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A New Reason to Lose Sleep

Could the brain be more vulnerable to apnoea if CPAP therapy is discontinued?

Could the brain be more vulnerable to apnoea if CPAP therapy is discontinued? iStockphoto

By Caroline Rae

Are people with sleep apnoea prone to brain injury from oxygen deprivation?

Every night, people get into bed and go to sleep. But for some people what should be a restful and restorative time between the sheets can turn into a repetitive fight to breathe.

During sleep, the muscles in the upper airway relax, narrowing the airway. In obstructive sleep apnoea the airway relaxes too much, becoming closed and preventing the person from breathing. Hence the term obstructive sleep apnoea, meaning that the airway is obstructed, the person is asleep and is “without breath” (from the Greek “apnoea”).

In medical terms, an apnoea is defined as a period of ceased breathing that lasts for 10 seconds or more. When breathing stops, blood oxygen levels drop and are not restored until the person starts breathing again.

When an apnoea occurs, sleep is disrupted. Sometimes the person may wake up completely, but they could also rouse from a deep level of sleep into a more shallow level of sleep.

In severe obstructive sleep apnoea, sufferers can do this more than 40 times per hour! This level of sleep disruption can mean that the person is very sleepy during the day and can have difficulty concentrating or paying attention.

We know that the brain is a large user of oxygen and that disruption of oxygen supply to the brain can result in brain damage. This can occur, for example, when a person has a heart attack or a stroke, or when a person drowns and is resuscitated after a period without breathing.

We also know that we can hold our breath for more than 10 seconds without undue problem. So is the disruption to oxygen supply that occurs in sleep apnoea something that potentially could damage the brain?

In order to find out if there are any effects on the brain caused by obstructive sleep apnoea, we use a technique called magnetic resonance spectroscopy. This differs from standard MRI investigations in that it measures the small molecules that are present, not just the tissue water. Magnetic resonance spectroscopy is a completely safe and non-invasive way of measuring the level of chemicals in someone’s brain.

In 2004 we studied an area of the brain called the hippocampus in people with severe obstructive sleep apnoea (more than 40 arousals per hour). The hippocampus is an area of the brain that is highly susceptible to damage when oxygen supply to the brain is disrupted.

We measured the levels of creatine-containing compounds in the hippocampus using proton magnetic resonance spectroscopy. Creatine is derived exclusively from meat, and acts as an energy buffer in the brain.

Phosphorylated creatine (phosphocreatine) is in fast exchange with a special molecule known as adenosine triphosphate (ATP). ATP is made by mitochondria using the energy gained from glucose metabolism, and is the major energy currency in the body. The energy you get from breaking one of the high energy phosphate bonds in ATP is used to power major processes such as muscle contractions, maintenance of membrane potentials and a host of active uptake processes undertaken by cells. You turn over your entire bodyweight in ATP every day.

ATP can be “banked” by converting the high energy phosphate bond to phosphocreatine. This allows metabolic activity to continue to make more ATP, as the ATP that has been converted to phosphocreatine does not provide feedback inhibition of metabolism in the way that existing ATP levels do.

The creation of phosphocreatine also allows high energy phosphate bonds to be moved around the cell more easily, as phosphocreatine diffuses faster than ATP. This helps to create an energy buffer in the brain, so that there are high energy phosphate bonds in reserve in the event of high energy demand.

This reserve is not insubstantial. We showed in 2003 in a double-blind, placebo-controlled, crossover trial that dietary supplementation with creatine produces significant improvements in the speed of brain processing, resulting in better short-term memory and intelligence!

So what role does brain metabolism play in obstructive sleep apnoea? In our 2004 study we found that the levels of creatine in the hippocampus of people with severe obstructive sleep apnoea were significantly lower than those in controls. We also found that the amount of creatine was related to how severe the person’s obstructive sleep apnoea was and the severity of their cognitive impairment. In all cases, lower creatine was associated with worse performance and more severe apnoea.

