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Microsleep

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Example of an EEG alpha wave
Example of an EEG theta wave

A micro-sleep (MS) is a temporary episode of sleep which may last for a fraction of a second or up to 30 seconds (4-5 seconds according to AAA.com) where an individual fails to respond to some arbitrary sensory input and becomes unconscious.[1][2] MSs occur when an individual loses awareness and subsequently gains awareness after a brief lapse in consciousness, or when there are sudden shifts between states of wakefulness and sleep. In behavioral terms, MSs manifest as droopy eyes, slow eyelid-closure, and head nodding.[2] In electrical terms, microsleeps are often classified as a shift in electroencephalography (EEG) during which 4–7 Hz (theta wave) activity replaces the waking 8–13 Hz (alpha wave) background rhythm.[3]

MSs often occur as a result of sleep deprivation, though normal non-sleep deprived individuals can also experience MSs during monotonous tasks.[4] Some experts define microsleep according to behavioral criteria (head nods, drooping eyelids, etc.), while others rely on EEG markers.[5] Since there are many ways to detect MSs in a variety of contexts there is little agreement on how best to identify and classify microsleep episodes.

Microsleeps become extremely dangerous when they occur in situations that demand constant alertness, such as driving a motor vehicle or working with heavy machinery. People who experience microsleeps often remain unaware of them, instead believing themselves to have been awake the whole time, or to have temporarily lost focus.[6]

Background and significance

Eyelid closed, demonstrating microsleep event according to eye-video test
Traffic collision, a possible consequence of microsleep

With over 1,550 fatalities and 40,000 nonfatal injuries occurring annually in the United States alone as a result of drowsy driving, sleep loss has become a public health problem.[7][8] When experiencing microsleeps while driving an automobile, from the perspective of the driver, he or she drives a car, and then suddenly realizes that several seconds have passed by unnoticed. It is not obvious to the driver that he or she was asleep during those missing seconds, although this is in fact what happened. The sleeping driver is at very high risk for having a collision during a microsleep episode.[9]

Historically, many accidents and catastrophes have resulted from microsleep episodes in these circumstances.[10] For example, a microsleep episode is claimed to have been one factor contributing to the Waterfall train disaster in 2003; the driver had a heart attack and the guard who should have reacted to the train's increasing speed is said by his defender to have microslept, thus causing him to be held unaccountable. On May 31, 2009, an Air France plane (Air France Flight 447) carrying 228 people from Brazil to France crashed into the Atlantic Ocean, killing everyone on board. The pilot of the plane reported "I didn't sleep enough last night. One hour – it's not enough," handing over control to the two co-pilots who did not respond appropriately when the plane was in distress.[11][12] Perhaps the most notable example was the Chernobyl nuclear reactor accident in the Ukraine in April, 1986. The reactor began to overheat at about 1:30am because critical cooling valves were shut off. The shiftworkers, sleep-deprived and likely experiencing microsleeps with consequent reduced decision-making ability, mistakenly disabled the cooling system, causing the reactor to overheat. As a result, there was a destructive explosion, resulting in numerous radiation-related injuries and casualties.[13]

Thus, microsleeps are often examined in the context of driver drowsiness detection and prevention of work-related injuries and public safety incidents (e.g. truck crashes, locomotive crashes, airplane crashes, etc.). Some statistics are below:

  • 44% of drivers during late-night driving become dangerously sleepy.[14]
  • Extremely fatiguing work protocols increase accident probability from near 0% to 35%.[15]
  • Chronic microsleeps (MSs) not only increase probability for injury but also decrease worker productivity and increase likelihood for absenteeism from work.[16]
  • According to one Centers for Disease Control and Prevention (CDC) study, among 74,571 adult respondents in 12 U.S. states, 35.3% reported <7 hours of sleep during a typical 24-hour period, 48.0% reported snoring, 37.9% reported unintentionally falling asleep during the day at least once in the preceding month, and 4.7% reported nodding off or falling asleep while driving at least once in the preceding month.[7]
  • The National Highway Traffic Safety Administration estimates that 2.5% of fatal crashes and 2% of injury crashes involve drowsy driving.[17]
  • Fatigue is associated with 250 fatalities in air carrier accidents in last 16 years[18]

