Know Your Brain: Tourette syndrome

Background

Georges Gilles de la Tourette, circa 1870

After graduating from medical school in 1881, Georges Gilles de la Tourette moved to Paris to refine his medical knowledge by working under one of his idols (and one of the great figures in the history of neurology): Jean-Martin Charcot. While under Charcot’s supervision, Gilles de la Tourette began studying a class of ailments known as the paroxysmal movement disorders. These conditions are characterized by brief episodes of abnormal, involuntary movements (like an unintentional swinging of the arm up in the air). Gilles de la Tourette’s investigation led to the publication of a paper in which he described a particular affliction he called the maladie des tics.

In the paper, Gilles de la Tourette discussed nine patients who had a similar constellation of symptoms that centered around sudden uncontrolled movements or vocalizations. Soon after the publication of Gilles de la Tourette’s paper, Charcot suggested the maladie des tics be renamed after Gilles de la Tourette, leading to the modern-day designation of Tourette syndrome (TS).

Up until the past few decades, it was thought that TS was an exceedingly rare condition. More recent research, however, has identified cases of TS in every country studied. Prevalence estimates vary significantly due to differences in methodology, but the Centers for Disease Control and Prevention (CDC) estimate that around 3 out of every 1,000 children and adolescents aged 6-17 suffers from the condition. For reasons that are not completely clear, boys are about three times more likely to experience TS than girls.

Symptoms

As suggested by Gilles de la Tourette’s original name for the disorder, the hallmark sign of Tourette syndrome (TS) is the appearance of sudden involuntary actions called tics, which might consist of either movements or sounds. The tics are classified as simple or complex. Simple tics involve only one group of muscles (e.g. eye blinking, shoulder shrugging) or one type of sound (e.g. sniffing, throat clearing). Complex motor tics involve coordinated movements (e.g. reaching out to touch someone, bending over), and sometimes can consist of a series of simple tics (e.g. shoulder shrugging combined with a facial grimace). Complex vocal tics may involve the utterance of phrases or sentences, and describe the symptom most frequently linked to TS: coprolalia, or the involuntary use of obscene or inappropriate language. Despite the perception, however, coprolalia is thought to occur in less than 20% of TS cases.

For a patient to be diagnosed with TS, he must have experienced motor and vocal tics before the age of 18, and the tics must have lasted for at least one year after appearing. Typically, tics develop before the age of 10 and become most severe between the ages of 10-12. In most patients, the severity of tics begins to decline after reaching this peak, and by adulthood tics are usually occurring much less frequently or have disappeared altogether. In the most severe cases of TS, however, tics not only continue into adulthood but also may become more debilitating during this time. In some patients, these more severe tics can involve potentially self-harming actions like head-banging or eye-poking.

Tics are often accompanied by what are known as premonitory urges. These are uncomfortable sensations that precede the tic and make the patient feel like the tic is inevitable or necessary. For example, a patient might have the sensation that something is in his throat just before performing a throat-clearing tic. Premonitory urges are often compared to something like feeling the need to sneeze, and thus perhaps it’s not surprising that execution of the tic can cause patients to experience a short-lived sense of relief in satisfying the premonitory urge.

Unfortunately, more than half (and perhaps up to 90%) of patients with TS experience other psychiatric problems as well. The two most common disorders that TS patients suffer from are attention-deficit hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD), although a number of other conditions (e.g. depression, anxiety, learning disability) may also occur simultaneously with TS, making TS that much more challenging to endure.

Basal ganglia (within red square).

The neuroscience of Tourette syndrome

What goes on in the brain to cause Tourette syndrome (TS) is not completely clear, but most hypotheses suggest an important role for a group of structures known as the basal ganglia. The term basal ganglia describes a collection of regions found deep within the cerebral hemispheres that include the: caudate, putamen, globus pallidus, substantia nigra, and subthalamic nucleus.

The basal ganglia form a network that is thought to be involved in a variety of cognitive, emotional, and movement-related functions. Relevant to our discussion of TS, many neuroscientists consider the basal ganglia to play an important role in suppressing unwanted actions, thoughts, and emotions. According to this perspective, there are inhibitory signals sent from select basal ganglia nuclei to the cerebral cortex (primarily by way of the thalamus). These signals work to inhibit a long list of unwanted actions—like your leg involuntarily kicking out in front of you or your head suddenly turning to one side for no apparent reason. But the inhibition can also be more complex, involving things like curbing the desire to have an unnecessary snack or suppressing the impulse to yell at your boss out of anger.

Watch this 2-Minute Neuroscience video to learn more about the basal ganglia.

