by D. F. Swaab
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.
OBESITY
What goes into someone’s mouth does not defile them, but what comes out of their mouth, that is what defiles them.
Matthew 15:11
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.
Certain drugs, such as antipsychotics, can have the extremely unpleasant side effect of massive weight gain. A boy treated with drugs of this kind gained 150 pounds in a very brief time and subsequently refused any further medication.
Patients suffering from psychiatric disorders like depression also risk becoming obese, as do people with disorders like bulimia and a syndrome that causes nighttime binge eating. Only very rarely are neurological processes in the hypothalamus the cause of obesity. When I was an intern in a pediatric department, I was assigned an eight-year-old patient who was massively overweight but who claimed to eat very little. It turned out, however, that she ate constantly, consuming vast quantities of candy. The cause of her obesity was a tumor in her hypothalamus, which meant that she never felt satiated and so believed that she wasn’t eating enough.
Children whose early months in the womb coincided with the famine that struck the Netherlands in the last winter of the Second World War tended to become obese as adults. In a situation like that, a fetus’s hypothalamus registers scarcity and calibrates systems so as to retain every calorie that’s consumed. If an individual then encounters a surplus of food in later life, he or she runs a great risk of becoming obese. The same problem still affects children who are born underweight because of a malfunctioning placenta or because their mother had high blood pressure or smoked during pregnancy. Maternal obesity during pregnancy, high cholesterol, and the overfeeding of newborn babies also increases the likelihood that a child will later become obese.
Social, cultural, and environmental factors that appear to promote obesity include the mass marketing of candy and chocolate, the universal availability of cheap fast food, and the prevalence of “comfort eating” in response to difficulties. A lower socioeconomic status increases one’s risk of obesity. Certain industrial substances that enter the environment have also recently been discovered to cause obesity even in low concentration. Dubbed obesogens, they include estrogens and substances that obstruct the normal functioning of sex hormones during development—endocrine disruptors, for instance (which come from compounds found in certain plastics), and the toxic organotins (which are present in plastic and paint).
Although our gluttony used to have an evolutionary advantage and fat was considered desirable in Rubens’s day, nowadays we discriminate against fat people. The common prejudices are that fat people are stupid and lazy, have no self-discipline, and lack initiative. Extremely fat people, moreover, cause feelings of physical repulsion. The dangers of obesity to health are incontrovertible, so there are plenty of reasons to lose weight. But the most effective remedy for obesity—eating less and exercising more—is very difficult to sustain. According to a recent study, retraining eating behavior, using scales that provide feedback by weighing everything you eat, appears to be effective. Rimonabant, a cannabis antagonist, was heralded as a miracle drug, effective against both nicotine addiction and obesity. Unfortunately, however, it not only made people’s weight go down but also had the same effect on mood. The drug increased the risk of depression and suicidal thoughts, and the registration application at the FDA has been provisionally withdrawn. The European Medicines Agency made the manufacturer, Sanofi, send all doctors a letter stressing that the drug should no longer be prescribed to patients with depression or at risk of depression. Experiments are being carried out with depth electrodes in the hypothalamus, but so far that hasn’
t proved effective; one side effect of such stimulation has been to call up memories of the distant past (see chapter 11). And in certain cases, even depth electrodes can cause weight gain. Parkinson’s sufferers who have electrodes inserted in their subthalamic nucleus to treat their motor disorders often become overweight.
All in all, in this society of surplus, it’s something of a miracle if you manage to keep reasonably trim!
CLUSTER HEADACHE
“as if a red-hot poker were being stuck in my eye.”
Functional MRI scans (fMRI) are crucial tools for brain research, but the clinical significance of the technology is limited. There is, however, one shining exception: It has provided fresh clinical insights and a therapeutic strategy in the diagnosis and treatment of cluster headaches. This syndrome (which is luckily rare, affecting fewer than one in a thousand people), causes excruciating headache attacks, mainly for periods of several months; these are the “clusters” after which it is named. The attacks last between fifteen minutes and three hours. Between those periods the patients experience no headaches at all. But around 10 percent have attacks every day or nearly every day, year in, year out, without remission. The unilateral pain around and behind the eye was described by a patient to be “as if a red-hot poker were being stuck in my eye.” Cluster headaches are so horrendously painful that the condition is also known as “suicide headache.” During a cluster period attacks can be brought on by drinking alcohol or exposure to an environment with low oxygen pressure, for instance in mountainous areas above six thousand feet or in planes with low cabin pressure. More men than women suffer from cluster headache.
