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

2-Minute Neuroscience: Pineal Gland

The pineal gland is a pine cone shaped structure located in the diencephalon whose main function is the secretion of melatonin, a hormone that is best known for its role in regulating circadian rhythms. The pineal gland secretes melatonin throughout the 24-hour cycle, with secretion being highest in the middle of the night and lowest during daylight hours. In this video, I discuss the pineal gland and melatonin secretion, including 24-hour patterns of melatonin secretion and how the pineal gland uses signals from the retina about how much light is in the environment to determine what the time of day is.

Know your brain: Suprachiasmatic nucleus

Where is the suprachiasmatic nucleus?

the suprachiasmatic nucleus is represented by a small green area within the hypothalamus (indicated by red arrow).

The suprachiasmatic nuclei are two small, paired nuclei that are found in the hypothalamus. Each suprachiasmatic nucleus only contains approximately 10,000 neurons. The nuclei rest on each side of the third ventricle, just above the optic chiasm. The location provides the rationale for the naming of the structure, as supra means above and chiasmatic refers to its proximity to the optic chiasm. 

What is the suprachiasmatic nucleus and what does it do?

Circadian rhythms are biological patterns that closely follow a 24-hour cycle. The term circadian comes from the Latin for around (circa) and day (diem), and circadian rhythms govern a large number of biological processes including sleeping, eating, drinking, and hormone release. In the 1960s, researchers noticed that damage to the anterior hypothalamus of the rat caused a disruption in the animal's circadian rhythms. Several years later, the specific nucleus in the hypothalamus whose integrity was necessary for maintaining circadian rhythms was identified as the suprachiasmatic nucleus.

Watch this 2-Minute Neuroscience video to learn more about the suprachiasmatic nucleus and the molecular clocks it contains.

We now know that the suprachiasmatic nucleus houses a type of biological clock that is able to keep our circadian rhythms on close to a 24-hour cycle, even without the help of external cues like daylight. Thus, if you were to lock someone in a room with no external light and no other way of telling the time, her body would still maintain a circadian rhythm of around 24 hours. The mechanism that regulates this biological clock was first elucidated in Drosophila, more commonly known as the fruit fly.

In Drosophila, the timekeeping of the circadian clock appears to be controlled by a cycle of gene expression that has an ingenious negative feedback mechanism built into it. Cells in the suprachiasmatic nuclei of Drosophila produce two proteins called Clock and Cycle. Clock and Cycle bind together and act to promote the expression of two genes called period (per) and timeless (tim). The protein products of the per and tim genes, Per and Tim, then bind together and proceed to inhibit the actions of Clock and Cycle, an action which in turn suppresses the production of Per and Tim. As the sun rises, however, the Per and Tim proteins begin to break down. When Per and Tim degrade fully, Clock and Cycle are free to act again; they go back to promoting the expression of per and tim, starting the cycle anew. The process consistently takes around 24 hours to complete before it repeats. Thus, it is thought that this cycle of gene expression is what acts as the molecular clock in Drosophila suprachiasmatic nucleus cells.

This understanding of the timekeeping mechanism in Drosophila laid the foundation for elucidating the process in mammals, where it is thought to be similar but more complex. The mammalian version of Cycle is called BMAL1 (which stands for brain and muscle ARNT-like 1). When CLOCK and BMAL1 bind together, they enhance the transcription of multiple period (Per1 and Per2) genes and multiple genes known as cryptochrome (Cry1 and Cry2) genes. The resultant PER and CRY proteins form complexes along with other proteins to inhibit the activity of CLOCK and BMAL1 until the PER and CRY proteins degrade (as above). 

We know that this process of gene expression and inhibition acts to keep a 24-hour clock within the neurons of the suprachiasmatic nucleus, but less is known about how the timekeeping within these neurons leads to the regulation of rhythmic activity throughout the body. It is believed, however, that the molecular clocks found within the neurons of the suprachiasmatic nuclei regulate neural activity within the nuclei, which in turn coordinates the activity of multiple signaling pathways as well the stimulation of projections to neuroendocrine neurons in the hypothalamus involved with hormone release.

Additionally, the suprachiasmatic nucleus helps to maintain circadian rhythms by coordinating the timing of billions of other circadian clocks found in cells throughout the rest of the brain and body. Not long after the discovery of the suprachiasmatic nucleus, it was also learned that similar types of molecular clocks exist in most other peripheral tissues and in many areas of the brain. These clocks, sometimes called slave oscillators (while the suprachiasmatic nucleus is considered the master oscillator) appear to depend on signals generated by the suprachiasmatic nucleus to synchronize their time-keeping with that of the suprachiasmatic nucleus. These signals can be associated with rhythms that the suprachiasmatic nucleus helps to establish, like feeding patterns, rest and activity behaviors, etc., or by direct neuronal or hormonal output from the suprachiasmatic nucleus.