This made us wonder whether there was any observable dynamic effect on the levels of phosphocreatine during an apnoea. Synthesis of ATP by mitochondria is absolutely dependent on oxygen supply, so if oxygen delivery was affected by a blocked airway, would this effect brain ATP or phosphocreatine levels?

Evidence from brain scans of people who have suffered strokes taken some hours after the stroke suggests that the oxygen insult has to be fairly severe for ATP levels to be altered, but phosphocreatine levels can change on a rapid time scale. If the brain is made to do hard work, levels of phosphocreatine fall.

This can be demonstrated fairly easily by showing a person a flashing chequerboard display that makes the visual cortex work very hard in response. Phosphocreatine levels fall rapidly but are restored within seconds once the flashing stimulus is turned off. These experiments have demonstrated that ATP levels are buffered very efficiently by phosphocreatine.

Studies of temporary oxygen deprivation in healthy awake individuals have shown no effect of this hypoxia on brain energy levels. However, the brain regulates its blood flow differently during sleep, and the normal cerebrovascular compensation methods (such as increases in blood pressure and blood volume that allow you to hold your breath for more than 10 seconds without detriment) do not work so well. The deeper the sleep, the less well these compensatory effects operate. There is also evidence to show that these compensatory effects are impaired in people who suffer from obstructive sleep apnoea even when they are awake.

Therefore we recruited 13 men with newly diagnosed severe obstructive sleep apnoea. We obtained phosphorus magnetic resonance spectra from a large area of the left temporal lobe while they were still awake, and then let them fall asleep in the MRI scanner and monitored their blood oxygen levels using a pulse oximeter attached to their finger.

Most of these men went to sleep in the magnet and five of the 13 had a number of severe apnoea episodes while they were asleep (Fig. 1). We acquired phosphorus spectra (Fig. 2) during these apnoea episodes in order to see whether oxygen deprivation was altering the levels of high energy phosphate compounds in the brains of these men. We compared the spectra that we obtained while their oxygen levels were more than 10% lower than normal (i.e. during apnoea) with those we obtained when levels had returned to normal (when the subject had aroused from sleep and started breathing again).

We found that ATP levels during an apnoea (where there was more than a 10% reduction in oxygen saturation) would fall, and levels of the by-product inorganic phosphate would rise. Inorganic phosphate is a breakdown product formed by the hydrolysis of high energy phosphate bonds, but it also plays a role in phosphate homeostasis in the brain. Generally, higher levels of inorganic phosphate are associated with poorer brain function.

Surprisingly there was no evidence at all for any effect on phosphocreatine or the creatine–kinase buffering system. Brain pH was not altered by this reduction in oxygen.

We interpreted this to mean that brain mitochondria, the energy powerhouse for the brain, are taking the brunt of the hypoxic insult. The exact reason why this might happen is not clear but it may be a compensatory mechanism to prevent mitochondrial death. What is clear is that the brain is plainly more vulnerable to oxygen deprivation when asleep.

It is well-known that a mild hypoxic event can cause a phenomenon known as “hypoxic pre-conditioning”, which can offer some protection against subsequent hypoxic events. Hypoxic preconditioning is mediated through a cascade of biochemical events and it may well be that the metabolic response of the brain that we have seen in obstructive sleep apnoea is related to preconditioning.

But what impact would this have for people with obstructive sleep apnoea who are treated using continuous positive airway pressure (CPAP)? In CPAP treatment during sleep, a mask is worn which is connected to a pump. This pump maintains a positive air pressure that keeps the upper airway open, preventing apnoea and ensuring a continuous supply of oxygen to the brain. People who use CPAP sleep better, since they are not continually having to rouse from sleep to clear their airway.

Does CPAP reverse the deleterious effects on the brain of years of apnoea? Could the brain be more vulnerable to apnoea if the person subsequently decides to discontinue CPAP therapy?

These are the next questions we will be working to answer.

Caroline Rae is Professor of Brain Sciences at The University of New South Wales and is based at Neuroscience Research Australia. This work was also conducted in collaboration with the Woolcock Institute of Medical Research.