Simply put, inhibitory signaling from the basal ganglia is thought to be critical to ensuring that we don’t do things we don’t really want to do. But in TS, that mechanism of inhibition may become faulty. Neurons in the basal ganglia that are assigned to inhibit unwanted signals from reaching the cortex fail to do so, causing the execution of a habitual action (i.e. tic) that the patient would prefer to suppress.

This failed inhibition may also be coupled with increased activity in motor pathways that generate movements. Thus, TS patients might experience the particularly problematic combination of abnormally high motor activity that is aimed at generating habitual patterns of behavior, along with abnormally low inhibitory activity that typically keeps those patterns of behavior from being acted out.

Causes and treatment

As with most neurodevelopmental disorders, a full understanding of the factors that cause one child to develop TS while others do not remains elusive. Genetics do seem to play an important role, and having a first-degree relative with TS increases one’s risk of developing TS by anywhere from 10 to 100 times. The genetics of TS are complex, however, with a number of gene variants across the genome (rather than one clear TS-gene) being linked to an increased risk of developing the disorder.

But, as with most disorders that have some genetic basis, there are likely other non-genetic factors that play a critical role in the development of TS as well. One hypothesis that has some support suggests that environmental insults in early prenatal or perinatal development (e.g. infections, stress during pregnancy, smoking during pregnancy)— combined with genetic susceptibility—might prompt excessive immune responses that could impact brain development to increase the risk of developing TS. But researchers are still attempting to elucidate the details of this type of immune system interaction and what factors might be involved.

Scientists also continue to seek a cure for TS, but unfortunately at this point there is not even a treatment that is universally effective. Because TS can be very different in its presentation from patient to patient (as can the disorders, like ADHD and OCD, that often occur along with it), treatment typically needs to be adjusted to each individual patient’s needs. Still, there are a number of therapeutic approaches that can be beneficial.

For patients with mild tics, medication is often not necessary. Many of these individuals will respond to behavioral interventions that teach them to manage the symptoms of TS with things like: noticing premonitory urges and immediately engaging in an action that is contradictory (e.g. using muscles that make execution of the tic especially difficult), relaxation training, social support, etc.

Because most of the medications for TS have significant side effects, they are typically reserved for cases where behavioral interventions are ineffective or not viable, or where tics are severe enough to substantially disrupt quality of life. The most effective medications to treat TS tend to be antipsychotic drugs (e.g. risperidone), which typically inhibit dopamine activity (excessive dopamine activity in the basal ganglia may contribute to the symptoms of the disorder). These drugs are usually not the first course of treatment, however, because they are associated with problematic side effects ranging from movement disorders to weight gain (the specific side effects experienced depend on the medication).

Thus, the first-line pharmacological approach often instead involves the use of drugs that stimulate the alpha-2 adrenergic receptor, a receptor involved with sympathetic nervous system activation. Although they stimulate alpha-2 adrenergic receptors, these drugs actually cause decreased sympathetic nervous system activity, and may help to reduce tics in some patients. The effects, however, are not typically as potent as those seen with antipsychotic drugs.

There are a number of other drugs that can sometimes be effective in treating TS, and TS patients will often be prescribed additional medications to help with concurrent psychiatric disorders. Other treatment options continue to be explored as well, with the hope that one day the impact of this disorder on patients’ lives can be mitigated further.

References (in addition to linked text above):

Jahanshahi M, Obeso I, Rothwell JC, Obeso JA. A fronto-striato-subthalamic-pallidal network for goal-directed and habitual inhibition. Nat Rev Neurosci. 2015 Dec;16(12):719-32. doi: 10.1038/nrn4038. Epub 2015 Nov 4.

McNaught KS, Mink JW. Advances in understanding and treatment of Tourette syndrome. Nat Rev Neurol. 2011 Nov 8;7(12):667-76. doi: 10.1038/nrneurol.2011.167.

Robertson MM, Eapen V, Singer HS, Martino D, Scharf JM, Paschou P, Roessner V, Woods DW, Hariz M, Mathews CA, Črnčec R, Leckman JF. Gilles de la Tourette syndrome. Nat Rev Dis Primers. 2017 Feb 2;3:16097. doi: 10.1038/nrdp.2016.97.

Learn more:

Know Your Brain: Basal ganglia

The mysterious dancing mania and mass psychogenic illness

Try to imagine yourself walking along the streets of a city (maybe the one you live in, or one you’ve visited, or one you simply make up in your head—as long as you can picture it clearly it doesn’t matter much). Think of the shops and businesses you might pass as you stroll down the sidewalk, the smells of food emanating from nearby restaurants, and the noises you’d hear—intermittent car horns, snippets of conversation, the discordant sounds of construction equipment. Now, imagine you approach a street corner, and as you do you begin to hear some rhythmic music playing from just out of view—on what sounds like bagpipes (to really set the mood, click play on the video below for some appropriate background music). As you turn the corner, curious to find the source of the music, you see a large city park. It charmingly interrupts the asphalt and concrete of the city with expansive green grasses, dense leafy trees, and a bubbling decorative fountain. But despite its beauty, the park is also the backdrop to one of the strangest spectacles you’ve ever witnessed.

