Ideally, humans sleep for at least eight hours every day, meaning that we spend about a third of our lives “unconscious.” Scientists have yet to agree on why this unconsciousness is vital, but we know that without sleep, all mammals and birds would die [1]. Because sleep has only become the subject of research in the recent past, rare neurological disorders like fatal familial insomnia (FFI), which causes patients to die within a year or two of its onset, (usually in the patient’s early fifties) ranks very low on the list of things to cure. Though in this case the cause of death is mostly attributable to neural degeneration, death is clearly hastened by a marked “disruption of critical functions” due to lack of sleep [2]. And before death, all FFI patients display symptoms that are clear manifestations of damage to a mass of grey brain matter called the thalamus. In fact, according to National Geographic, “before FFI was investigated, most researchers didn’t even know the thalamus had anything to do with sleep” [1]. By studying the effects of FFI, it is likely that scientists will accrue key insight into the exact role of the thalamus in sleep—and maybe even insights into the function of sleep as well.
The thalamus belongs to the limbic system, which lies deep in the cortex and extends to the top of the brain stem [4]. The cortex is the outer layer of the cerebrum, the front part of the mammalian brain. Generally, scientists agree that the limbic system is involved in olfaction, the interpretation of emotions, storage of certain types of memories, and regulation of certain hormones. [4] The thalamus itself acts as a sort of control tower, receiving sensory messages from the spinal cord and then relaying those signals along to their corresponding locations in the cerebrum [5]. Ann M. Akroush of the University of Michigan’s Department of Natural Sciences calls the thalamus “the area [of the brain] responsible for sleep,” noting that during sleep, it is generally thought that “the thalamus becomes less efficient…allowing for the vegetative state of sleep to come over an individual” [3].
Sleep includes long periods of non-rapid eye movement, punctuated by rapid eye movement (REM), the latter that amounts to about a quarter of the total sleeping time. During non-REM sleep, most neurons in the brain stem, cerebral cortex, and adjacent forebrain regions—all connected to the thalamus—stop firing [6]. Non-REM sleep, it seems, gives cells a chance to repair themselves from daily wear and tear. Jerome M. Siegel of the Brain Research Institute at University of California, Los Angeles, accounts for this conjecture by pointing to the fact that “bigger animals,” such as humans, “need less sleep” on the whole than smaller animals, such as cats, because smaller animals “have higher metabolic rates” [6]. The set of chemical reactions that constitute a metabolism generate free radicals, chemicals that are known to cause a lot of damage to or even kill cells; thus, these smaller animals are likely to experience greater rates of tissue injury, and a higher need for self-repair [6].
Victims of FFI are unable to “get past” the first stages of sleep and enter REM sleep, which is generated by the brain stem—right below the thalamus [1]. Although the exact purpose of REM sleep remains a mystery, we know it “profoundly affects brain systems that control the body’s internal organs” [6]. For example, during REM our heart rate and breathing become “irregular” as in our waking state [6]. Like a reptile’s, our body temperature drifts toward that of our environment [6]. The body temperature of sufferers of FFI instead “soars and crashes” marked by extensive sweating and chills [1].
Additionally, in 1973 a group of scientists discovered that during REM sleep, neurons completely cease their release of a group of neurotransmitters called monoamines—which include dopamine and serotonin [6]. Siegel believed that this halt could be “vital for the proper function of these neurons and of their receptors,” due to the fact that a “constant release” of monoamines tends to desensitize their receptors [6]. Thus, he says, the “interruption of monoamine release during REM sleep…may allow the receptor systems to “rest and regain full sensitivity” [6]. Without either type of sleep, and consequently neither a period of rest nor a chance for cell repair, the outlook for FFI patients seems dim. Furthermore, the question of whether FFI patients actually die from lack of sleep seems intimately tied to understanding the exact function of the thalamus, as evidenced by the locations of brain activity during sleep. Could it be that the thalamus is most vital to us because of its connection to sleep?
FFI is part of a family of diseases called transmissible spongiform encephalopathy (TSE), or prion disease. “Spongiform encephalopathies” are brain infections distinguished by the appearance of a bunch of little holes in the affected region, as in a sponge. They are transmissible because they can spread. TSEs are caused by fatal misfoldings of “prion” proteins, which in turn recruit the cells around them to misfold, and together these proteins become indigestible to enzymes [7]. In FFI patients, rogue malformed prion proteins attack the thalamus [1]. First, the victim will display signs of worsening insomnia. Then, he or she will start to panic, hallucinate and sweat. After the patient loses all ability to sleep, rapid weight loss will ensue. Next, the patient will experience dementia and irresponsiveness, and finally sudden death [3]. Like the rest of the TSEs, FFI is “autosomal dominant”: if one of your parents is a carrier of the gene for FFI, you are automatically doomed to be a victim of the disease.
