Ruled by the Body: How Physical Illness Affects the Brain

When I first met Tina, a woman in her late 20s, she had been seeing mental health professionals for virtually her entire life. “One day I’m energetic and creative,” she told me during one of our therapy sessions, “the next I am aimless, or I cry and feel worthless.” Tina had been diagnosed with depression, borderline personality disorder and even schizophrenia. Doctors prescribed antidepressants and later antipsychotics—but the meds only seemed to make her worse. At first I, too, saw her difficulties through the lens of a psychologist, thinking she had bipolar disorder. But later I noticed that her mood swings were accompanied by symptoms such as a racing heart, nausea and joint pain. So I asked her doctors to do a thorough blood workup.

Finally, after her 30th birthday, a doctor discovered the real cause of her suffering: porphyria, a group of rare genetic metabolic disorders. In people with porphyria, precursors of hemoglobin (the molecule that carries oxygen in red blood cells) called porphyrins accumulate in various body systems, causing symptoms from abdominal pain to depression. The female sex hormone progesterone tends to aggravate the condition, so Tina’s moods followed her menstrual cycle. Because the disorder affects the liver, the body has difficulty processing medication, so drugs often create perplexing new symptoms.

Porphyria is rare, but its effects on mental well-being provide an example of a far more widespread, though similarly unrecognized, notion: many physical ailments can surreptitiously erode the psyche. For example, inflammation from infections and chronic disorders can spawn depression. Sadness and lethargy may also result from hormone imbalances or nutrient deficiencies. Anxiety symptoms can be a sign of allergies or an overactive thyroid gland. And something as simple as a lack of water or iron can impair the ability to learn, remember and plan.

Doctors often forget to ask patients about psychological symptoms. Conversely, psychologists and psychiatrists may treat mental troubles in isolation without looking for a physical cause. But now some doctors and psychologists are reviving the decades-old discipline of somatopsychology, which centers on the effects of physical illness on the brain.

Infectious Moods
In Western culture people have long treated body and mind as separate. This dichotomy, popularized by French philosopher Ren Descartes in the 17th century, is still reflected in medical practice, as the specialists who look after our bodies remain different from those who attend to our psyches. Of course, the division has blurred in recent decades. We now know, after all, that the mind is housed in a physical entity, the brain, which is part of the body. And most people are also aware that psychological problems can produce physical symptoms in the form of psychosomatics; for instance, mental stress can spawn headaches, an upset stomach or even heart problems.

But fewer people appreciate that the influence also runs in the other direction—that changes in your body can profoundly perturb your mental state. These changes can range from rare maladies such as Tina’s to the common cold. Although German psychiatrist Karl Jaspers coined the word “somatopsychology” back in 1923, the discipline is still somewhat obscure; a search for the term on PubMed brings up only four papers on the topic. Nevertheless, the data linking specific bodily ailments to psychiatric troubles are far more prevalent, especially in the case of depression.

If you have been feeling tired, low and adrift from your friends—and cannot shake your bad mood—you may have symptoms of depression. Although psychiatric drugs and counseling are the standard remedies, they do not always work. In some cases, these treatments fail because the root of the problem lies in the body—and in particular the immune system.

Your body’s defenses affect the brain, in large part, through immune signaling molecules called cytokines. These substances cross the blood-brain barrier and bind to receptors on neurons in brain structures that govern emotions. The brain cells respond by unleashing substances called neuropeptides, which produce fatigue, lowered concentration and social withdrawal.

As a result, when you are fighting a cold, for example, symptoms such as a runny nose and sore throat are accompanied by a feeling of exhaustion and a desire to be alone, reactions that stem from the brain and serve to inhibit physical activity. When inflammation becomes chronic—say, after bacteria entrench themselves inside isolated pockets of the body, such as the tonsils and sinuses—so can your bad mood. Safe from immune system attacks in these locations, the pathogens proliferate and spread out through the body at a slow but steady rate. Although you no longer feel sick, your immune system’s continued vigilance can keep you in low spirits for weeks and months.

In 2010 epidemiologist Julie Pasco and her colleagues at the University of Melbourne in Australia found evidence that chronic inflammation raises a person’s risk of acquiring depression and may be a cause of this mental disorder. The researchers followed 644 mentally healthy women from 20 to 84 years old for a decade, periodically measuring their blood levels of C-reactive protein (CRP), a marker for low-grade inflammation, and assessing them for symptoms of depression. They found that the risk of depression (which 48 of the women developed) increased with CRP concentration, even after adjusting for various lifestyle factors and illnesses.