The park is filled with people—perhaps a hundred, maybe more. Many of them are naked. Others are wearing clothes that are dirty, ripped, and often hanging loosely from their undernourished bodies. A large group of them have formed a circle by holding hands, and many others are contained within the circle. Someone you can’t see is playing the aforementioned upbeat (almost eerily so, now that you can see the whole picture) tune on the bagpipes, and nearly everyone is dancing—but not in a choreographed manner you might see from a flash mob today. Instead, this dancing is convulsive and jerky, and almost out of control—like there is a maniacal puppet master manipulating their movements from above.

As you cautiously take a few steps closer to this bizarre scene, you see that many of the dancers are staring blankly up at the sky, as if in a trance. Occasionally, they yell—shriek might be the more appropriate word—unintelligibly into the air. Some of these shrieks become agonized screams, and you can clearly make out the word “help!” shouted at least once or twice. You notice that, in the middle of the circle, several couples are on the ground having sex with one another. The whole thing looks like a drug-fueled ritual/orgy, but it’s taking place right out in the open, for everyone to see.

One of the dancers suddenly falls to the ground and starts convulsing. He’s clearly having some sort of seizure, his body thrashing about wildly and uncontrollably—but everyone just ignores him. After what must be about 30 seconds, he recovers, slowly gets up, and begins dancing again.

Think of the shock and horror you would feel when you encountered this scene. Now consider that if you lived in certain parts of Europe between the fourteenth and seventeenth centuries, this spectacle may not even have been cause for alarm. These types of dancing displays were not unheard of, and it’s very possible you would have seen one before.

In those days, the people who participated in the dancing rituals were thought to be afflicted by some malady (often assumed to be demonic possession) that led to compulsive dancing. The ailment was deemed contagious, and it was believed onlookers could be overcome and compelled to join the dancing at any moment. The condition was often called the dancing mania or St. Vitus’ dance, the latter name coming into use because the afflicted would often dance near the churches or shrines of St. Vitus, the patron saint of dancers. Priests from these churches frequently tried to intercede, frantically attempting to exorcise the demons from those who were affected before they were able to pass the sickness on to members of the clergy.

A depiction of dancing mania by Pieter Brueghel the Younger.

One such event occurred in 1374 and spread across a large area of Europe that included western Germany, Belgium, the Netherlands, Luxembourg, and northeastern France. Dozens of independent chroniclers of the events agree that thousands of people were affected, and the dancing went on for weeks. Another incident in Strasbourg in 1518 involved around 400 people, a number of whom were reported to have died while dancing in oppressively high summer temperatures. There were many other smaller occurrences of dancing mania, and sporadic reports of it persisted up until the mid-1600s.

While it’s possible some of the details of these events have been embellished, the number of independent verifications of them suggest they did occur in some form. So what could have caused this strange behavior? To this day, scientists are stumped. Some have suggested the culprit might have been widespread ergot poisoning. Ergot is a fungus that grows on rye; it has strong psychoactive effects when it’s ingested, and it can cause hallucinations, tremors, and convulsions (a constituent of ergot, lysergic acid, can be used to synthesize LSD). Is it possible, then, that widespread consumption of tainted rye could have led to these “epidemics?”

It doesn’t seem very likely. Ergot poisoning is characterized by spasms and convulsions, but also by symptoms like nausea and diarrhea, making it improbable sufferers could have danced for days on end. Additionally, ergot poisoning often involves the appearance of gangrene (i.e. tissue dying due to a lack of blood flow—it causes gruesome blackened skin that’s difficult to overlook) on the toes and fingers, but reports of dancing manias don’t include such descriptions. Finally, outbreaks of dancing mania also sometimes occurred in regions where rye wasn’t a common crop.

Of course it’s possible there was some other environmental exposure we haven’t identified that had a widespread influence on behavior, but such things are difficult to ascertain so long after-the-fact. And due to the lack of viable alternative explanations, many scientists have begun to believe the dancing mania was a manifestation of something called mass psychogenic illness, or MPI.

MPI involves the appearance of symptoms that spread throughout a population, but don’t have a clear physical origin. In other words, in MPI the brain is causing the patient to think they are afflicted by some ailment—even though the brain itself is the creator and orchestrator of the illness. This doesn’t mean that the symptoms aren’t real; there can be legitimate physical manifestations of MPI. But there’s no evidence the symptoms are produced by something (like a poison or a germ) other than the nervous system.