However, most microsleeps are not dangerous. Microsleeps can be induced from monotonous tasks such as staring at a wall or listening to a boring lecture. In this context, these microsleeps are called daytime parahypnagogia (DPH) episodes, which can last for less than a second to a few seconds and often occur when the eyes are open.[19]

Neural correlates

Generally, microsleeps are characterized by a decrease in activity in wakefulness-related regions of the brain and an increase in activity in sleep-related regions of the brain. Looking at neural correlates of microsleeps is difficult because microsleeps can also be triggered by monotonous tasks (e.g. such as driving or dozing off in class). Therefore, it is important to examine neural correlates of microsleep events with respect to experimental set-ups (e.g. simulated driving set-up, reaction time set-up, etc.). Individual variability in brain structure also makes it difficult to diagnose microsleep events objectively.

In one study neural activity underlying MSs was investigated by simultaneously measuring eye video, response behavior, EEG, and fMRI in normally-rested individuals engaged in a sensory-motor task.[2] Twenty participants tracked a visual stimulus with a joystick for 50 minutes in 2 dimensions (up/down/right/left) on a computer screen. Participants performed this task in an fMRI scanner such that joystick response, right eye-video, EEG (60 EEG electrodes), and fMRI data were recorded simultaneously. Most participants had frequent microsleeps (>35) in a continuous visuomotor task (tracking visual stimulus on a screen), corresponding with decreased activity in arousal-related brain regions over time (thalamus, midbrain, and the posterior cingulate cortex).[2]

Another study examined the activation patterns of 5 people who woke up from microsleeps in a simulated driving experiment.[4] It was found that upon awakening the visual area, frontal cortex, limbic lobe were activated (in the intense activation phase) and the frontal cortex, temporal cortex, primary motor area, and insula were activated (in the post abrupt awakening phase). Therefore, the study concluded that decision-making was not activated immediately upon waking up from a MS episode, likely increasing risk of injury in intense decision-making tasks like driving or surgery.

The transition from wakefulness to sleep is regulated by a variety of chemicals. Dopamine likely causes the 'feeling sleepy' side of microsleeps, while adenosine likely reduces microsleep events by promoting wakefulness. It has been shown that microsleeps correlate with spontaneous pontine-geniculate-occipital (PGO waves) waves, which suppress visual processing in the basal ganglia. When this pathway is not activated, cells in the superior colliculus (which causes release of dopamine) cannot be dis-inhibited via the basal ganglia, leading to poor processing ability and microsleep onset.[20]

Detection methods and classifications

There are currently many ways to detect microsleeps; however, there is a lack of general consensus as to the best way to identify and classify microsleeps. The simplest methods to detect these events seem to be through psychological tests, speech tests, and behavioral tests (e.g. yawn test and eye-video test). More complex and expensive ways to detect microsleeps include EEG, fMRI, EOG, and PSG tied to various software platforms. When multiple tests are used in parallel, detection of microsleeps most likely will become more accurate.[2]

Method Description or examples
Polysomnography (PSG) PSG monitors many body functions including brain (EEG), eye movements (EOG), muscle activity or skeletal muscle activation (EMG) and heart rhythm (ECG) during sleep.
Electroencephalography (EEG) EEG records the brain's spontaneous electrical activity over a short period of time, usually 20–40 minutes, as recorded from multiple electrodes on the scalp.[21] Microsleeps have EEG shift to slower frequencies (from alpha to theta waves).[22]
Functional magnetic resonance imaging (fMRI) A functional neuroimaging procedure using MRI technology that measures brain activity by detecting associated changes in blood flow (detects what regions of brain are active during microsleep events).[23]
Psychological tests Reaction time test, Karolinska Sleepiness Scale (KSS),[24] Maintenance of Wakefulness Test (MWT),[25] Multiple Sleep Latency Test (MSLT).[26]
Electrooculogram (EOG) EOG is a technique for measuring the resting potential of the retina in the human eye.[27]
Eye-video test Measures eyes blinking and eye movements to detect microsleep events.[28][29]
Mouth yawning test Counts number of yawns over a period of time.[30]
Speech tests Examines emotions and/or prosody in speech to predict microsleep episodes.[24][31][32]