Various factors indicate that cluster headaches are a disease of the hypothalamus. The first such indicator is that the patient experiences autonomic symptoms generated by the facial nervous system on the same side of the face that’s affected by the pain, such as sweating, tearing up, a runny nose (or, conversely, a blocked nose), and eye redness. The eyelid may droop, and the pupil may constrict. All of these symptoms point to increased activity in the center of the autonomic nervous system, the hypothalamus.
Second, the biological clock in the hypothalamus plays an important role in generating cluster headache attacks. The biological clock (fig. 18) is responsible for all of our day-night and seasonal rhythms, including during periods of illness. The cluster headache attacks often strike at a set time of the day or night, and they show seasonal fluctuation. What’s more, the hormonal day and night patterns of cluster headache patients change in a way that suggests alterations in the biological clock, and activity is also noted in that area when attacks are provoked.
Professor Michel Ferrari, headache specialist at Leiden University Medical Center, finds that cluster headache responds better than other headache disorders to treatment; medication often proves extremely effective. Attacks can often be effectively treated with oxygen or sumatriptan and prevented with calcium antagonists or lithium. Only 20 percent of patients don’t respond to treatment. The main problem, however, is that the disease often goes unrecognized or is only identified far too late, sometimes after decades of pain, during which desperate patients often undergo extremely drastic therapies, ranging from severing the facial nerve and undergoing major sinus operations to having all of their teeth removed.
Scans carried out during attacks to establish the source of the pain have revealed an increase in grey matter at the rear of the hypothalamus, bordering on the thalamus, indicating that patients have more than the normal number of brain cells on the side of the attacks. And fMRI scans have shown increased activity at this location during attacks (activity ceased during the period of recovery). These patients then had a depth electrode inserted into the rear of their hypothalamus, which was continually stimulated. Eight years of experience have now been amassed using this technique on over forty patients. Electrical stimulation of the area where the headache attacks are generated stops the attacks in 60 percent of patients and makes them sleep better. This treatment doesn’t provide instant relief; it usually takes effect after about a month.
Long-term stimulation appears to be safe, although we don’t know exactly how it works. PET scanning, a technique that shows changes in brain activity, reveals that the electrode treatment stimulates far more brain areas than just the hypothalamus. In fact, a change of function is induced in a whole network of brain structures involved in pain processing.
The operational mechanism is interesting, but the most important fact is that patients are helped by the therapy. After all, we don’t even quite know how aspirin works. But whether using depth electrode stimulation to treat cluster headache is truly effective can only be shown by a controlled clinical trial. A French group of researchers decided to carry out such a trial on a group of eleven patients (randomly selected and split into two subgroups, without the patients knowing which subgroup they belonged to). In the first month after the electrodes had been implanted by a neurosurgeon, one subgroup had their electrodes stimulated, while the other half did not. After a week’s rest, the patients’ treatment was then reversed (crossover). After this two-month period, however, no difference was seen between the month with and the month without electric stimulation. In other words, the experiment didn’t suggest that the treatment was effective. One could of course argue that the group was small and that the method of stimulation wasn’t optimal. Whatever the case, the electrodes in the brains of all eleven patients were subsequently activated for the period of a year. Six of the eleven patients benefited from the treatment. This result was in line with expectations, but the effectiveness of the method had not been proven in a controlled trial. So after receiving permission from the ethical committee, the researchers asked the patients if they were prepared to undergo another experimental period in which their electrodes were alternately stimulated or switched off. The patients refused, frightened that the cluster headaches would come back with their old severity. So far, therefore, nothing has been proven. In the meantime it appears that stimulating a subcutaneous nerve at the back of the head—a much less drastic process—can also be effective. So it’s extremely debatable whether one should go on implanting electrodes in the brains of cluster headache patients. Clinical research is far from simple.