MPI is surprisingly common throughout history. Before dancing mania, there was a condition known as tarantism that occurred during the Middle Ages in Southern Italy. Victims of tarantism suffered from a number of symptoms ranging from headache to difficulty breathing, which, according to the victims, began immediately after the bite of a tarantula. (In those days, tarantula referred to a wolf spider, not the spiders we typically think of as tarantulas. Regardless, whether a spider bite was really involved was usually difficult to verify; it’s suspected that in many cases, the spider—like the resultant condition—was a phantom of the mind.) Once the malady took hold, however, the victims didn’t seek out antidotes to spider venom. Instead, they immediately began to take part in the only recognized cure: dancing. Patients would dance on and off for hours, days, or even weeks to upbeat melodies now known as tarantellas (this is what you heard in the video clip above).

Since these dancing disorders of the Middle Ages and early modern times, there have been hundreds of other potential instances of MPI as well. But, you might be thinking, perhaps MPI occurred in the distant past because people were more superstitious and easily-duped than they are today. Surely, we must have advanced past this era of gullibility, right?

Wrong. There is a long list of examples of possible MPI in modern times. For instance, in 2011, twenty classmates at a high school outside Buffalo, NY suddenly began to experience tics, verbal outbursts, and other symptoms that resembled those of Tourette syndrome. Despite investigations by doctors and state health department officials, no environmental cause of the condition was identified, and most doctors eventually agreed that the students’ conditions were brought on by psychological factors. Some doctors even suggested that social and mainstream media contributed to the “spread” of the affliction. Those who were more inclined to post frequently about their ailment on sites like Facebook and those that gave frequent interviews to the press were thought to have the most aggravated conditions. The students who avoided these practices tended to improve more quickly.

Havana syndrome is potentially an even more recent example. Havana syndrome began in late 2016 in Cuba, when American and Canadian diplomatic personnel started reporting a number of symptoms—like headaches, nausea, dizziness, memory problems, hearing loss, and even “mild brain trauma”— which typically appeared after hearing a prolonged harsh, high-pitched noise. Strangely, other people nearby usually didn’t report hearing anything. By 2018, up to 40 cases of Havana syndrome had been documented among American and Canadian diplomatic personnel in Cuba. And in early 2018, similar claims began to be made by U.S. diplomats in China.

At first, many thought this was a case of international espionage at its finest—perhaps Moscow testing a secret acoustical weapon. But evidence to support that theory is lacking, and a number of scientists have now decided it’s more likely the diplomats were experiencing MPI. (Some have even suggested the high-pitched noise the diplomats heard was actually the sound of a particularly noisy type of cricket.)

There are many more examples of MPI in both modern times and the distant past. So, what is actually going on here? Well, first it’s important to point out that it’s almost impossible to completely eliminate other potential causes in these cases. There’s always the chance the unexplained symptoms linked to occurrences of putative MPI could be better explained by a toxin in the environment, a pathogen, or something else altogether that we just haven’t been able to identify. Perhaps, for example, Havana syndrome really was caused by some new weapon being surreptitiously tested by the Russians. We don’t know for sure.

But it’s also likely that at least some of these cases of potential MPI are due mainly to psychological factors. And if so, we’re at a loss to explain how, exactly, that might occur.

Some have suggested that extreme stress, pushing the brain to its cognitive breaking-point, might be a risk factor. Dancing mania, for instance, often affected areas that had recently been ravaged by harsh societal blights like food shortages, devastating diseases, etc. Others have argued that MPI preys primarily on the most suggestible people in the population. According to this hypothesis, there are some who are simply more inclined to believe a mysterious illness is taking hold of them, especially after they’ve heard about or seen someone else affected by that “illness.” (These might also be the same people who are most likely to be susceptible to the influence of something like hypnosis.) And still others are unconvinced that MPI is a viable diagnosis in many cases, since it implies a certainty we can’t possess (that there is no other cause of the condition) and assumes we have the ability to explain behavior that might have been prompted by any number of factors ranging from actual physical illness to cultural elements we may not completely understand.

Thus, at this point, MPI is controversial. We can’t explain why it might happen, and we also can’t say for sure how often it really does. But, there are many scientists who believe this type of mass hysteria is a legitimate phenomenon that has the potential to affect anyone, given the right circumstances. That’s a sobering thought, although it’s still unclear if it’s grounded in reality or if it, like the condition in question, is merely an example of the inherent fallibility of the brain.