Although the suprachiasmatic nucleus is capable of maintaining circadian rhythms independently of any environmental signals (e.g. daylight), it does rely on cues from the environment to make adjustments to the circadian clock. For example, when you fly across multiple time zones, your body's circadian clock becomes significantly out of sync with the timing of the day (e.g. your body might be preparing for sleep when it is still light out). To make adjustments to the circadian clock in such instances, the suprachiasmatic nucleus relies on information it receives from the retina about light in the environment. Such information travels from the retina to the suprachiasmatic nucleus along a path called the retinohypothalamic tract. Additional inputs to the suprachiasmatic nucleus provide more information about light in the environment and other non-photic information about time of day to help to adjust the circadian clock.

Due to the importance of our circadian rhythms to normal functioning, the integrity of the suprachiasmatic nucleus is essential to health. Disrupted function of the suprachiasmatic nucleus is being explored as a potential influence in a variety of psychiatric disorders as well as a factor in age-related decline in healthy sleep. Thus, although we have much more to learn about the suprachiasmatic nucleus, it is clear that it plays a very critical role in healthy brain and bodily function.

References (in addition to linked text above):

Colwell, C. (2011). Linking neural activity and molecular oscillations in the SCN. Nature Reviews Neuroscience, 12 (10), 553-569.

Dibner, C., Schibler, U., Albrecht, U. (2010). The mammalian circadian timing system: organization and coordination of central and peripheral clocks Annual review of physiology, 72 (1), 517-549.

Why do we sleep?

Why do we sleep? Sleep is an activity that takes up about 1/3 of our lives, so you would probably guess that neuroscience has a clear answer to why we do it, right? Wrong. The fundamental reason behind why we sleep is still shrouded in mystery. We know that we have to sleep (without it we would die). But we still don't know what its physiological function is.

There are a variety of hypotheses about why we sleep that have garnered some support. For example, sleep may have evolved in order to help our ancestors save energy during a time when food was more difficult to obtain. According to this hypothesis, sleep is a period of adaptive inactivity, and may also have protected our ancestors during the time when their poor night vision would have made them more susceptible to predatory attacks.

Sleep also seems to serve a restorative function. While sleeping, we may be replenishing energy reserves that we have utilized throughout the course of our day. For example, to meet daily needs, your brain uses up stores of glycogen for energy. Sleep is an opportunity to decrease demands on the brain so those stores can be replenished.

Another hypothesis suggests that sleep is important for memory consolidation. Disrupting sleep has been shown to make recall of information learned the previous day more difficult (at least in some circumstances). This has led to the suggestion that sleep is crucial to the consolidation and integration of information learned throughout the day.   

Of course, none of these hypotheses are mutually exclusive. But recent research has begun to elucidate one of the ways that sleep may work to maintain a healthy brain - and what happens when it is prevented from doing so. Late last year, a study published in Science suggested that during our waking hours, waste products begin to accumulate in the fluid between the cells in our brain. These waste products include proteins (e.g. amyloid-beta and tau proteins) whose buildup is associated with neurodegenerative diseases like Alzheimer's disease. The study showed that during sleep in mice, the flow of cerebrospinal fluid (CSF) throughout the brain is increased. One of CSF's most important roles is waste removal, so increasing CSF flow facilitates the removal of these potentially damaging proteins. If this increased CSF flow and waste removal turns out to be a feature of human sleep as well, it might help to explain why poor sleep quality and shorter sleep duration have been found to be associated with higher levels of amyloid-beta protein accumulation in the brain. 

A study published last week also showed that chronically shortening the amount of time mice had in the light each day (which reduced the amount of time they slept because mice are nocturnal) led to impaired cognition. The study was done using a strain of mice genetically engineered to be a model for human Alzheimer's disease. These mice begin displaying signs of cognitive dysfunction at around a year of age, and then within a couple of months generally show the hallmark signs of Alzheimer's disease in the brain, which include aggregations of amyloid-beta and tau proteins. These aggregations are referred to as amyloid-beta plaques and neurofibrillary tangles, respectively. Although the mice subjected to sleep deprivation didn't display overall differences in amyloid-beta and tau accumulation, tau metabolism was altered in the sleep-deprived mice, which may have been an early indicator of tau aggregation. There were also other markers of synaptic pathology that would be consistent with neurodegeneration.

The purpose of sleep remains a mystery, but some of these recent studies underscore its significance to the health of the brain. It is important, however, to avoid misinterpreting findings like these as support for the idea that everyone needs a certain amount of sleep (in truth, everyone varies in the amount of sleep they need). What these findings suggest, though, is that chronic sleep disturbances may be especially detrimental to our brains as we get older.


Di Meco, A., Joshi, Y., & Praticò, D. (2014). Sleep deprivation impairs memory, tau metabolism, and synaptic integrity of a mouse model of Alzheimer's disease with plaques and tangles Neurobiology of Aging DOI: 10.1016/j.neurobiolaging.2014.02.011