Other studies have shown that people with a diagnosis of depression or bipolar disorder tend to exhibit higher levels of inflammation than people without mental illness. In addition, the depressed patients most likely to show signs of persistent inflammation are those who have been most resistant to antidepressants and talk therapy. What is more, inhibiting inflammatory cytokines seems to help relieve the blues in these cases, research suggests.

A newly identified player in this process is an enzyme called IDO that is elevated in inflammatory disorders such as type 2 diabetes and rheumatoid arthritis. In 2009 immunophysiologist Keith Kelley and his colleagues at the University of Illinois induced low-grade chronic inflammation in mice by giving them tuberculosis vaccine. The injection boosted IDO levels in their brains, presumably a result of the actions of cytokines. The mice got sick, but even after they recovered they showed signs of rodent depression: placed in a bucket of water, they made little effort to escape. The behavior of the mice vastly improved, however, after the researchers gave them a drug that blocked IDO, indicating that the enzyme is a critical link between inflammation and sour mood. [For more on infections that wreak havoc on the brain, especially during development, see “Infected with Insanity,” by Melinda Wenner; Scientific American Mind, April/May 2008.]

Hormone Havoc
Bad moods can also arise from changes in hormones, signaling molecules that circulate in the blood. Compared with the electrical and chemical signals neurons send to one another, hormones act more slowly, but their influence on the body and brain endures for longer periods, exerting psychological effects through specialized receptors on brain cells involved in regulating emotions.

If you are a man older than 40 and you feel tired, unmotivated, irritable and down, your “midlife crisis” could stem from lack of the hormone testosterone, which declines slowly but steadily with age. This hormonal drop is associated not only with physical symptoms such as erectile dysfunction and muscle weakness but also with lasting self-doubt and depression.

Fluctuating hormone levels may also precipitate moodiness in women approaching menopause. A drop in the hormone estrogen, in particular, can lead to bouts of sadness and hopelessness or, in some cases, clinical depression. A rise in progesterone and a dip in estrogen toward the end of the menstrual cycle are also thought to underlie premenstrual syndrome, an array of physical and psychological symptoms, including depressed mood, that many women experience just prior to their periods.

In some people, fatigue and bad moods, especially if accompanied by weight gain, are signs of an underactive thyroid, a gland in the neck that controls metabolic rate through its own suite of hormones. Hypothyroidism affects about 1 percent of people, leading to significant physical and mental distress. In a 2010 study physician Rolf Larisch and his colleagues at Heinrich Heine University in Germany gave 254 patients with thyroid abnormalities a health questionnaire that identifies mood disturbances. They found that hypothyroid patients with physical symptoms scored above average on the screening test, suggesting that the condition erodes mental health. From statistical analysis of the results, the researchers concluded that hypothyroidism boosts a person’s risk of a mood disorder sevenfold.

In addition to hormonal changes, inadequate intake of several micronutrients, including folate, vitamin B12, calcium, iron and omega-3 fatty acids, can influence a person’s emotional state. Calcium in particular is essential to a healthy brain; nerve cells need it to create the electrical impulses they use to communicate with one another.

Nutrient deficiencies may also underlie some postpartum depression. One of the primary culprits may be the omega-3 fatty acids, molecules found most prominently in oily fishes such as salmon, herring and sardines. Various studies, among them trials in which researchers manipulated the amount of these fats in women’s diets, have linked low omega-3 levels to a higher incidence of maternal depression. In a 2011 review article, neuropharmacologist Beth Levant of the University of Kansas Medical Center described research explaining how a lack of omega-3 oils could bring on depression. In one study, researchers associated a diet-induced decrease in an omega-3 fatty acid called DHA in the brains of female rats with diminished levels of serotonin, a neurotransmitter thought to be involved in depression, in the brain’s frontal cortex.

Pregnant women eating a typical Western diet often fail to consume adequate amounts of these fatty acids, research suggests. In addition, many lack other nutrients that are important for emotional stability, such as folate, B vitamins, iron and calcium. [For more on postpartum depression, see “Misery in Motherhood,” by Katja Gaschler; Scientific American Mind, February/March 2008.]

Smart Water
Depression’s close cousin, anxiety, can also have a physical basis. Allergies are among the more surprising causes of such distress and are all the more likely if your nervousness is seasonal. Microscopic arachnids known as house-dust mites are a common source of such covert allergies. When inhaled by a sensitive person, proteins in the mite feces often cause asthma and a runny nose. But sometimes these allergic reactions are mild enough to go unnoticed, and a person instead experiences splitting headaches, nausea and a racing heart, symptoms that are often mistaken for an anxiety disorder.