References (in addition to linked text above):

Bartholomew RE. Tarantism, dancing mania and demonopathy: the anthro-political aspects of 'mass psychogenic illness'. Psychol Med. 1994 May;24(2):281-306.

Waller J. A forgotten plague: making sense of dancing mania. Lancet. 2009 Feb 21;373(9664):624-5.

Know Your Brain: Alzheimer's Disease

Background

Auguste Deter, the subject of Alois Alzheimer’s case study describing what would come to be known as Alzheimer’s disease.

In 1906, at a meeting of psychiatrists in Germany, Alois Alzheimer gave a lecture in which he detailed the unusual case of Auguste Deter. Alzheimer had encountered Deter about five years prior, when he was working as an assistant physician at a psychiatric institution in Frankfurt am Main in Germany. Deter had made an impression on Alzheimer because she was relatively young, but was suffering from a unique constellation of severe, dementia-like symptoms.

Deter was 51 years old when Alzheimer met her. Her most noticeable symptoms had begun in the previous year, when her behavior became alarmingly erratic. First, she began displaying uncharacteristic jealousy of her husband. Then, her memory started to deteriorate rapidly. She would easily become disoriented, and often lose touch with reality, consumed with paranoid delusions. As Alzheimer described it:

“…sometimes she thought somebody was trying to kill her and started to cry loudly…Sometimes she greets the attending physician like company…sometimes she protests loudly that he intends to cut her…Then again she is completely delirious, drags around her bedding, calls her husband and daughter and seems to suffer from auditory hallucinations. Often she screamed for many hours.”

Alzheimer was intrigued by the case. Deter seemed to be afflicted with a form of senile psychosis, which was probably a symptom of dementia. But it was rare to see dementia this severe in someone so young.

In addition to being a physician, Alzheimer was also an industrious researcher. He was intensely interested in pathological changes in the nervous system that accompanied psychiatric and neurological illnesses. Thus, when Deter died at the age of 55, Alzheimer requested her brain be sent to him for study. Upon examination, Alzheimer found the brain had suffered widespread neuronal loss and was riddled with abnormal structures (later learned to be the protein deposits discussed below).

Deter’s age, symptom profile, and neural deterioration convinced Alzheimer that she was a unique case. The psychiatrists present at his lecture on the topic didn’t seem to feel the same way, however, as there were no questions, comments, or other indications of interest following his presentation (the attendees seemed much more intrigued by the next presentation on compulsive masturbation). But little did Alzheimer know that his lecture would mark a historic moment, as only a few years later the renowned psychiatrist (and Alzheimer’s colleague) Emil Kraepelin introduced the term Alzheimer’s disease (AD) to describe an early-onset form of senile dementia.

It wasn’t until the late 1970s that researchers began to recognize that most cases of AD are not early-onset, and occur in patients over the age of 65. Today, AD is one of the greatest health concerns for people in this age group, and due to the fact that this population continues to increase in number (which is, ironically, a result of our improved ability to keep people alive longer), it is a rapidly growing problem. Today, about 1 in every 10 people over the age of 65 suffers from AD, and the number of people with AD in the United States is expected to nearly triple by the year 2050.

What are the symptoms of Alzheimer’s disease?

AD is a type of dementia, a term used to describe a condition that involves memory loss and other cognitive difficulties. There are a number of different types of dementia, however—each with its own causes and specific symptom profile. AD is just one variation.

The best-recognized sign of mental decline in AD is problems with memory. In the early stages of the disease, this often manifests as difficulties creating new memories, and problems are especially noticeable with declarative memories, or memories about information and events (as opposed to memories for how to do routine things like tie your shoes or eat with utensils, which are known as non-declarative memories). Early on, patients are typically able to maintain older memories and non-declarative memories. Over time, however, all memory can be affected, and even the most enduring memories may deteriorate.

But memory deficits are just one aspect of AD symptomatology. Patients can also experience problems with communication, and the ability to read and write may be impaired. Unpredictable mood disturbances, ranging from apathy and depression to angry outbursts, can occur. Thinking often becomes delusional, and a substantial subset of patients (up to 20%) even experience visual hallucinations.

It’s not just cognition that’s affected, though. Movement is hindered, causing patients to begin to lose mobility and have trouble performing even the simplest acts of self-care. Basic motor functions like chewing and swallowing become faulty, and incontinence eventually occurs.

In the end (if a patient survives this long), there aren’t many brain functions that haven’t been affected in some way, and patients become completely dependent on caregivers to help with even the most basic daily activities like eating and going to the bathroom. The disease is always fatal.

What happens in the brain in Alzheimer’s disease?

When Alois Alzheimer examined the brain of Auguste Deter, he noted a few distinct pathological changes. The first was that the brain had undergone significant atrophy. It appeared somewhat shrunken compared to a healthy brain.

