Millions of people rely on strong coffee every morning to really wake up. All-night truck drivers sometimes take amphetamines to stay conscious on the road, and for centuries South American peoples have chewed coca leaves to stay alert and increase physical endurance. Yet none of these compounds are specific “consciousness” drugs. They stimulate waking along with many side effects. A novel pharmaceutical, modafinil (provigil), may be the most specific consciousness-promoting drug yet.

In France, modafinil has been prescribed for the sleep disorder narcolepsy since 1994 and in the United States since 1998. Enough time has passed, therefore, to collect clinical data on longterm use. So far there seem to be few longterm side effects, although about 5 percent of users encounter discomfort such as nausea.

The exact way modafinil works in the brain is still not clear. It is remarkable in several ways, however. First, it allows night workers and people with sleep disorders to stay awake in ways that compare well with other drugs. But unlike competing drugs, modafinil does not lead to a sleep rebound; and compared to amphetamines it does not usually lead to jitteriness, anxiety, excessive heart rate, or physiological addiction.

Sleep is homeostatically regulated, so that we do not sleep either too much or too little. Loss of sleep on one night leads to a predictable rebound the next night, apparently to make up for some loss. The REM dream state has its own homeostatic rebound effects. In sum, the fact that modafinil promotes wakefulness with no next-day rebound is a big surprise.

How does it work? First, in human beings the cerebral cortex is the “seat” of conscious contents --- perception, inner speech, emotional feelings, mental images. But waking consciousness and sleep are turned on and off by small nuclei below the cortex, which spray neurochemicals throughout the forebrain. A few thousand neurons in small nuclei influence the operation of billions of cortical cells.

At least two nuclei control sleep and waking. Let’s take the thalamus as our starting point. The thalamus is the traffic controller of the brain, located at the top of the brainstem and the bottom of the forebrain. Almost all input and output pathways go through the thalamus, and can be controlled by it. Just below the thalamus is a tiny but powerful clump of neurons --- controlling such things as sex, anger, eating, and homeostatic control of blood pressure, blood sugar, fat regulation, oxygen, and several major hormones. It is the hypothalamus (literally “below thalamus”).

Although tiny, the hypothalamus divides into even smaller nuclei with distinct and powerful effects. The posterior division of the hypothalamus has a small nucleus called the Posterior Lateral Nucleus (i.e. in back and to the side). The PLN has a few thousand neurons that project widely to cortex and wake up the brain by spraying chemicals, particularly a peptide called hypocretin. Very recent research suggests that hypocretins are involved in the maintenance of waking consciousness, and that modafinil may work by promoting the widespread spraying of hypocretins.

To maintain a balance between sleep and waking, there is also a sleep-promoting nucleus. It has the intimidating name of the “ventrolateral preoptic nucleus” (VLPO). (Ventrum means “belly” and lateral means “side,” so it is the clump of neurons located on the bottom and side of the nucleus just behind the optic nerve). There is evidence that modafinil also inhibits the sleep-promoting function of this center. Thus modafinil may work in at least two different ways: To promote a waking cortex, and to inhibit its tendency to go to sleep.

The entire sleep-waking system involves a complex network of nuclei and neurochemicals. After all, the brain is enormous in size and complexity, and the decision to stay conscious or go to sleep comes with immense biological risks. A sleeping animal can easily become a tasty protein snack for a predator. But evolution makes it impossible to avoid sleep completely, for reasons that are still unknown. The sleep-waking system has been evolving for perhaps half a billion years, so that it is both complex and highly adaptive.

The discovery of modafinil gives us a deeper understanding of the control mechanisms of consciousness. But it is not the end of the story; there is much more to learn. Even if it turns out to be as safe as coffee, modafinil is hardly the end of sleep. Total sleep deprivation, carried on long enough, leads to death. Long before that point, sleep-deprived people and animals become impaired in consciousness, the ability to direct attention, in memory, motor control, and subjective comfort. Even the best new medication will not abolish the need for sleep. But we may be finding better tools to help with sleep problems that come from jet lag, night work, and sleep disorders.

References
*Saper CB, Chou TC, Scammell TE. (2001) The sleep switch: hypothalamic
control of sleep and wakefulness. Trends Neurosci 2001 Dec 1;24(12):726-31

More than 70 years ago, von Economo predicted a wake-promoting area in the posterior hypothalamus and a sleep-promoting region in the preoptic area. Recent studies have dramatically confirmed these predictions. The ventrolateral preoptic nucleus contains GABAergic and galaninergic neurons that are active during sleep and are necessary for normal sleep. The posterior lateral hypothalamus contains orexin/hypocretin neurons that are crucial for maintaining normal wakefulness. A model is proposed in which wake- and sleep-promoting neurons inhibit each other, which results in stable wakefulness and sleep. Disruption of wake- or sleep-promoting pathways results in behavioral state instability.

*Engber TM, Dennis SA, Jones BE, Miller MS, Contreras PC (1998) Brain
regional substrates for the actions of the novel wake-promoting agent
modafinil in the rat: comparison with amphetamine. Neuroscience Dec;
87(4):905-11

Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Modafinil also lacks the pronounced effects on the extrapyramidal motor system which are characteristic of amphetamine and other psychomotor stimulants, implying that the effects of modafinil are not mediated by the dopamine system and that modafinil may selectively increase wakefulness with fewer side effects.

*Caldwell JA Jr, Caldwell JL, Smythe NK 3rd, Hall KK (2000) A double-blind,
placebo-controlled investigation of the efficacy of modafinil for sustaining
the alertness and performance of aviators: a helicopter simulator study
by Psychopharmacology (Berl) 2000 Jun; 150(3):272-82

RATIONALE:
In 1998, the FDA approved modafinil for treating excessive daytime sleepiness in narcoleptics, and this has raised questions about the appropriateness of this compound for enhancing alertness in sleep-deprived controls. This study explored the efficacy of modafinil for maintaining the performance of volunteers required to accomplish highly demanding tasks despite sleep loss.
OBJECTIVE:
The principal objective was to determine whether prophylactic doses of modafinil would attenuate decrements in aviator performance and arousal throughout 2 days and 1 night without sleep.
METHODS:
Six pilots were exposed to two 40-h periods of continuous wakefulness. In one, three 200-mg doses of modafinil were given and in the other, matching placebos were administered. Helicopter simulator flights, resting EEGs, and Profile of Mood States (POMS) questionnaires were evaluated.
RESULTS:
Modafinil attenuated sleep deprivation effects on four of six flight maneuvers, reduced slow-wave EEG activity, and lessened self-reported problems with mood and alertness in comparison to placebo. The most noticeable benefits occurred between 0330 and 1130 hours, when the combined impact of sleep loss and the circadian trough was most severe. The most frequently observed drug side effects were vertigo, nausea, and dizziness. These could have been related to: 1) the motion-based testing, 2) the use of a simulator rather than an actual aircraft (i.e., "simulator sickness"), and/or 3) the administration of more than 400 mg modafinil.
CONCLUSIONS:
Modafinil is a promising countermeasure for sleep loss in normals; however, additional studies aimed at reducing side effects are needed before it should be used in aviators.

* Buguet A, Montmayeur A, Pigeau R, Naitoh P (1995) Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep. J Sleep Res 1995 Dec; 4(4): 229-241

Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night.

Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups.

This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.

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