4. Sleep Bruxism Apnea Shift Work Insomnia Restless Leg Syndrome Delayed Sleep Phase Nocturnal enuresis Exploding Head Syndrome Narcolepsy
5. Narcolepsy Comes from French word narcolepsie Narco - numbness or stupor and (lepsis)- "attack" or seizure Is a type of dyssomnia, characterized by excessive daytime sleepiness (EDS) People with narcolepsy may visibly fall asleep at unpredicted/ inappropriate moments (such motions as head bobbing are common). Is a “neurological sleep disorder”? Affects 1 in 2000 people, no gender bias Inherited factors account for1-2% of family members of Narcoleptics also having the condition. (Mignot, 1998)
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8. Symptoms 2.Cataplexy (muscle weakness) loss of muscle tone while awake. Muscle weakness affects part or all of your body. Cataplexy may make your head nod or make it hard for you to speak. Weak knees or Grips-drop things you're holding. Some people lose all muscle control and fall(collapse). Strong emotions—such as anger, fear, laughter, or excitement—can trigger this weakness.
9. Symptoms 3. Hallucinations vivid dreams while falling asleep, waking up, or dozing. These dreams can feel very real. You may feel like you can see, hear, smell, and taste things. 4. sleep paralysis condition prevents you from moving or speaking while falling asleep or waking up. However, you're fully conscious (aware) during this time. Sleep paralysis usually lasts just a few seconds or minutes automatic behavior you're not aware of your actions, so you don't do them well. I.E: writing before falling asleep, you may start to scribble rather than form words. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms
10. Diagnosis Two tests that are commonly used in diagnosing narcolepsy are the 1. polysomnogram and the 2. multiple sleep latency test (MSLT). polysomnogram involves continuous recording of sleep brain waves and a number of nerve and muscle functions during night time sleep. multiple sleep latency test, person is given a chance to sleep every 2 hours during normal wake times. Observations are made of the time taken to reach various stages of sleep.
11. Causes: Hypocretins and orexins Two Names due to simultaneous discovery, interchangeable terms pair of excitatory neuropeptide hormones produced by a very small population of cells in the lateral and posterior hypothalamus Hypocretinseems to promote wakefulness and Feeding. Most patients with narcolepsy-cataplexy have no hypocretin-1 molecules in their CSF
12. Role of orexin projections to the midbrain in the regulation of the loco motor system A. The REM sleep generating system was inhibited by orexin through activation of GABAergic input. B. normal orexin maintained an excitability of the locomotor system and suppressed the REM sleep generating system. C. narcolepsy an orexin deficit may decrease the excitability of the locomotor system , the excitability of the REM sleep generating system could be increased. Emotional signals may thus produce cataplexy. + and − signs indicate excitatory and inhibitory effects, respectively. (Takakusaki et al, 2005)
15. Research:Narcolepsy in orexin Knockout Mice To target the mouse orexin gene, they constructed a targeting vector , and swapped the genes using homologous recombination with 2 crosses transfected a 129/Sv mouse Embryonic Stems cell line with the linearized targeting vector
16. In situ hybridization in orexin knockout mice Wild Type Heterozygous Homozygous Brain section of lateral hypothalamus labelled with 33P-labeled antisense riboprobe for orexin.
17. Results Behavioural Characterization Mice are active at night, Used infrared camera Showed behavioural arrest “narcoleptic episodes” in orexin null mice during the dark phase No narcoleptic episodes were identified on videotapes of the wild-type or heterozygote mice. average duration of episodes for individuals varied, overall group average of 65.6 s
18. Hypnogram of the orexin knockout mouse W, represents wakefulness S, non-REM sleep R, REM sleep.
19. Current treatments: (Drugs for EDS) Amphetamines-They inhibit the vesicular monoamine transporter, causing the emptying of vesicular dopa-mine stores into the cytoplasm. Causes increase in dopamine release Modafinil promotes wakefulness in both normal and hypocretin-deficit narcolepsy patients. The mechanism of action of modafinil is still debated but it may involve dopamine reuptake inhibition
20. Gene Markers A factor that seem to influence narcolepsy is found on area of Chromosome 6 known as the HLA complex (human leukocyte antigen) HLA-DR2 is marker for Narcolepsy-Cataplexy HLA-DQB1*0602 is better marker, found in 90% of Narcolepsy patients with Cataplexy Currently Not Many research on Affect on Autoimmune Influence on Narcolepsy but…
21. Autoimmune Study: Body Attacking itself? Mignot (2009), Stanford University induced narcolepsy-like symptoms in the muscles of mice by injecting them with antibodies from the blood of nine people with the disorder. Mice injected with antibodies not develop symptoms. The research suggests that in some narcolepsy patients the immune system produces antibodies which inflict damage on the brain tissues, and trigger symptoms of narcolepsy.
