We Are Our Brains (19 page)

Located in the brain stem are three more stress systems that produce the chemical messengers noradrenaline, serotonin, and dopamine and regulate many brain areas, including the hypothalamus. Their possible link with depression was discovered by chance as the result of a side effect of reserpine, a common medication for high blood pressure. The drug was shown to reduce the amount of noradrenaline and serotonin in the brain stem, and depression was a not uncommon side effect. Conversely, the first antidepressants, MAO inhibitors, increased noradrenaline and serotonin levels. The most commonly used antidepressants nowadays are selective serotonin reuptake inhibitors (SSRIs), compounds that increase the level of serotonin by preventing its reabsorption into the body. This gave rise to the theory—now immensely popular—that depression may be caused by abnormally low concentrations of noradrenaline or serotonin. However, patients whose depression can definitely be ascribed to low serotonin levels are in the minority. The mere fact that it takes
a few weeks for SSRIs to become effective, even though they raise the serotonin level almost instantly, shows that the link between serotonin and depression isn't that clear-cut. In the case of depressive patients who are very fearful, however, serotonin systems can be disrupted. Low serotonin and noradrenaline levels have also been found in the cerebral fluid of patients who had ended their lives violently, for instance by jumping in front of a train. This group was also found to have high levels of the stress hormone cortisol. Dopamine, the chemical messenger of the reward system, is also involved in the symptoms of depression. When depressive patients are unable to enjoy life anymore, it is probably because of a dip in dopamine.

Our examination of postmortem tissue from the brains of depression sufferers also revealed that the circadian clock, the suprachiasmatic nucleus, is less active in people who suffer from depression. This explains not only their disturbed day-night rhythms but also the effectiveness of light therapy.

Functional scanning studies of depressive patients showed changes in the activity of the temporal and prefrontal cortex as well as the amygdala. The latter may explain the increase in fearfulness. The reduced activity in these brain areas may partly result from raised cortisol levels.

To sum up, an entire network of brain systems and various chemical messengers are involved in the onset of depression. The systems that are the prime cause of depression vary from individual to individual, but in all cases the stress axis is central to the pathological process.

Therapies

Many therapies are used to treat depression that would appear to have nothing in common with one another, but ultimately they all normalize stress axis activity.

SSRIs are very commonly prescribed for depression. In the Netherlands, around nine hundred thousand people take antidepressants.
In around 75 percent of these cases, the patient is indeed very down but not suffering from severe depression, so they won't help very much. Indeed, SSRIs aren't very effective at all. They start to work only after a couple of weeks, during which period there's a real risk of suicide. (And that's not a negligible problem. Around fifteen hundred people kill themselves every year in the Netherlands, and ten times as many attempt to do so). Moreover, these drugs have a placebo effect of 50 percent. Indeed, it's not so strange that the placebo effect is so marked in the case of depression. The expectation that a placebo will alleviate one's pain is linked to increased activity in the prefrontal cortex (see
chapter 16
). This inhibits the hypothalamus, thus normalizing the activity of the stress axis. Stimulating the inhibitory effect of the cerebral cortex on the stress axis explains why transcranial magnetic stimulation of the cortex is effective. Cognitive therapy and online treatment for depression are successful for the same reason; they produce the same inhibitory effect on the stress axis as transcranial magnetic stimulation, but by different means. We don't know why electroshock therapy is so effective in the case of very severe depression. Perhaps it's a bit like when your computer seizes up: You switch the power off, switch it back on again, and hey presto, it works again. A disadvantage of this therapy is that it can impair memory.

Lithium, the classic medication for bipolar disorder, affects the circadian clock, inhibiting the overactive stress axis and stabilizing mood.

