A new drug for Consciousness?

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”).

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. Copyright � B.J. Baars 2004