This atrophying of the AD brain is due to the death of brain cells that occurs in the disease. AD is what is known as a neurodegenerative disease, which is a classification used to refer to diseases that cause the degeneration and death of neurons. A number of diseases fall into this category (e.g. Parkinson’s disease, amyotrophic lateral sclerosis), but AD is the most common of the group.

Alzheimer also noted unusual formations both within and surrounding neurons. He remarked that “distributed all over the cortex…there are…foci which are caused by the deposition of a special substance,” and he also mentioned “many fibrils located next to each other…they appear one by one at the surface of the cell.” Alzheimer was describing what today are the two hallmark neurological signs of AD: amyloid plaques and neurofibrillary tangles.

The first of these structures, amyloid plaques, consist of collections of small peptides (essentially a smaller version of a protein) known as amyloid beta, or Aβ, that form large clusters outside of neurons. Normally, enzymes called proteases can help to get rid of unwanted peptides and proteins in the brain. But amyloid plaques are especially resistant to degradation by proteases. Thus, they build up in the brain as the disease progresses; their presence is a defining feature of an AD brain.

Watch this 2-Minute Neuroscience video for a summary of the way Alzheimer’s disease affects the brain.

The other structure observed by Alzheimer, neurofibrillary tangles, also consist of abnormal deposits of proteins. In this case, the protein culprit is called tau. Tau normally plays an important role in helping to transport materials throughout the cell, but in AD it loses its normal function and clusters together in the tangles Alzheimer described. Like amyloid plaques, normal mechanisms the brain uses to remove unwanted protein deposits fail to effectively clear away neurofibrillary tangles. In fact, even after an affected neuron dies, the tangles found within it remain like a reminder of the neuron that was.

As the disease progresses, amyloid plaques and neurofibrillary tangles accumulate more and more in the brain. Thus, the appearance of these abnormal structures is correlated with the severity of the symptoms of AD. At the same time, exactly what role these structures play in the development of the disease remains unclear. For example, researchers are still unsure if amyloid plaques themselves are damaging to neurons, or if they represent an effort by the brain to sequester toxic Aβ peptides to protect neurons from their detrimental effects. There are similar questions about neurofibrillary tangles. Their appearance seems to be disruptive to neuronal function, and their spread throughout the brain correlates even better with neurodegeneration and symptoms than the proliferation of amyloid plaques. Nevertheless, their specific contribution to the progression of AD remains uncertain.

Causes and treatments

Thus, there are a lot of questions still surrounding the disease process of AD. Similarly, uncertainty surrounds why the disease affects some people but not others. In a small fraction of AD cases, the disease can be linked to mutations in a handful of identified genes whose protein products are involved in the production of the Aβ peptides mentioned above. But for most patients, there is no clear genetic or environmental cause of the disease.

There are, however, some known risk factors. For example, a variant of a gene called Apolipoprotein E, or ApoE, is known to increase the risk of AD by 10 to 20 times. ApoE encodes for a protein that is involved with the transport of cholesterol and other lipids in the blood, but it’s not yet clear why it might be involved with AD risk. High lipid and cholesterol levels, however, have also been identified as possible risk factors for the disease.

There are a number of other potential risk factors, like smoking, repetitive head injuries, poor cardiovascular health, and diabetes. Researchers are still unsure, however, just how these factors might increase the chances of developing AD. And by far the greatest risk factor remains one that we can’t avoid: old age.

Thus, the causes of AD remain somewhat obscure, which perhaps makes it unsurprising that our treatments are similarly unsatisfying. The most common treatment for the disease involves drugs that raise levels of the neurotransmitter acetylcholine in the brain. Acetylcholine is thought to play important roles in learning and memory, and large repositories of acetylcholine neurons (e.g. the nucleus basalis) are decimated during AD—likely contributing to memory loss.

Drugs called acetylcholinesterase inhibitors (AChEIs) suppress the activity of an enzyme called acetylcholinesterase, whose normal function is to remove acetylcholine from the synapse—in effect reducing the effect the neurotransmitter can have at that synapse. By inhibiting acetylcholinesterase activity, AChEIs cause acetylcholine levels to increase. In the process, these drugs can lead to modest improvements in memory. Because the effects are modest, however, AChEIs are often not very useful in the later stages of the disease. In fact, clear improvement in cognitive symptoms is only seen in less than 10% of patients taking the drugs. Additionally, AChEIs can only treat the symptoms of AD—they don’t do anything to stop the disease from progressing.

