Being awake and sleeping are fundamental physiological processes that occur at natural daily rhythms. Healthy sleep is a basic necessity. However, it is still not known in detail how the sleep-wake rhythm is regulated on the molecular and electrophysiological levels. “Although we are all aware that sleep is necessary for optimal functioning, the scientific investigation of these processes is relatively difficult,” says Dr. Lukas Frase from the Department of Psychiatry and Psychotherapy at the Freiburg University Medical Center. Pathological tiredness is associated with a high degree of psychological strain that can be caused by burnout, depression, anxiety disorders, brain damage, tumours and many other things. Ten to fifteen percent of the German population suffer from chronic sleep disorders. However, such disorders can have many different causes.

According to Frase, sleep apnoea, iron deficiency and hypothyroidism are the three most common causes of sleep disorders. Pronounced daytime sleepiness can be due to sleep apnoea, which is a condition where normal breathing is interrupted during night-time sleep. Periods of breathing pauses can occur up to 40 times per hour, and can lead to a very non-restful sleep. People with sleep apnoea consequently feel very sleepy during the day. Brain lesions caused by accidents, inflammation and strokes can also be associated with high sleep requirements. This is thought to be due to the vast number of repair processes going on in these particular situations.

We feel awake and well rested when our brain has a sufficiently high degree of cortical activity. In psychology, the term arousal refers to the degree of vigilance and alertness during wakefulness. It can be measured with alertness and reaction tests. People suffering from Parkinson’s disease and depression have a much lower arousal level than healthy people, and as a result a very high need for sleep. Generally speaking, although arousal processes are reduced when we are sleeping, numerous microarousals or wake signals that last for a few milliseconds tend to occur without us noticing them. “EEGs reveal that healthy people wake up and change position up to 70 times per night, but are nevertheless convinced that they have slept through the entire night when they wake up the next morning.”

Frase’s research is particularly focused on sleep disorders and daytime sleepiness with no apparent organic causes. In the feasibility study he is currently carrying out along with Prof. Dr. Christoph Nissen's team, Frase is studying periods of wakefulness and sleepiness in order to be able to achieve a better understanding of the regulation of arousal and sleep. The idea is to use electrostimulation to reduce or increase the overall sleep time in patients suffering from extreme tiredness or extreme insomnia. Conventional therapies involving medicines are good for treating these kinds of disorders, but are associated with risks such as adverse drug effects and addiction. They are, therefore, not suitable for long-term medical treatment.

Neurone activity can be modulated electrically using a non-invasive method that involves applying low DC current to the patient's head via contact electrodes on the scalp (transcranial direct current stimulation, tDCS). The low current leads to a change in membrane potential in the area of interest in the brain, and causes a slight tingling sensation on the scalp. Transcranial brain stimulation is mostly used for treating diseases characterised by brain regions that have either a lower or higher level of activity than normal. The treatment goal is therefore to modulate neural excitability. “An electric field is generated, which, depending on the polarity of the neural cell regions below, causes polarisation/depolarisation of the resting membrane potential, which either decreases or increases neural excitability,” says Frase. The tests involved healthy volunteers who underwent a 30-minute activating, deactivating or sham brain stimulation before sleep for several consecutive nights. The EEGs provided information on brain activities for the total stimulation and sleep time.

Current modulates sleeping patterns

The Freiburg researchers were testing the hypothesis that total sleep time in humans can be modulated by transcranial direct current stimulation (tDCS) by way of frontal activation or deactivation. The study is the first to examine whether there is a relationship between activation level in the frontal cortex and total sleep time. Current treatments for disturbed arousal and sleep target the nucleus of the brainstem (‘bottom-up’ pathway) where the control of arousal or sleep originates and determines the excitatory state of the cerebral cortex. Sleeping pills mainly target neurotransmission in the brainstem.

Frase has chosen an approach involving a ‘top-down’ pathway of sleep-wake regulation that targets cortical neurones with non-invasive brain stimulation, namely the prefrontal cortex where so-called slow waves originate. These slow waves put the brain into a highly synchronised sleep mode. The prefrontal cortex has a higher metabolic activity in people who are awake; the brain is desynchronised and no rhythms can be deduced. “We assume that the cerebral cortex is able to influence sleep centres by feedback processes, and thus contributes to the generation of these slow rhythms,” Frase explains. EEG studies show that slow waves spread across the entire brain and are responsible for the onset and maintenance of sleep. Frase wants to use this ‘top-down’ pathway to provide novel inroads into the treatment of clinical conditions of disturbed arousal and sleep. However, generating slow waves is unfortunately not very easy.

It is much easier to increase cortical excitability in the prefrontal cortex using anodal stimulation, which leads to greater state of arousal. Frase and his colleagues were able to show that transcranial brain stimulation with a low direct current of two milliamperes led to activity modulations in the patients’ neocortex. In line with their hypothesis, anodal stimulation led to higher levels of arousal in the prefrontal cortex. As a result, total sleep time decreased on average by around 30 minutes per night in relation to the control group. No effects on sleep architecture were observed; anodal transcranial brain stimulation appeared to increase the duration of wake periods without affecting the frequency of awakening.

Contrary to what they had supposed in their hypothesis, the researchers were not able to increase total sleep time with the cathodal stimulation of the cortex. Frase believes that this is due to ceiling effects: “Healthy people sleep around 90 percent of the night, so it is difficult to further prolong sleep in such cases.” He believes that the method has the greatest clinical potential when it is used for treating abnormal daytime sleepiness and low arousal levels (e.g. hypersomnia). This has already been achieved in a reanimated patient who had been suffering from extreme tiredness for as long as ten years due to an anaphylactic shock caused by bee stings. The application of transcranial direct current stimulation for a period of three months reduced the patient’s daytime sleep by an hour as well as considerably increasing his level of arousal. This makes the optimisation of this non-invasive therapy very promising, especially as it is simple to apply at home and has no adverse effects or risks.

Reference:

Frase L, Piosczyk H, Zittel S, Jahn F, Selhausen P, Krone L, Feige B, Mainberger F, Maier JG, Kuhn M, Klöppel S, Normann C, Sterr A, Spiegelhalder K, Riemann D, Nitsche MA, Nissen C. Modulation of Total Sleep Time by Transcranial Direct Current Stimulation (tDCS). Neuropsychopharmacol. 2016. doi: 10.1038/npp.2016.65.