Despite attempts to globally classify microsleeps through these detection methods (with particular emphasis on EEG and slow eyelid closure tests), there is great variability in the types of microsleeps that people experience.[33] Subjective, self-reported psychological tests like the Karolinska Sleepiness Scale (KSS), though widely adopted and positively correlated to EEG, often have limited utility because individuals sometimes are not aware of their level of sleepiness.[34] Future research needs to focus more on objective microstates (e.g. detailed electrical output in briefer intervals) that underlie microsleep events so that electrical events can be understood in terms of behavioral events with greater accuracy.[35] Then microsleep events could be more seamlessly distinguished from other states of consciousness, such as silent consciousness experienced during meditation.[36]

Diseases, clinical studies, and pharmacology

Microsleeps are often tied to diseases. Sleep apnea is by far the most significant disease tied to microsleeps in terms of prevalence, affecting roughly 10–15 million people.[37] Other diseases that may be tied to microsleeps include narcolepsy, hypersomnia, schizophrenia, and other causes of excessive daytime sleepiness. Microsleep episodes are often neglected and are not used as a diagnostic indicator for these diseases. Instead, clinicians use instrumentation like PSG to do a sleep study on patients to assess overall sleep quality in a laboratory setting.[38]

Microsleeps that recur and negatively influence day-to-day living often are clustered into the category of excessive daytime sleepiness. Thus, most clinical studies related to microsleeps are in the context of reducing microsleeps in excessive daytime sleepiness through the use of pharmacological interventions. Particularly, modafinil has become a popular drug to reduce microsleeps due to its stimulant effect with little to no side effects, and new drugs are often compared to the results of modafinil and placebo to assess efficacy (e.g. methylphenidate in Parkinson's Disease). Modafinil is also being tested across a range of diseases such as schizophrenia, narcolepsy, cataplexy, and sleep apnea. Overall, the trajectory of clinical studies relating to negative symptom microsleeps seems to more thoroughly test modafinil across more diseases and compare new drugs to the efficacy of modafinil to reduce the negative effects of microsleeps on people across a spectrum of diseases.

Title Interventions Conditions
Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy.[39] Drug: BF2.649, Drug: Modafinil, Drug: Placebo Treatment of Excessive Daytime Sleepiness in Narcolepsy.
Efficacy and Safety Study of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy[40] Drug: BF2.649, Modafinil, Placebo Narcolepsy, Excessive Daytime Sleepiness, Cataplexy, Sleep Disorders
Dose Range Finding Study of BF2.649 Versus Placebo to Treat Excessive Daytime Sleepiness in Parkinson's Disease Patients[41] Drug: Placebo, Drug: BF 2.649 5 mg, Drug: BF 2.649 10 mg, Drug: BF 2.649 20 mg, Drug: BF 2.649 40 mg Excessive Daytime Sleepiness, Parkinson's Disease
A Study Of A Novel Compound For Excessive Daytime Sleepiness Associated With Narcolepsy[42] Drug: Placebo, Drug: PF-03654746 Excessive Daytime Sleepiness, Narcolepsy
Treatment of Refractory Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea/Hypopnea Syndrome (OSA/HS) Using Nasal Continuous Positive Airway Pressure (nCPAP) Therapy (0249-015)[43] Comparator: MK0249, Drug: Comparator: placebo, Drug: Comparator: modafinil Sleep Apnea (Obstructive), Hypopnea Syndrome, Excessive Daytime Sleepiness
Pitolisant to Assess Weekly Frequency of Cataplexy Attacks and EDS in Narcoleptic Patients (HARMONY CTP)[44] Drug: Pitolisant, Drug: Placebo Narcolepsy with Cataplexy, Excessive Daytime Sleepiness
Comparison of Modafinil and Methylphenidate in Treatment of Excessive Daytime Sleepiness in Patients With Parkinson's Disease[45] Drug: modafinil, Drug: methylphenidate Parkinson's Disease
Modafinil Augmentation Therapy for Excessive Daytime Sleepiness and Negative Symptoms in Patients With Schizophrenia[46] Drug: Modafinil, Drug: Placebo Schizophrenia
Efficacy and Safety of BF2.649 in Excessive Daytime Sleepiness (EDS) in Parkinson's Disease[47] Drug: BF2.649 (Pitolisant) Parkinson's Disease
Trial of Xyrem for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson's Disease (PD)[48] Drug: sodium oxybate Parkinson's Disease

Microsleeps sometimes are a side effect of various drugs, particularly in reference to dopamine-stimulating drugs in Parkinson's Disease. Particularly, somnolence is a recognized adverse effect of dopamine agonists, pramipexole and ropinirole. These drugs are known to cause sudden-onset sleep spells in roughly 50% of patients with Parkinson's disease (PD) while they were driving.[49] Therefore, clinical interventions pertaining to microsleeps may also encompass reducing excessive sleepiness as a side effect of drug administration.

