Insomnia and the Mechanisms of Sleep

Sleep is needed for our proper nervous system and daily function as well as for our physical and mental health. It is essential for our survival. People with problems falling asleep or staying asleep may wake up during the night or wake up too early the next morning. Lack of sleep makes them feel sleepy during the day and also affects their driving ability, performance, cognitive skill, psychomotor coordination, mood, memory, concentration and enjoyment of family and social life. This sleep disorder is called Insomnia.

This paper presents the prevalence of chronic insomnia characteristics, causes, and consequences, followed by an overview of current understanding of the regulation of the sleep-wake cycle and finally, a discussion on treatment based on new developments of sleep biology.

Insomnia is a common problem that affects almost everyone at some point in their life and can become a chronic condition for many sufferers. Chronic insomnia is a major public health problem involving millions of people, their families and communities. According to the National Institutes of Health State-of the-Science Conference Statement on the Manifestations and Management of Chronic Insomnia in 2005, approximately 30% of the general population occasionally experience insomnia and 10% have chronic insomnia [1]. How is insomnia diagnosed? The sleep symptoms require a nighttime sleep disturbance coupling with daytime impairment, distress or complaints of fatigue. Insomnia is known to be big risk factors for developing diabetes and high blood pressure. Insomnia also decreases the quality of life and contributes to the high costs of insurance.

For over a century, researchers have tried to understand how and why the brain sleeps. They could only assess the relationship between the brain and sleep with surface electrophysiology using polysomnography. [2] This method only helps with the understanding of the different stages of sleep-wake cycle like rapid eye movement sleep (REM) and non-REM (NREM) and the variation of heart rate and breathing patterns during the sleep episodes. Scientists have realized that sleep is not a passive homogenous state that was initiated by withdrawal of sensory input. They learned that our brains are very active during the dormant stage of our day and that there is an active mechanism that facilitates brain withdrawal.

In the past decade, the development of new technologies of neuroimaging such as CT scan and MRI has allowed the identification of brain circuitries and neurotransmitters that regulate the sleep, wake cycles and the monitoring of the electrical activity of the brain and its dramatic variations during sleep. Researchers discovered that a network of groups of cells activate the thalamus and the cerebral cortex during wakefulness. During sleep a key switch in the hypothalamus turns off this arousal system. Other hypothalamic neurons help stabilize the switch. Without them, inappropriate switching of behavioral states would occur. It is also known that a chemical called adenosine that causes drowsiness builds up in our blood while we are awake and slowly breaks down while we are sleeping. Researchers believe that sleep helps the neurons to close down and tune up themselves. Lack of sleep will make these neurons run out of battery and become malfunctioned.

Recently, according to Zee PC; Manthena P [2], the master circadian clock is found in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus and has an almost round the clock period of electrical activity even in the absence of stimuli. The molecular mechanisms in the neurons of the SCN generate this circadian rhythm. [3] An alerting pulse is sent out throughout the day, reaching its peak about 2-3 hours before one’s regular bedtime. It offsets the homeostatic drive that accumulates during waking time. The circadian clock is regulated by inputs such as glutamate from the retinohypothalamic tract, melatonin from the pineal gland and neuropeptide Y from the intergeniculate leaflet. [2] Light, social and physical activities reinforce the SCN. In turn, the SCN influences the physiologic and behavioral functions such as sleep-wake and endocrine cycles as well as attention and temperature regulation.

Berson DM and colleagues [4] agreed that the timing of the circadian system is reinforced by regular exposure to daylight and darkness at night. The normal rhythm of sleep and wake is contributed by the natural momentum of the movement of the circadian. The SCN also influences the roles of other hypothalamic regions which regulate sleep and waking and controls the pineal gland pattern of production of melatonin. The level of melatonin is very low during the day then gradually rises at bedtime and plateaus during the night. Throughout the period of sleep, the melatonin levels are usually high.

The researchers identified two subtypes of melatonin receptors and named them MT1 and MT2. The firing rate slows down when melatonin interacts with the MT1 receptor. This reduces the evening arousal signal and allows the promotion of a fast bedtime sleep onset. It was shown that the melatonin agonist activity at the MT2 receptor reinforces the timing of the SCN circadian system. According to the scientists, as the melatonin level increases in the evening, sleep onset is enhanced. It is likely that the evening sleepiness occurring at approximately the same time on the following nights also will increase.

Although the ventrolateral preoptic nucleus (VLPO) is a group of neurons in the hypothalamus, [5] only the VLPO plays a role in reinforcing the physiologic state of sleep through projection to all hypothalamic nuclei and brainstem that promote arousal. The VLPO neurotransmitters are galanin and gamma-aminobutyric acid (GABA). They are referred to as the “sleep switch”. The sleep drive, or homeostat, accumulates during wakefullness, peaking in the evening, and diminishes during sleep. To fully discharge the homeostat, a consolidated 8 hours of sleep are needed.

With the scientific advancements and armed with an understanding of the mechanisms of sleep, can scientists target new therapeutic strategies to treat sleep disorders? Currently, there are several treatments of insomnia, including prescription medication and self-treatments such as alcohol and over-the-counter sleep remedy. Alcohol can help induce sleep but causes significant sleep disturbance. Most over-the-counter sleep medications contain antihistamine diphenhydramine which causes daytime drowsiness and side effect issues. Doctors prescribe sedating antidepressants, such as trazodone, doxepin and remeron. Unfortunately, we don’t know the extent of their toxicity since they are not developed for insomnia. [6] Development of therapies for sleep disorders, including de-synchronization of circadian rhythms based on the regulation of the sleep-wake cycle by the SCN is a possibility. New approaches of influencing and treating insomnia can be designed using molecules and chemical agents. Disease management can also replace sedation therapy.

Even though the understanding of consciousness is still elusive and the neurophysiology of sleep is still not completely comprehended, we now enjoy a great deal about how the sleep-wake cycle is regulated. This has provided us important insights into a small part of the great mysteries of neuroscience.

References:

1. National Institutes of Health. National institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28:1049-1057. http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm

2. Zee PC; Manthena P, Department of Neurology, Northwestern University School of Medicine. The Brains’ Master Cicadian Clock: Implications and Opportunities for Therapy of Sleep Disorders. P-zee@northwestern.ed.

3. Dijk DJ, Lockley SW. Interaction of human sleep-wake regulation and circadian rhythmicity. J Appl Physiol. 2002;92:852-862

4. Berson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science. 2002;295:1070-1073.

5. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257-1263.

6. Neubauer, David, MD. Redefining the Management of Insomnia: Focus on the Biology of Sleep. Medscape. August 31, 2007.