Neurophysiology and Treatment of Disorders of Consciousness Induced by Traumatic Brain Injury: Orexin Signaling as a Potential Therapeutic Target

Background: Traumatic brain injury (TBI) can cause disorders of consciousness (DOC) by impairing the neuronal circuits of the ascending reticular activating system (ARAS) structures, including the hypothalamus, which are responsible for the maintenance of the wakefulness and awareness. However, the effectiveness of drugs targeting ARAS activation is still inadequate, and novel therapeutic modalities are urgently needed. Methods: The goal of this work is to describe the neural loops of wakefulness, and explain how these elements participate in DOC, with emphasis on the identification of potential new therapeutic options for DOC induced by TBI. Results: Hypothalamus has been identified as a sleep/wake center, and its anterior and posterior regions have diverse roles in the regulation of the sleep/wake function. In particular, the posterior hypothalamus (PH) possesses several types of neurons, including the orexin neurons in the lateral hypothalamus (LH) with widespread projections to other wakefulness-related regions of the brain. Orexins have been known to affect feeding and appetite, and recently their profound effect on sleep disorders and DOC has been identified. Orexin antagonists are used for the treatment of insomnia, and orexin agonists can be used for narcolepsy. Additionally, several studies demonstrated that the agonists of orexin might be effective in the treatment of DOC, providing novel therapeutic opportunities in this field. Conclusion: The hypothalamic-centered orexin has been adopted as the point of entry into the system of consciousness control, and modulators of orexin signaling opened several therapeutic opportunities for the treatment of DOC.