Most microsleeps are not clinically significant, however. Individuals who feel sleepy and wish to maintain alertness often consume over-the-counter stimulants such as caffeine in coffee. More specifically, it has been shown that high-frequency low-dose caffeine intake is effective at countering poor work performance effects due to extended wakefulness, confirming the hypothesis that adenosine is a mediator of performance decrements associated with extended wakefulness.[50] Other stimulants that could decrease microsleep frequency include Adderall, amphetamine, cocaine, and tobacco.[51][52]

Microsleep is featured extensively in the popular horror film franchise A Nightmare on Elm Street. It is referred to as "micro naps" in the 2010 reboot specifically.

In 30 Rock season 7 episode 5 'There's No I in America', Liz asks "How do you sleep at night, Jack?", and Jack replies "I don't. I take thousands of micro-naps during the day".

See also

References

Footnotes

  1. ^ International Classification of Sleep Disorders Diagnostic and Coding Manual, http://www.esst.org/adds/ICSD.pdf, page 343
  2. ^ a b c d e Poudel, G. R., Innes, C. R., Bones, P. J., Watts, R., & Jones, R. D. (2012). Losing the struggle to stay awake: Divergent thalamic and cortical activity during microsleeps. Human Brain Mapping: 00:000-000
  3. ^ Paul, Amit; Linda Ng Boyle; Jon Tippin; Matthew Rizzo (2005). "Variability of driving performance during microsleeps" (PDF). Proceedings of the Third International Driving Symposium on Human Factors in Driver Assessment, Training and Vehicle Design. Retrieved 2008-02-10.
  4. ^ a b Chou, Y. H., Chuang, C. C., Zao, J. K., Ko, L. W., & Lin, C. T. (2011, August). An fMRI study of abrupt-awake episodes during behavioral microsleeps. In Engineering in Medicine and Biology Society, EMBC, 2011 Annual International Conference of the IEEE (pp. 5060-5063). IEEE.
  5. ^ Poudel, G.R.; Innes, C. R. H.; Bones, P.J.; Watts, R.; Jones, R. D.,. "Losing the struggle to stay awake: divergent thalamic and cortical activity during microsleeps" (PDF). Human Brain Mapping. doi:10.1002/hbm.22178. Retrieved 2013-03-20.{{cite web}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  6. ^ Higgins, Laura; Fette Bernie. "Drowsy Driving" (PDF). Retrieved 2013-06-12.
  7. ^ a b Insufficient Sleep Is a Public Health Epidemic. http://www.cdc.gov/features/dssleep/
  8. ^ US Department of Transportation, National Highway Traffic Safety Administration, National Center on Sleep Disorders Research, National Heart Lung and Blood Institute. Drowsy driving and automobile crashes [National Highway Traffic Safety Administration Web Site]. Available at http://www.nhtsa.gov/people/injury/drowsy_driving1/Drowsy.html#NCSDR/NHTSAExternal Web Site Icon Accessed February 10, 2011.
  9. ^ "Microsleep". sleepdex.org. Retrieved 15 May 2015.
  10. ^ Blaivas AJ, Patel R, Hom D, Antigua K, Ashtyani H (2007). "Quantifying microsleep to help assess subjective sleepiness". Sleep Medicine Reviews. 8 (2): 156–9. doi:10.1016/j.sleep.2006.06.011. PMID 17239659.
  11. ^ BEA final report, section 1.5, page 24 (PDF page 26 of 224): "The crew had left Paris on Thursday 28 May 2009 in the morning and arrived in Rio de Janeiro in the evening of the same day"
  12. ^ "Revealed: Pilot of Air France jet that crashed in Atlantic Ocean killing 228 people had just ONE HOUR sleep before flight", The Daily Mail (UK), 2013-03-15.
  13. ^ Coren, Stanley. Sleep Thieves: An Eye-Opening Exploration into the Science & Mysteries of Sleep. New York: The Free Press, 1996. p. x, 241–44
