Mikhail Poluektov

Abstract: Since Gelineau's description of narcolepsy's symptoms in 1880, this condition has become one of the most thoroughly studied sleep-wake disorders. The disease develops as a result of autoimmune inflammation of the hypothalamus—diencephalitis. Symptoms of narcolepsy, such as excessive daytime sleepiness and cataplexy attacks, become evident after the destruction of 90% of the neurons that produce the excitatory neurotransmitter orexin. The excess immune response occurs as a result of an infectious disease, vaccination, or without the evident cause. It most likely occurs in individuals having a specific histocompatibility antigen haplotype, HLA-DQB1*06:02. This trait alone does not fully explain the increased susceptibility to this disease. Other candidates include the human equivalent of the canarc-1 gene for canine narcolepsy and the hcrtr2 gene for the hypocretin/orexin receptor type 2.
Understanding the pathophysiology of narcolepsy leads to the creation of laboratory animals with knockout genes for the orexin receptors type 1 and type 2. They have the same behavioral features of the disease.
Selective destruction of orexin neurons is a unique opportunity to study the role of this neurotransmitter in cognitive, emotional, and behavioral processes in humans. Cognitive impairments un narcolepsy affect vigilance, selective attention, sustained attention, and alertness, as well as executive functions such as decision-making. Memory is also impaired. It has been shown that cognitive impairment is not related to the severity of sleepiness but represents a distinct process. Orexin is considered an "activator of activators" for systems involved in cognitive processing. For example, the attention network involves acetylcholine neurons in the basal forebrain ganglia, dopamine neurons in the ventrotegmental area, and noradrenergic neurons in the locus coeruleus. The absence of additional orexin stimulation leads to malfunctioning of these systems.
Cataplexy attacks in narcolepsy patients are known to be more often triggered by positive than negative emotions. The orexin system has been shown to be involved in modulating the activity of dopaminergic ventrotegmental area. This explains the observed underactivation of the amygdala in patients with narcolepsy when presented with negative stimuli and overactivation in response to positive ones. The freezing response, a "false death" reaction that occurs in healthy individuals only to strong negative emotions, occurs in narcolepsy when presented with emotions of the opposite modality. Dysregulation of the dopamine system due to orexin deficiency also explains the phenomenon of narcolepsy patients' lack of dependence on dopaminergic psychostimulants.
Patients with narcolepsy exhibit difficulty making choices in ambiguous situations due to a dysfunction of the fronto-amygdalar reward system due to a lack of orexin stimulation. They do not experience difficulty making choices in risky situations depending from a different fronto-cortico-striatal system, which is less dependent on orexin.
Autonomic disturbances also reflect the orexin dysfunction in narcolepsy. Hypocretin hypothalamic neurons project to the nucleus of the solitary tract and the dorsal motor nucleus of the vagus nerve, the rostral ventrolateral medulla, and the lateral columns of the spinal cord.
A defect in orexin transmission leads to impaired sympathetic activation in response to stimuli of various modalities, resulting in insufficient heart rate reaction to stiluli and elevated blood pressure. Orexin dysfunction leads to metabolic disturbances. Weight gain in these patients develops due to decreased sympathetic stimulation of adipose tissue receptors, which mediate lipolytic processes.
Further advances in studying the role of the orexin system in the regulation of higher nervous functions are linked to the analysis of the brain neural networks in narcolepsy. For this purpose, approaches involving sleep microstaging (5-second epochs) and the use of AI engines that process large amounts of neurophysiological data in real time look promising.

Speaker: Mikhail Poluektov works as an associate professor at the Department of Nervous Diseases at Sechenov University in Moscow. He is also the head of the sleep medicine department at the same institution and the acting president of the Russian Society of Somnologists. In 1993 he graduated from the Medical University by I.M. Sechenov, then specialized in neurology. His PhD, received in 1998, was devoted to studying the effect of autonomic neuropathy on sleep-disordered breathing. As an associate professor, Mikhail Poluektov teaches sleep medicine in neurology and general medicine, organizes conferences on somnology, and publishes regular issues on sleep disorders in «S.S. Korsakov Journal of Neurology and Psychiatry» and «Effective pharmacotherapy». Serves as a reviewer editor in «Frontiers in Psychiatry», «Frontiers in Neurology». Author of more than 250 publications in Russian and foreign journals, 5 monographs in Russian, 3 popular books about sleep.