NARCOLEPSY: WEAK WITH LAUGHTER
All the narcolepsy patients began to laugh as soon as he came in, until they fell to the ground, completely weak with laughter.
Narcolepsy is a sleep disorder. People who suffer from it are excessively sleepy and less alert during the day, while at night, paradoxically, their sleep is disturbed. Although serious, these symptoms aren’t in themselves specific to this brain disorder. Narcoleptic patients also tend to be overweight, but this is of course very common in itself and isn’t necessarily connected with narcolepsy.
Narcolepsy does have a number of distinguishing symptoms. In many cases, an emotional experience can make sufferers suddenly lose muscle tone in their arms and legs and fall to the ground (fig. 19). They are so completely weak from laughter or shock that they appear to have lost consciousness, but after the event they can relate everything that happened. This characteristic symptom is called cataplexy. One of our PhD students was so cheerful and full of fun that the narcolepsy patients would begin to laugh as soon as he came into the room, causing the ones with cataplexy to collapse on the floor. This attribute made him the secret weapon of our research. If patients with a history of cataplexy are shown funny cartoons while lying in a functional MRI scanner, their scans show overactivity in the emotional brain circuits and, possibly in response to this, activity in an inhibitory system of the prefrontal cortex. The hypothalamus, where the condition originates, in fact shows reduced activity during the period of cataplexy that follows the laughing fit.
People with narcolepsy can also suffer from sleep disorders that aren’t typical of their condition. Some often find themselves unable to move for several minutes after waking up. Such sleep paralysis can be very frightening. Moreover, narcolepsy patients often
have extremely vivid dreams—or more frequently nightmares—in the transition between waking and sleeping. These are known as hypnagogic hallucinations and can be so powerful that patients lose touch with reality. A woman who had often hallucinated that all her teeth were being pulled out just as she was waking up didn’t realize that a later visit to the dentist was real and not a hallucination. She jumped out of the chair and ran for dear life, just as she did in her hallucination, leaving a very puzzled dentist behind. Other people have hallucinated that dwarfs were stabbing them, that they were being sucked into a corpse, or that they were dying in terrible, violent ways. Hypnagogic hallucinations can be similar to schizophrenic hallucinations and sometimes provoke out-of-body experiences that resemble near-death experiences. Functional scanning does in fact reveal changing activity patterns in the temporal lobe, just as in near-death experiences caused by lack of oxygen (see chapter 16).
The symptoms of narcolepsy are caused by the absence of a chemical messenger in the hypothalamus called hypocretin (or orexin). Degeneration of the cells in the hypothalamus (a phenomenon that has yet to be explained) can induce the symptoms of narcolepsy. This process can be tracked by measuring hypocretin levels in the cerebrospinal fluid. Narcolepsy with cataplexy can also arise when the brain becomes unreceptive to the message of hypocretin. This is caused by a tiny mutation in the DNA of the gene producing the protein that receives this message: the hypocretin receptor. These mutations are rare in humans, but when I was a guest lecturer at Stanford University in the United States, I encountered a dog who had it. It wasn’t easy to get to see the dog: My team had to fill out endless forms at checkpoint after checkpoint and comply with all kinds of safety measures and clothing requirements. The animal quarters at Stanford are so costly that, as the head of the research team sighed, “The dog is more expensive to maintain than a post-doc.” We had taken along a tin of the dog’s favorite food, and we were not disappointed by the effect. The massive Doberman wagged his tail and went into paroxysms of joy. Then his back legs suddenly collapsed beneath him (fig. 19), followed by his front legs, after which he fell asleep on his side. He recovered very rapidly and began to munch contentedly on his favorite meal. We crept away, closing the door of his pen behind us, and returned to the checkpoints. Suddenly I heard the patter of footsteps behind me. I turned around to find myself looking right into the eyes of the Doberman, who was following me, his head on a level with my shoulders. He wanted some more of that delicious dog food and had somehow managed to get the door open. Clearly, the mutation in question doesn’t impair the intellect.