  14. ^ Åkerstedt, T., Hallvig, D., Anund, A., Fors, C., Schwarz, J., & Kecklund, G. (2013). "Having to stop driving at night because of dangerous sleepiness–awareness, physiology and behaviour." Journal of Sleep Research.
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  18. ^ "Pilot fatigue is like 'having too much to drink'." CNN, May 15, 2009. http://www.cnn.com/2009/TRAVEL/05/15/pilot.fatigue.buffalo.crash/
  19. ^ Gurstelle, E. B., & De Oliveira, J. L. (2004). "Daytime parahypnagogia: a state of consciousness that occurs when we almost fall asleep." Medical Hypotheses, 62(2), 166–168.
  20. ^ Silkis, I. G. (2010). Analysis of the effects of neuromodulators on the generation of spontaneous pontine-geniculate-occipital (PGO) waves. Neurochemical Journal, 4(3), 170-177.
  21. ^ Davidson, P. R., Jones, R. D., & Peiris, M. T. R. (2006, January). Detecting Behavioral Microsleeps using EEG and LSTM Recurrent Neural Networks. InEngineering in Medicine and Biology Society, 2005. IEEE-EMBS 2005. 27th Annual International Conference of the (pp. 5754-5757). IEEE.
  22. ^ Boyle, L. N., Tippin, J., Paul, A., & Rizzo, M. (2008). Driver performance in the moments surrounding a microsleep. Transportation research part F: traffic psychology and behaviour, 11(2), 126-136.
  23. ^ Chou, Y. H., Chuang, C. C., Zao, J. K., Ko, L. W., & Lin, C. T. (2011, August). An fMRI study of abrupt-awake episodes during behavioral microsleeps. InEngineering in Medicine and Biology Society, EMBC, 2011 Annual International Conference of the IEEE (pp. 5060-5063). IEEE.
  24. ^ a b Krajewski, J., Wieland, R., & Batliner, A. (2008). An acoustic framework for detecting fatigue in speech based Human-Computer-Interaction. In Computers Helping People with Special Needs (pp. 54-61). Springer Berlin Heidelberg.
  25. ^ Gast, H., Schindler, K., Rummel, C., Herrmann, U. S., Roth, C., Hess, C. W., & Mathis, J. (2011). EEG correlation and power during maintenance of wakefulness test after sleep-deprivation. Clinical Neurophysiology, 122(10), 2025-2031.
  26. ^ Blaivas, A. J., Patel, R., Hom, D., Antigua, K., & Ashtyani, H. (2007). Quantifying microsleep to help assess subjective sleepiness. Sleep Medicine Reviews,8(2), 156-159.
  27. ^ Sommer, D., Chen, M., Golz, M., Trutschel, U., & Mandic, D. (2005). Fusion of state space and frequency-domain features for improved microsleep detection. In Artificial Neural Networks: Formal Models and Their Applications–ICANN 2005 (pp. 753-759). Springer Berlin Heidelberg.
  28. ^ Poudel, G. R., Innes, C. R., Bones, P. J., & Jones, R. D. (2010, August). The relationship between behavioural microsleeps, visuomotor performance and EEG theta. In Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE (pp. 4452-4455). IEEE.
  29. ^ Malla, A. M., Davidson, P. R., Bones, P. J., Green, R., & Jones, R. D. (2010, August). Automated video-based measurement of eye closure for detecting behavioral microsleep. In Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE (pp. 6741-6744). IEEE.
  30. ^ Noor, H. A. M., & Ibrahim, R. (2010). Fatigue detector using eyelid blinking and mouth yawning. In Computer Vision and Graphics (pp. 134-141). Springer Berlin Heidelberg.
  31. ^ Krajewski, J., Batliner, A., & Wieland, R. (2008, December). Multiple classifier applied on predicting microsleep from speech. In Pattern Recognition, 2008. ICPR 2008. 19th International Conference on (pp. 1-4). IEEE.