Light improves mood among depressive patients, through its effect on the circadian clock. The latter becomes more active, inhibiting the CRH cells of the stress axis. In the northern United States, seasonal depression is more common than in the sunny southern states. Physical activity can also stimulate the clock, so walking the dog is doubly effective because of the extra light and the extra activity. We found that increasing the amount of light in the living areas of patients with dementia also improved their mood (see
chapter 18
). Antidepression lamps work just like sunlight, although they're
not as efficient. Even on a cloudy day, you're exposed to more light outside than you can obtain from a lamp of this type. (Incidentally, using a light box can get out of hand, and it can very occasionally induce mania or psychosis, so light therapy needs to be carried out under the supervision of a doctor.) In older people, lack of vitamin D can also increase the risk of depression. Vitamin D is made in the skin in response to sunlight. That's why people who live in towns are more likely to have this deficiency than people in rural areas. So sunlight protects you in two different ways. Disrupting the day-night rhythm (for example by going without sleep for a night) has also been found to improve mood, but the effect is unfortunately brief.

When considering all these therapeutic options, we must however bear in mind that depression is essentially an early developmental disorder and that the cause, disrupted brain development, can't be remedied by these therapies. That's why depression frequently recurs.

A wealthy Japanese businessman, the CEO of a car parts factory, married a biologist, and they had two sweet little daughters. But it was unthinkable in Japan for a daughter to inherit his business, so they decided to have a third child. During the pregnancy, the wife felt
far fewer signs of life than on the previous occasions. The child was born three weeks prematurely, and the birth was much more prolonged and difficult than before—but it was a boy! However, the baby was so floppy that he couldn't suck, so he was given tube feeding. When he was eighteen months old he started to eat—and seemed to be making up for lost time. However much he ate, he was never satiated; he invariably cried for more and became grossly overweight. When he was four years old he was diagnosed with Prader-Willi syndrome. The parents were also told that the child would always be mentally disabled and that they would face a lifelong struggle to prevent him from becoming obese and getting diabetes, with all its attendant dangers. The mother put electronic locks on the kitchen food cupboards and devoted all of her time to teaching him, stimulating him, and giving him new experiences to take his mind off food. As a result, the child had a strikingly normal build for a young Prader-Willi patient. Yet all of the mother's efforts couldn't prevent the boy from occasionally falling prey to terrible bouts of rage. She joined the Japanese Prader-Willi Association and took him with her to a biennial international conference at which scientists and parents meet to learn from each other. Parents often take their Prader-Willi children to these gatherings, and you can spot them on the flight on the way there: lots of obese children from Europe, Japan, India, and North Africa overflowing their seats, with their disproportionately small hands and feet and their typical almond-shaped eyes. You need only follow them to find the conference.

It was at that conference that the mother of the Japanese boy heard about a new growth hormone therapy that normalized the metabolism of Prader-Willi children, allowing even the fattest children to regain a normal build and ending the incessant battle against hunger. She was fortunate in being able to afford the expensive new therapy, because her Japanese insurance company wasn't yet prepared to foot the bill.

In the United States, Prader-Willi syndrome is known as H3O syndrome (hypomentia, hypotonia, hypogonadism, and obesity). The
symptoms are largely due to a disturbance of the hypothalamus. The abnormal birth is actually the first sign of the child's defective hypothalamus, because that brain system plays an active role in timing the start of the birth and in speeding up its various stages (see
chapter 1
).

Most Prader-Willi patients lack a small piece of chromosome 15; in others, that section of the chromosome doesn't function at all. It's located in the section that they inherited from their father. The opposite strand—the one inherited from their mother—was chemically silenced at the very earliest stage of development and so can't compensate for the absence or malfunctioning of the paternal part. This process whereby the expression of genes is determined by the parent who passed them on is known as imprinting. When we examined the hypothalamus of Prader-Willi patients, we found that the paraventricular nucleus, the center of autonomic and hormonal regulation, was a third smaller than normal and contained only half the normal number of oxytocin neurons. The latter act as your “satiation neurons,” signaling to your brain when you have eaten enough. Disabling these neurons in laboratory animals has been shown to cause increased appetite and obesity, and the fact that Prader-Willi patients have fewer oxytocin neurons may account for their inability to feel satiated no matter how much they eat. We're still searching for a link between the Prader-Willi genes at chromosome 15 and the malfunction of the hypothalamus.