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24. References: Takakusaki K. et al. Orexinergic projections to the cat midbrain mediate alternation of emotional behavioural states from locomotion to cataplexy,The Journal of Physiology, (2005) 568: 1003-1020 Chemelli R.M., et al. Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation (1999) Cell, 98 (4), pp. 437-451. Doghramji P. et al. Understanding, diagnosing, and successfully managing narcolepsy, The Journal of Family Practice(2007) Vol. 56: S17-S32 Giselia Telis, Narcolepsy: A Case of the Body Attacking Itself? (2009) http://news.sciencemag.org/sciencenow/2009/05/04-02.html
Editor's Notes
REM, rapid eye movement.Comparison of a polysomnography from a control subject (top tracing) and a subject with narcolepsy (bottom tracing). In the control trace, the subject cycles through the 4 slow wave sleep stages (stage 1, stage 2, and the Delta stages S3 and S4) before entering REM sleep; REM sleep occurs more than 1 hour after the subject falls asleep. In the bottom trace, the subject with narcolepsy enters the REM stage almost immediately upon falling asleep. The subject with narcolepsy also spends more of the night in the awake state than does the control subject.
A link between orexin and Alzheimer's disease has been recently suggested.[14] The enigmatic protein amyloid beta builds up over time in the brain and is correlated with Alzheimer's disease. The recent research shows that amyloid beta expression rises during the day and falls during the night, and that this is controlled by orexin.[14] Sleep deprivation is suggested to lead to amyloid beta plaque development
In b it’s normal level of oxerin and inhibits REM generator (causes sleep paralysis)In c, decrease levels of orexinSNr=The substantianigra is a brain structure located in the mesencephalon (midbrain) that plays an important role in reward, addiction, and movement.REM and atonia systems, and possible mechanisms of induction of cataplexy in narcolepsy
Note the symmetric distribution of labeled neurons in the wild-type and heterozygote mice and the absence of signal in the homozygote. No detectable signal beyond background was generated by the sense riboprobe.
Note episodes of sleep-onset REM, marked by arrowheads, greater non-REM sleep episode fragmentation, and reduced wakefulness periods in the hypnogram of the orexin knockout mouse during this period.
The researchers analyzed DNA from nearly 4000 participants, all of whom shared the same narcolepsy-linked HLA but only about half of whom had narcolepsy. They found that the narcoleptics in the study shared a version of another gene that tells T cells--the immune cells that destroy intruders--how to react to the pathogens that HLA molecules bring them. The result indicates that T cells and HLA, which together regulate much of the body's immune response, gang up in a unique way to destroy narcoleptics' hypocretin cells, the team reports online this week in Nature Genetics.
The SCN are anatomic structures that are located in the anterior hypothalamus over the optic chiasm and contain approximately ten thousand cells. Collectively, the SCN are the biological clock, able to generate its own endogenous rhythm that can be synchronized by signals from internal or environmental sources (sunlight).SCN cells transmit the synchronized light-dark rhythm information to other adjacent hypothalamic nuclei responsible for hormone secretion periodicity, temperature changes in the CNS, food ingestion, tendency and duration of sleep-wake cycle and melatonin secretion.7 The SCN signal can also be synchronized by other nonphotic stimuli, stimuli from the limbic system and other social rhythms, such as meal timingThe SCN efferent projections to the VLPO, lateral hypothalamus and LC are those that are the most important for the sleep-wake cycle. The functional role of SCN efferent projection to the VLPO is to block its inhibition at the end of wakefulness (when the SCN signal decreases), thereby allowing the initiation of NREM sleep
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