  32. ^ Krajewski, J., Golz, M., Sommer, D., & Wieland, R. (2009, January). Genetic algorithm based feature selection applied on predicting microsleep from speech. In 4th European Conference of the International Federation for Medical and Biological Engineering (pp. 184-187). Springer Berlin Heidelberg.
  33. ^ Galley, N., Schleicher, R., & Galley, L. (2003). Oculomotor Indicators of Driver Fatigue. Driver Behaviour and Training: v. III, 1, 97.
  34. ^ Shahid, A., Wilkinson, K., & Marcu, S. (2012). Karolinska Sleepiness Scale (KSS). In STOP, THAT and One Hundred Other Sleep Scales (pp. 209-210). Springer New York.
  35. ^ Cvetkovic, D., & Cosic, I. (2011). Sleep Onset Process as an Altered State of Consciousness. In States of Consciousness (pp. 157-185). Springer Berlin Heidelberg.
  36. ^ Baars, B. J. (2013). A scientific approach to silent consciousness. Frontiers in psychology, 4.
  37. ^ Kanagala, R., Murali, N. S., Friedman, P. A., Ammash, N. M., Gersh, B. J., Ballman, K. V., ... & Somers, V. K. (2003). Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation, 107(20), 2589-2594.
  38. ^ Tufik, S., Santos-Silva, R., Taddei, J. A., & Bittencourt, L. R. A. (2010). Obstructive sleep apnea syndrome in the Sao Paulo epidemiologic sleep study. Sleep Medicine Reviews, 11(5), 441-446.
  39. ^ Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy. http://clinicaltrials.gov/ct2/show/record/NCT01638403
  40. ^ Efficacy and Safety Study of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy. http://ClinicalTrials.gov/show/NCT01067222
  41. ^ Dose Range Finding Study of BF2.649 Versus Placebo to Treat Excessive Daytime Sleepiness in Parkinson's Disease Patients . http://ClinicalTrials.gov/show/NCT00642928
  42. ^ A Study Of A Novel Compound For Excessive Daytime Sleepiness Associated With Narcolepsy. http://ClinicalTrials.gov/show/NCT01006122
  43. ^ Treatment of Refractory Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea/Hypopnea Syndrome (OSA/HS) Using Nasal Continuous Positive Airway Pressure (nCPAP) Therapy (0249-015). http://ClinicalTrials.gov/show/NCT00620659
  44. ^ Pitolisant to Assess Weekly Frequency of Cataplexy Attacks and EDS in Narcoleptic Patients (HARMONY CTP). http://ClinicalTrials.gov/show/NCT01800045
  45. ^ Comparison of Modafinil and Methylphenidate in Treatment of Excessive Daytime Sleepiness in Patients With Parkinson's Disease. http://ClinicalTrials.gov/show/NCT00393562
  46. ^ Modafinil Augmentation Therapy for Excessive Daytime Sleepiness and Negative Symptoms in Patients With Schizophrenia . http://ClinicalTrials.gov/show/NCT00546403
  47. ^ Efficacy and Safety of BF2.649 in Excessive Daytime Sleepiness (EDS) in Parkinson's Disease. http://ClinicalTrials.gov/show/NCT01066442
  48. ^ Trial of Xyrem for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson's Disease (PD). http://ClinicalTrials.gov/show/NCT00641186
  49. ^ Hobson, D. E., Lang, A. E., Martin, W. W., Razmy, A., Rivest, J., & Fleming, J. (2002). "Excessive daytime sleepiness and sudden-onset sleep in Parkinson disease. "JAMA: The Journal of the American Medical Association, 287(4), 455–463. Chicago
  50. ^ Wyatt, J. K., Cajochen, C., Cecco, A. R. D., Czeisler, C. A., & Dijk, D. J. (2004). "Low-dose repeated caffeine administration for circadian-phase-dependent performance degradation during extended wakefulness." SLEEP-NEW YORK THEN WESTCHESTER-, 27(3), 374–382.
  51. ^ Jacobs, A. (2005). "The Adderall advantage." New York Times, 31.
  52. ^ Gawin, F. H., & Ellinwood, E. H. (1988). "Cocaine and other stimulants: actions, abuse, and treatment." The New England Journal of Medicine.

Works cites

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