The invention of EEG by Hans Berger marks a turning point in the history of sleep science. Until then, sleep was considered primarily a passive state and a fatigue-modulated state resulting from the partial disconnection of the sensory motor circuitry from higher level neural regulators. At the beginning and after the first recordings of brain electrical activity, Berger generated alpha and beta waves as EEG dominant oscillations in healthy subjects.
He suggested an electrophysiological definition of being awake. Subsequent developments of Berger’s research allowed Frédéric Bremer, who worked on the cerebellum physiology and neural control of muscle tone, to further investigate the side effects of sleepiness after a lesion has been created in the hypothalamus. Although not fully involved in sleep research, Bremer’s curiosity to discover the functional effects of lower brain injuries led to cats deserebration by leaving the forebrain in place after an intercollegiate mesencephalic transection. The consequences of this approach – the “cerveau isolé” model, leads to a permanent and indeterminate state with the brain being deprived of ascending sensory information, except for olfactory and optical ones.
Bremer led him to think that the sleep hypothesis was the result of a complete lack of sensory input from the spinal cord. In this model, a high-amplitude, low-frequency activity, as observed in slow-wave sleep (SWS), was predominant in the cortical EEG model. The following experiments, in which brain transection was performed at the meeting point between the brainstem and spinal cord, revealed very different results. In this ‘encephal isolated’ model, a changeable oscillation between sleep and wakefulness states, an EEG pattern different from the spontaneous low frequency, high amplitude activity usually observed in SWS, and high frequency, low amplitude activity, Typical wakefulness and rapid eye movement were observed, is not different from what can be noticed in the situation.
RAS was described about 14 years later by Moruzzi and Magoun, who contributed significantly to sleep-wake physiology by showing that brainstem reticular formation stimulation eliminates EEG low frequency activity and induces high frequency activity in cortical recordings. Other experiments using the transection technique have concluded that the RAS underlies wakefulness, its absence or “silence” accelerating sleep.
However, these results were obtained in acute experiments where the EEG was evaluated immediately after brain injury. However, Villablanca observed that in animals transfected and maintained days or weeks after the surgical procedure, a wakefulness-like EEG activity characterized by low-amplitude high-frequency waves was observed, which is the magnocellular region of the forebrain containing normal rhythm, particularly cholinergic, GABAergic, and glutamatergic neurons.
This allowed the conceptualization that wakeful state modulation, particularly the forebrain, could be dependent regions located parallel to the RAS. Some studies have shown that electrical stimulation of the posterior hypothalamus and basal forebrain in the isolated cat forebrain stimulates rapid cortical EEG rhythms. On the other hand, cholinergic stimulation of these areas has been shown to induce arousal, suggesting a role in the modulation of the awakening mechanism.
In a “diencephalic model” that results from the removal of the cortex and striatum, and the thalamus, hypothalamus and basal forebrain to remain attached to the brain stem, animals are hyperactive, hyperreactive against sensory stimuli, and low amplitude frequency activity in the high thalamus. In the “atalamic animal” from which the thalamus was removed, they were also hyperactive and reactive to sensory stimuli, but were unable to localize the stimuli and did not show much awareness with only short periods of low-amplitude, high-frequency activity.
To evaluate how close the relationship is between the structure and the resulting command to enhance awakening, one can inference using the delay of a stimulus to induce the awake EEG. Stimulation of the RAS-thalamic pathway is several times faster than stimulating the basal forebrain or lateral hypothalamic / orexin pathways in creating a wakefulness-like pattern, thus meaning that projection to another location is needed for both regions to induce such an awake EEG pattern.
During the flu epidemic in the 1920s, a new type of encephalitis that attacks brain regions and regulates sleep and wakefulness was described by Constantin von Economo. This disorder, eventually called encephalitis lethargica or von Economo’s sleeping sickness, swept across Europe and North America, with some patients exhibiting severe insomnia, while others slept 20 hours or more a day and appeared only to eat and drink for a short period of time. Postmortem autopsies of these patients show that those with a phenomenon similar to insomnia have an anterior hypothalamus damage, while those with abnormally increased sleep times show an abnormal posterior hypothalamus.
In light of this, an ascending arousal system originating from the brain stem that keeps the forebrain awake was proposed and later described as the ascending reticular activating system by Moruzzi and Magoun. Subsequent studies clarified the nature of this path in the 1980s. Although Von Economo’s work represents a major feat for sleep research, seminal studies of the hypothalamic-hypocretin system were carried out by Lecea and Kilduff, who characterize mRNA-encoding hypocretin and determined that neurons are responsible for its production.
Shortly after their findings, the relationship between hypocretin / orexin neurons and narcolepsy was established by a mutation in the orexin-2 / hypocretin-2 receptor observed in a narcoleptic dog. The symptoms of narcolepsy, a disorder characterized by emotion-induced hypersomnolence and muscle weakness (cataplexy), are also manifested by the absence of orexin / hypocretin and the absence of orexinergic / hypocretinergic neurons or the orexin / hypocretin 2 receptor. The cell bodies of these neurons are in the periphoric area and in the lateral hypothalamus (LH), responsible for the activation of RAS and tuberomammillar nucleus (TMN) neurons and are active during wakeful state and rapid eye movement (REM) sleep.
Writer: Ozlem Guvenc Agaoglu