Through a network of Prader-Willi parents and scientists, we received a request from a mother in New Zealand who was working as a nurse in a nursing home. She detected in her thirty-nine-year-old son symptoms that she recognized from elderly people with dementia. Was it possible that Prader-Willi patients ran the risk of early aging and Alzheimer's? That question had never come up before, because until recently, Prader-Willi patients died relatively young. In tissue taken from the brains of the few Prader-Willi patients who had lived beyond the age of forty, we indeed found changes that were typical of Alzheimer's (see
chapter 18
). Since then, reports of early dementia in this patient group have been coming in from all over the
world via the Prader-Willi network. Some believe that it sets in very early, before the age of thirty; others speak of a dramatic decline at around the age of forty. Systematic research of this phenomenon is now under way. Does early-onset Alzheimer's form part of Prader-Willi syndrome, or might it be caused by morbid obesity? We know, after all, that certain symptoms of obesity are risk factors for Alzheimer's, such as diabetes mellitus, vascular disorders, high blood pressure, and high cholesterol. If the latter is the case, we can expect to face an explosion of premature brain aging and Alzheimer's as a tidal wave of obesity rolls across the globe.

The hypothalamus regulates our body weight within very strict limits. Yet on average we all gain about one gram per day. That doesn't sound like much, but obesity has now ballooned into a world health problem: Around 300 million people are obese, and one billion are overweight. Being overweight greatly increases the risk of diabetes, heart and vascular diseases, high blood pressure, certain forms of cancer, and dementia. In the Western world, around 60 percent of adults are overweight, and 30 percent are obese. The recent rapid increase in childhood obesity is particularly alarming. In the United States, 30 percent of children are overweight or obese. For years I was amazed by the increasingly gigantic pairs of jeans I saw in America. But now obesity is everywhere, from China and Japan to Mexico.

We find food tasty, something that used to have a huge evolutionary advantage. Our ancestors spent millions of years in the barren savannas, where every calorie had to be tracked down and consumed. These long periods of scarcity meant that we failed to develop a protective
mechanism against eating too much. Food was seldom available in overabundance and then had to be stored as fat, a necessary reserve to get us through the next lean period, which always came. Our autonomic nervous system, guided by the hypothalamus, ensures that in women, fat is stored on hips, breasts, and buttocks, while men develop bellies. Obesity results from a permanent food surplus, less physical labor, and a lack of physical exercise. These days we also eat more carbohydrates and fats and less protein than formerly. But that so many people are fat isn't just due to a lack of self-control. Predisposition is certainly a factor. Obesity has a strong genetic component. Studies of twins, adopted children, and families indicate that around 80 percent of the variation in body weight is determined by genetic factors.

Some people become so fat that their hearts can no longer cope, and they die prematurely. Some are too fat even to leave their homes and have to be hoisted out of the window when hospital admittance becomes necessary. Certain rare genetic factors for extreme obesity that regulate appetite and metabolism in the hypothalamus have now been discovered. Prader-Willi syndrome is one such genetic type of obesity (see earlier in this chapter). Patients with this condition can be so fat that the apron of flesh hanging over their genitals prevents you from knowing whether they are male or female. Normally, the hypothalamus registers how much fat our body has stored by measuring the amount of leptin, a hormone produced by fat tissue. If there are mutations in the leptin gene or the leptin receptor, the hypothalamus will conclude that there's no fat tissue and continually prompt you to eat, resulting in morbid obesity. Mutations have also been identified in which the brain no longer produces α-MSH, a substance responsible for hair pigmentation and appetite inhibition, or no longer receives the chemical message transmitted by α-MSH. Mutations of the α-MSH system often produce extremely fat children with red hair. Such children also don't enter puberty. Reduced sensitivity to α-MSH is found in 4 to 6 percent of obese people. Obesity can also be caused by a mutation in the receptor for
corticosteroids as well as by hormonal disorders (like a lack of thyroid hormones, growth hormones, or sex hormones) or an excess of the adrenal hormone cortisol.