Hormone imbalances can make you anxious, too. For more than 20 years, a woman who would later become my patient suffered from mood swings, including attacks of rage and anxiety, that she was unable to control despite psychotherapy, meditation and relaxation techniques. She also felt constantly agitated and had trouble sleeping. Eventually her marriage fell apart. When she came to me for behavioral therapy, she had bulging eyeballs and a slight goiter (swelling of the thyroid gland in the neck). I recognized these as symptoms of a hyperactive thyroid; the gland was overproducing its hormones, which were elevated in her blood, thereby putting her metabolism into overdrive. Damage to the adrenal gland can render it unable to produce enough cortisol, which helps the body respond to stress. A lack of this hormone can result in signs suggestive of anxiety such as a racing heart, irritability and sweating.

Changes in your body can also erode your ability to think clearly. One common offender is a lack of water. Without enough of it, brain cells shrivel up, shrinking brain tissue and enlarging the spaces within the brain, called ventricles. The withered tissue is less able to efficiently process information. In young adults, research suggests, even mild dehydration leading to a loss of 2 to 3 percent of body weight can significantly impair cognitive capacities such as short-term memory, attention and ability to solve math problems. The danger may be greater in the elderly because older people often do not feel thirsty when they should, and insufficient fluids can lead to phases of forgetfulness, speech problems and confusion that relatives often mistake for dementia.

A recent study suggests that your brain has to work harder when you are dehydrated. In 2010 psychiatrist Matthew J. Kempton and his colleagues at King’s College London asked 10 healthy teenagers to lie inside a functional MRI machine while solving a puzzle, both while fully hydrated and after becoming parched from exercise. The teens did the task equally well under both conditions, but their brains had to exert greater effort in the dehydrated state: blood flow, a measure of neural activity, increased in the frontal and parietal (side) parts of the brain when the body lacked water. The frontal lobe in particular governs so-called executive functions such as planning and decision making. Thus, the researchers conclude, given the brain’s limited resources, if a person fails to imbibe enough water over an extended period, his or her ability to plan and to process certain types of information is likely to suffer.

Even under ordinary conditions, just having a drink could help you think—at least if you are a kid. In a 2009 study psychologists Caroline J. Edmonds and Ben Jeffes of the University of East London found that giving mildly dehydrated six- and seven-year-olds a glass of water before a test improved their scores. In another study of seven- to nine-year-olds, additional water similarly boosted performance in an assessment of visual attention.

Inflammatory Thoughts
Cognitive troubles can stem from inflammation as well. In a 2010 investigation biological psychiatrist Clive Holmes of the University of Southampton in England and his colleagues found that patients with Alzheimer’s disease who showed signs of chronic inflammation from disorders such as arthritis had four times as much memory loss over six months as patients without the additional immune reaction. Patients who also experienced short-term inflammation—say, from an infection—showed an even faster decline, probably because the excessive immune response killed brain cells, the researchers surmise. Surgery similarly spurs the immune system to action; it produces inflammation that leads to temporary mental fogginess in 7 to 26 percent of patients who have had a recent operation.

Some vitamin and mineral deficiencies can impair cognition. In the developed world, about 10 percent of all women and one in four pregnant women are deficient in iron, which red blood cells need to carry oxygen. In a study published in 2007 nutrition researcher Laura Murray-Kolb, now at the Johns Hopkins Bloomberg School of Public Health, and her colleagues gave 113 young women a test of cognitive function and then put them on either iron supplements or dummy pills for 16 weeks. The lower a woman’s iron stores, the worse she performed on the initial test, the researchers found. In addition, the women who took the supplements improved markedly on a repeat test, demonstrating better attention, memory and learning, even though many had not been initially anemic. The results show that even mild deficiency can disrupt cognition and that boosting iron levels can make you smarter.

Seeing mental illness in the context of the entire body can thus help us see sources of distress that we might otherwise miss. In many cases, these bodily imbalances are easier to correct than ailments that originate in the brain itself. Vitamin and mineral deficiencies are relatively simple to rectify with supplements, although a doctor should advise you about the dose because some vitamins can be toxic in large amounts. One harmless remedy for cognitive lapses is drinking water, especially before tests or during tasks that require thought or concentration.

Other fixes may be more involved but nonetheless straightforward once a doctor has determined the cause of the problem. Thyroid or other metabolic disorders that spawn moodiness generally respond to standard therapies, as do hormonal deficits. Other cases of depression, especially those that have not been ameliorated by the usual remedies, may improve with drugs that target the immune system. In most instances, detecting and treating any such conditions require the advice of a doctor, although asking the right questions could improve the chances of a correct diagnosis—and a resolution of the problem.