A particular case report by psychologist Joyce Schenkein and neurologist Pasquale Montagna describes the efforts of one patient who was able to exceed the average survival time by nearly one year. He tried various strategies, including vitamin
therapy and meditation, using different stimulants and narcoleptics and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day [2]. Nonetheless, over the course of his trials, the patient succumbed to the classic four-stage progression of symptoms. The fact remains that there is no cure for FFI.
therapy and meditation, using different stimulants and narcoleptics and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day [2]. Nonetheless, over the course of his trials, the patient succumbed to the classic four-stage progression of symptoms. The fact remains that there is no cure for FFI.
We do not know if prions destroy every FFI victim’s thalamus in the same way—that is to say, if physiological function in the region directly corresponds to symptom manifestation. Schenkein and Montagna concluded that death was hastened by “the disruption of critical functions,” including ones related to “hypometabolism,” in which biochemical processes of the body move at a slower pace, and others related to “dysautonomia”, in which, the sympathetic nervous system, the control center for the “fight-or-flight” response, goes into overdrive, resulting in metabolic exhaustion [2]. So, does the thalamus indeed become “less efficient” during sleep, as Akroush put it, or do its functions simply shift? These directed questions could allow researchers to better understand the disease, its manifestations, and potential routes to cures.
Akroush cites gene therapy as a starting point for treatment possibilities. This would generally involve the re-introduction of a non-mutated version of the rogue gene into an affected individual’s genome with aims to correct his or her protein expressions. But this treatment is only an option if it is performed far before any FFI symptoms visibly manifest [3]. Worse, scientists have yet to isolate the corrective gene or to identify a proper vector for transfer. Indeed, if sleep weren’t such a private and mysterious bodily function, argues National Geographic, “governments would [themselves] declare war on” sleep disorders [1]. Still, our understanding does seem to be progressing, if slowly. We know that patients diagnosed with fatal familial insomnia die after substantial damage to the thalamus that directly causes an inability to sleep. From this, we can infer that the thalamus’s role is necessary to sustain human life and important for elucidating the mysteries behind mammalian sleep.
Yet the National Institutes of Health (NIH) contributes “only about $230 million a year to sleep research,” while spending well over $100 billion per year to treat obesity-related conditions, that might be solved simply with dietary modifications and moderate exercise. While obesity has only become an issue in the last century, the first accepted case of FFI was recorded in the eighteenth century [1]. Similarly, about thirty percent of Americans are obese, while over fifty percent of Americans complain of symptoms of insomnia [8]. Incidentally, there is an increasing body of research linking certain obesity cases to lack of sleep— but we sleep about “an hour and a half less a night than we did just a century ago” and our struggles continue [1]. For now, the fight against insomnia has been “largely left to drug companies and commercial sleep centers,” who target general client bases, while FFI victims and future generations of their family will continue to die until a cure is found [1].
References:
- Max DT. The Secrets of Sleep. National Geographic [serial on the Internet]. 2010 May; [cited 2011 January 24]; [about 5 screens]. Available from: http://ngm.nationalgeographic.com/2010/05/sleep/max-text
- Schenkein J, Montagna, P. Self-management of Fatal Familial Insomnia Part 2: Case Report. MedGenMed [serial on the Internet]. 2006 September 12; [cited 2011 January 24]; 8(3): [about 12 screens]. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1781276/?tool=pmcentrez
- Akroush, AM. Fatal Familial Insomnia [homepage on the Internet]. Case Studies in Virtual Genetics 1996-1997: John C. Thomas; [cited 2011 January 24]; Available from: http://www-personal.umd.umich.edu/~jcthomas/JCTHOMAS/1997%20Case%20Studies/AAkroush.html
- Regina Bailey. Limbic System [homepage on the Internet]. Biology About.com Guide. [updated 2011; cited 2011 January 24]. Available from: http://biology.about.com/od/anatomy/a/aa042205a.htm
- Thompson Learning, Inc. What are the main anatomical structures of the brain and what are their functions? [homepage on the Internet]. Thompson Learning, Inc; [updated 2002; cited 2011 January 24]. Available from: http://163.16.28.248/bio/activelearner/40/ch40c2.html
- Siegel, JM. Why We Sleep. Scientific American. 2003 November: 92-97.
- Zeman, A. A Portrait of the Brain. New Haven: Yale University Press; 2008.
- WB&A Market Research. 2002 Sleep in America Poll [homepage on the Internet]. Washington DC: National Sleep Foundation [updated 2002 April 2; cited 2011 May 3] Available from: http://www.sleepfoundation.org/sites/default/files/2002SleepInAmericaPoll.pdf
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