The Search for Sleep Biomarkers

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Doctors, nurses, scientist, and public health experts all would love to find a biomarker for sleepiness and sleep disorders.

What might a biomarker predict? It might give a quantitative level of how sleepy someone is, how long the person would sleep if allowed to go to bed, how much behavioral measures of performance will be lowered. It might have other uses in the diagnosis of sleep disorders. Insomnia is often of unknown cause and a reliable biomarker might help figure out what is producing disorders and untangling them from other morbidities.

An ideal biomarker would

  1. Change in level as subjective sleep propensity changes
  2. Affect sleep time and/or structure when given to the person from outside the body
  3. Affect disease states, e.g., infection, associated with altered sleep also change levels of the marker;

In other words, the biomarker would indicate history, necessity, or dysfunction of sleep.

But there does not appear to be a biomarker, or if there is one, it is elusive. There are many biochemicals and neurochemicals involved in sleep and the circadian cycles, so any realistic biomarker may be a combination of several chemicals.

The biochemistry of sleep is not understood – even for scientists sleep is something of a mystery – but over the decades sleep-regulatory substances have been identified. Often abbreviated SRSs in the medical literature, these would seem obvious candidates for biomarkers. Alternatively, other chemicals produced by metabolism or otherwise downstream of the SRSs in the brain could be biomarkers. There are an estimated 20,000 different proteins in blood serum.

The IL1 and TNF cytokines are involved with NREM regulation and indeed some of the symptoms of sleep loss (e.g. diminished cognitive abilities and enhanced sensitivity to pain) can be induced by injecting a person with those cytokines. The energy molecule adenosine triphosphate (ATP) in the body’s fluids (outside the cell walls) plays a part in release of IL1 and TNF, and these biochemicals work on neurotransmitters that do not always make it outside the brain in any quantity. Scientists have even been able to include cortical columns in animal brains to flip into a sleep state with local micro-injection of TNF can flip a column into a sleep state. The problem with these are viable biomarkers is that sleep is an emergent property that flips when enough coritcal columns in the brain go to sleep. At any time during the day or night, some columns will be “asleep” and some will be “awake”. So these chemicals in the blood are not precise enough to identify whether the person is asleep or even sleepy.

As we have noted elsewhere on Tuck, there is a difference between sleepiness and sleep deficiency. A useful hypothetical biomarker may be distinguish between the two.

If a humoral biomarker could be found, it could help diagnosis of sleep disorders and may give a clearer picture of insomnia as a public health problem. One reason drowsy driving is such a troubling public safety problem is that police and prosecutors have a hard time proving the driver was sleepy behind the wheel. Drunk driving can be prosecuted because tests can indicate blood alcohol level, and indeed, the laws are written to make a certain blood alcohol level actionable by police. The blood alcohol level is actually a biomarker. If there were something like this for sleepiness that did not disappear from the body when the police car lights appear in the rear view mirror, that could be useful in helping police arrest or ticket drowsy drivers.

So far, no biomarker has been identified that is useful in diagnosis or treatment of sleep disorders. Although many neurochemicals and biological indicators are associated with aspects of sleep, every one has other functions in the body not related to sleep – you can call these pleiotropic factors – and is not specific enough to act as a biomarker.

If a biomarker is established it appears it will be a combination of several biochemicals and possibly other physiological indications.

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