There are a handful of other treatments, and many others being explored, but at this point we don’t have any means of halting the neurodegeneration that underlies the symptoms of AD. Thus, we remain somewhat limited in our ability to treat the disease. Hopefully, continued neuroscience research allows us to one day develop better methods of addressing the pathological changes that occur in the AD brain.

References (in addition to linked text above):

Alzheimer A, Stelzmann RA, Schnitzlein HN, Murtagh FR. An English translation of Alzheimer's 1907 paper, "Uber eine eigenartige Erkankung der Hirnrinde". Clin Anat. 1995;8(6):429-31.

Cipriani G, Dolciotti C, Picchi L, Bonuccelli U. Alzheimer and his disease: a brief history. Neurol Sci. 2011 Apr;32(2):275-9. doi: 10.1007/s10072-010-0454-7.

Sanes JR, Jessell TM. The Aging Brain. In: Kandel ER, Schwartz JH, Jessell TM, eds. Principles of Neural Science, 5th ed. New York: McGraw-Hill.

Know Your Brain: Fatal Insomnia

In 1991, Michel A. Corke was enjoying the summer break from his position as a music teacher in a Chicago high school when he started to develop sleeping problems. He had recently turned 40, and seemed to be in good health, but it was soon very obvious that he was suffering from more than just your run-of-the-mill insomnia. It wasn't just taking him longer to fall asleep than normal. Nor was he suffering from the common problem of waking up frequently over the course of the night. He wasn't sleeping at all.

Within a few months, Corke's lack of sleep was causing obvious physical and mental deterioration. He developed problems with balance and had trouble walking. He began to display signs of dementia and there were times when he appeared to lose touch with reality. Sometimes these episodes involved hallucinations.

After Christmas, he was admitted to the hospital. At that point, Corke was unable to communicate. He had become completely dependent on his family to help him perform even the simplest tasks like showering and getting dressed. His decline had been rapid and pervasive.

At first, doctors could not figure out was wrong with Corke. They diagnosed him with multiple sclerosis, despite the fact that he didn't really have the symptom profile of someone with the disease.

But doctors soon recognized that something was very unusual about Corke's "sleep." Even though Corke would often close his eyes and appear to be sleeping, measurements of his brain activity found that his brain never did actually fall asleep. This helped doctors to realize that he was suffering from a disease that had only been recognized within the previous decade, called fatal familial insomnia (now often called fatal insomnia because not all cases seem to be hereditary).

In the disease, sleep becomes progressively disrupted until patients exhibit little to no sleep. Eventually, death is inevitable.

Michel Corke's case was no exception. By the time he had been admitted to the hospital, about 130 days had passed with minimal sleep. When he died, he had essentially been awake for 6 months.

What are the symptoms of fatal insomnia?

Fatal insomnia is a rare disease that usually develops in middle age or later (the average age of onset is 51 years), and begins with complaints of trouble sleeping or excessive fatigue during the day. At first, due to this extreme daytime sleepiness, the assumption might be that the patient is plagued by a condition that is making him too sleepy.

Sometimes there are other abnormal signs early on, like double vision, impotence, hypertension, and increased perspiration, lacrimation (i.e. tear production), and/or salivation.

As the disease progresses, patients lose their ability to sleep altogether. A variety of movement problems appear, including difficulties with balance and coordination and abnormalities in gait. Patients also will sometimes become delusional and display unusual behavior that resembles dream-enactment, which involves unconsciously making movements related to what's going on in a dream.

Later in the disease, after a patient has been deprived of sleep for some time, he begins to spend more and more time in a stupor from which it's difficult to rouse him. He may experience sudden, spasmodic movements, but voluntary movement like standing and walking often become difficult to impossible. He may lose the ability to speak, have trouble swallowing, and fall into a vegetative state.

Death can occur at any time throughout these phases of the disease, but if the patient survives long enough often he will fall into a coma, which will lead to death. The duration of the disease ranges from 8 to 72 months, with an average disease course lasting just over 18 months.

What happens in the brain in fatal insomnia?

Brain activity during "sleep"

One way to verify the sleep disturbances occurring in fatal insomnia is to measure sleep activity over the course of a night using a technique known as polysomnography. Polysomnography measures the electrical activity in the brain (using an electroencephalogram, or EEG) along with a number of other physiological changes that occur during sleep like eye movement, muscle activity, and the electrical activity of the heart.

Polysomnography is often used to verify a case of fatal insomnia because patients may appear to spend periods of the night sleeping, as they have their eyes closed and aren't moving. Polysomnography reveals, however, that their brain activity doesn't resemble a pattern of normal sleep.

In a healthy person, during sleep the brain cycles from relatively light sleep into a period of deep sleep into a period a rapid eye movement (REM) sleep. A full cycle takes about 90-120 minutes and is repeated 4-6 times per night. These different stages of sleep have characteristic electrical activity that can be measured with an EEG.

