NEUROLOGY CORNER

A Brief Discussion of the Neurochemestry of Sleep

Richard Belli, D.C., D.A.C.N.B.

Sleep is a billion dollar industry in the United States, with a plethora of over‑the‑counter and prescription medications dedicated to the pursuit of a good night's sleep. Over 50% of the typical patient population has chronic sleep difficulties. These commonly come in three varieties, difficulty in getting to sleep, difficulty staying asleep, or a combination of the two.

Sleep is a wondrous symphony of chemistry, involving neurotransmitters and neuropeptides that can be altered by many internal and external factors. Sleep is a process of active inhibition of the central nervous system by neurotransmitters and neuropeptides. The neurotransmitters and neuropeptides involved in sleep depend on vitamins and minerals as well as normal gut function for their production and utilization.

For the "neuroanatomist," the structures involved in sleep include: raphe nuclei, upper medullary and lower pontine reticular formation, nucleus tractus solitarius, locus ceruleus, lateral pontine reticular formation, anterior hypothalamus, reticular nucleus of the thalamus, and basal fore brain‑preoptic area.

Sleep is an active process in which hypnogenic areas of the brain and neurochemical substances actively promote sleep and inhibit the arousal system. Over‑the‑counter sleep medications are typically antihistamine in nature, as histamine is a necessary central nervous system stimulant; the major side effect is drowsiness and depression the following day. Stronger prescription medications are GABAergic in nature, as GABA is the main neurotransmitter of the sleep cycle; these medications tend to be highly addictive.

There are two stages of sleep, REM, and NONREM. During REM sleep the following activities take place: rapid conjugate eye movements, fluctuations in body temperature, blood pressure, heart rate, and respiration decrease in muscle tone, increase in muscle twitches, and penile erections. Characteristic REM sleep EEG is low amplitude fast pattern, the same as a person in alert state with eyes open. Whereas NONREM will have no eye movements, wide spread decrease in brain activity, vital signs and autonomic activity will be stable. NON‑REM is predominant, representing 75‑8590 of sleep; REM comprises 202590. NON‑REM is mediated by anterior hypothalamus, basal fore brain‑preoptic area, dorsal medullary reticular formation, tractus solitarius. In contrast, REM sleep is mediated by dorsal lateral pontine reticular formation (especially just ventral and lateral to locus ceruluus). During the sleeping period, an individual passes through four to six alternating periods of slow wave sleep followed by REM sleep.

One characteristic of slow, wave sleep is the appearance of sleep spindles. We know that spindle activity in the cortex is due to the synchronous bursting activity of thalamocortical neurons. As long as the thalamocortical neurons are in a bursting pattern, afferent signals cannot pass through the thalamus to reach the cortex. GABAergic neurons of the reticular nucleus of the thalamus, through the cyclic generation of long duration IPSPs on thalamocortical neurons, are the pacemakers for thalamocortical bursting activity. Therefore, any modulation of these GABAergic oscillators should, therefore, effectively modulate sleep.

The norepinephrine cells in the locus ceruleus and the serotonin cells in the dorsal raphe nuclei become inactive during REM sleep, they are "REM off‑cells." Neurons in the region just ventral and lateral to the locus ceruleus fire at a faster rate during REM and are called "REM on‑cells." Cholinergic neuronal activity is increased during wakefulness and REM sleep, and decreased during NON‑REM sleep. The activity of monoamenergic neurons (NE, 5‑HT) is increased before arousal, is decreased before the onset of NONREM, and is minimal or ceases during REM sleep. In NON‑REM sleep, the wake mechanisms are deactivated, and there is decreased responsiveness to external stimuli. In summary, NE and ASH decrease bursting activity; bursting activity of the thalamocortical neurons block thalamic stimulation of the cortex. The inhibition of motor activity is at the lower motor neuron at the spinal cord level, probably from NE neurons of the locus ceruleus. Other parts of the locus ceruleus are also important for arousal states.

Serotonin facilitates sleep by decreasing sensory input and inhibition of the motor system. As previously mentioned, EEG activity during REM sleep is as active as in fully awakened individuals. The difference is that the cortex has been cut off from the environment by serotonergic inhibition of the dorsal horn and nucleus solitarius sensory input.

There is an actual decrease in serum serotonin during sleep, shedding some doubt on the actual function of serotonin in the sleep process. Some experts think there may be another chemical involved. Aside from its effect on circadian rhythms, this may be a functional area of melatonin. Melatonin is a metabolite of serotonin.

Cholinergic neurons are active during REM sleep, thus maintaining cortical activity. Cholinergic neurons of both the nucleus basalls in the basal forebrain and the dorsolateral tegmental area have a role in sleep. Both areas project to the reticular nucleus of the thalamus, inhibiting the spindle‑generating GABAergic neurons. Stimulation of either cholinergic pathway blocks thalamocortical bursting activity, effectively disinhibiting the thalamus.

Several chemical components for sleep are synthesized by the normal intestinal flora. These include biotin which is necessary for GABA binding, muramyl peptides necessary for serotonin function, and several unnamed sleep peptides. Muramyl peptides are a glycopeptide that is a constituent of bacterial cell membranes. These peptides are liberated during the normal die off of bacteria. The cyclic die off of bacteria may explain cyclic sleep. Incidentally, the average intestinal tract contains one kilogram of bacteria! Also prostaglandin D‑2 is necessary for sleep, it is stimulated by lymphokines of which are stimulated by muramyl peptides.

Medications utilized for sleep disorders are neuroactive and directed towards manipulation of the neurotransmitters involved in the sleep process. The function of these same neurotransmitters can easily be optimized by the application of the appropriate factors necessary for synthesis, release, binding, and metabolization. Examination of the basic function of sleep emphasizes the importance of adequate GABA activity as well as metabolization of norepinephrine, serotonin, and histamine.

When addressing sleep nutritionally, it is vitally important to look at the integrity of intestinal flora. Biotin is necessary for GABA binding at the receptor site, and muramyl peptides are necessary for normal binding of serotonin. GABA is produced by the citric acid cycle and by conversion of L‑glutamine that is stored by glial cells. A methyl donor such as B‑12 is necessary to convert NE to epinephrine. B‑2 and magnesium are necessary to metabolize epinephrine and serotonin. And finally, B‑2 and B‑6 are necessary to metabolize histamine. Interestingly enough, norepinepherine is highly antagonistic to GABA.

To ensure normal restful sleep, we need abundant GABA activity and normal metabolization of norepinephrine, serotonin, epinephrine, and histamine. The first aspect to check is prostaglandin metabolism, as these have a significant effect on the release of neurotransmitters. Secondly, you will want to check intestinal flora function, then B‑ 12, B‑6, B‑2, biotin, zinc, and other aspects of the citric acid cycle.

With an understanding of the neurochemical process of sleep and the sophistication of manual muscle testing, the applied kinesiology doctor has the ability to correct one of the greatest functional scourges of modern times‑‑difficulty with sleeping.