Patients with fatal insomnia will, of course, display drastically reduced total sleep time. But even at times when it appears as if they are asleep, the EEG still won't show these characteristics of healthy sleep. Instead, their brain activity generally indicates wakefulness for most of the night, with very brief periods of light sleep (i.e. stage 1 or stage 2 sleep) and occasional sudden episodes of REM sleep that only last seconds or minutes. Deep sleep mostly disappears, and as the disease progresses all traces of REM sleep may disappear as well.

The thalami are the orange, oval-shaped structures in the image. They are the site of the most significant neurodegeneration in fatal insomnia.

Neurodegeneration

Fatal insomnia is associated with severe neurodegeneration of the thalamus, which is thought to be a critically important structure in sleep regulation. The thalamus is believed to play an especially important role in the generation of a type of deep sleep known as slow-wave sleep. Over the course of the disease, up to 80% of neurons are lost in certain nuclei of the thalamus.

The inferior olivary nucleus, a structure in the brainstem that is densely interconnected with the cerebellum, also suffers significant neurodegeneration in the disease, losing more than 50% of its neurons. The role of the inferior olivary nuclei in the symptoms of fatal insomnia is still unclear. It may be involved in generating movement-related symptoms like tremor and spasmodic muscle contractions, but some evidence suggests the olivary nuclei and cerebellum are involved with sleep as well.

The disease is also sometimes associated with the formation of large abnormal compartments, or vacuoles, within neurons. These "holes" in the brain can give the brain a sponge-like appearance. In fatal insomnia, this occurs primarily in the cerebral cortex.

Accumulation of prion protein

Fatal insomnia is considered a prion disease, and thus also involves the accumulation of abnormally-folded forms of prion protein in the brain. These misfolded proteins have a tendency to accumulate into clusters that are resistant to being broken down by brain enzymes. The implications of these protein clusters forming in the brain is unclear, although they are often linked to pathological changes in the brain. (For a short primer on prion diseases, read this article.)

Prion proteins also are capable of passing their misfolded state on to other healthy proteins. Thus, they can spread within the brain of an infected patient, gradually increasing the number of misfolded prion proteins. Interestingly, their "infectious" quality also allows prions to cause disease if transmitted from one host to another. While it isn't thought that fatal insomnia is spread among people in this way, the disease has been transmitted to mice by injecting them with a liquefied piece of brain tissue from a human patient who had the disease.

In fatal insomnia, however, there are relatively few clusters of prion protein in the brain as compared to other prion diseases. And, while deposits in some areas of the brain increase in number as the disease progresses, this isn't true for the areas that experience the most neurodegeneration---like the thalamus. Thus, it's still unclear what exactly causes the neurodegeneration that produces the symptoms of fatal insomnia.

What causes fatal insomnia?

Most of the cases of fatal insomnia identified to date are considered genetic diseases, attributable to a genetic mutation in the PRNP, or PRionN Protein, gene---a gene that's implicated in other prion diseases as well. The mutation is an autosomal dominant mutation, which means that if someone with the mutation has a child, the child has a 50% chance of ending up with the same mutation. When fatal insomnia is inherited, it is generally referred to as fatal familial insomnia.

To date, just over 200 individuals worldwide are known to carry the mutation associated with fatal familial insomnia. Due to the global distribution of the disease, some researchers have suggested it is caused by a recurrent mutation that has happened independently in a number of families.

In 1999, the first cases of what seems to be non-hereditary fatal insomnia appeared. Non-hereditary fatal insomnia is commonly referred to as sporadic fatal insomnia, and to date 32 cases have been identified. These patients display most of the same symptoms and pathology as fatal familial insomnia patients, but they have no family history of the disease and do not have the mutation of the PRNP gene seen in fatal familial insomnia patients.

What is the treatment for fatal insomnia?

We are severely limited in our ability to treat fatal insomnia patients. Even the strongest sedatives (e.g. barbiturates, benzodiazepines) do not cause patients of the disorder to sleep. Thus, treatment focuses on relieving the symptoms of the disorder as much as possible (which alone is a challenge).

References (in addition to linked text above):

Cracco L, Appleby BS, Gambetti P. Fatal familial insomnia and sporadic fatal insomnia. Handb Clin Neurol. 2018;153:271-299. doi: 10.1016/B978-0-444-63945-5.00015-5.

Montagna P. Fatal familial insomnia and the role of the thalamus in sleep regulation. Handb Clin Neurol. 2011;99:981-96. doi: 10.1016/B978-0-444-52007-4.00018-7.

Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol. 2003 Mar;2(3):167-76. (in