Translational approaches to influence sleep and arousal

Abstract

Sleep disorders are widespread in society and are prevalent in military personnel and in Veterans. Disturbances of sleep and arousal mechanisms are common in neuropsychiatric disorders such as schizophrenia, post-traumatic stress disorder, anxiety and affective disorders, traumatic brain injury, dementia, and substance use disorders. Sleep disturbances exacerbate suicidal ideation, a major concern for Veterans and in the general population. These disturbances impair quality of life, affect interpersonal relationships, reduce work productivity, exacerbate clinical features of other disorders, and impair recovery. Thus, approaches to improve sleep and modulate arousal are needed. Basic science research on the brain circuitry controlling sleep and arousal led to the recent approval of new drugs targeting the orexin/hypocretin and histamine systems, complementing existing drugs which affect GABA_A receptors and monoaminergic systems. Non-invasive brain stimulation techniques to modulate sleep and arousal are safe and show potential but require further development to be widely applicable. Invasive viral vector and deep brain stimulation approaches are also in their infancy but may be used to modulate sleep and arousal in severe neurological and psychiatric conditions. Behavioral, pharmacological, non-invasive brain stimulation and cell-specific invasive approaches covered here suggest the potential to selectively influence arousal, sleep initiation, sleep maintenance or sleep-stage specific phenomena such as sleep spindles or slow wave activity. These manipulations can positively impact the treatment of a wide range of neurological and psychiatric disorders by promoting the restorative effects of sleep on memory consolidation, clearance of toxic metabolites, metabolism, and immune function and by decreasing hyperarousal.

Keywords: CBT-I; Deep brain stimulation; Non-invasive stimulation; Pitolisant; Suvorexant; Zolpidem.

Fig. 1.

Non-invasive stimulation approaches to influence sleep and arousal. Sleep, arousal, and the cortical oscillations characteristic of different sleep-wake states can be manipulated through a variety of techniques. Transcranial electrical stimulation (TES) and transmagnetic stimulation (TMS) techniques increase, decrease, or entrain the activity of specific cortical areas and indirectly affect subcortical circuits. Low-intensity ultrasound can be targeted to deep brain areas such as the thalamus or basal forebrain. Activation of sensory systems using light, sound, or vestibular stimulation (not shown) alters arousal and cortical oscillations via relays in the hypothalamus and brainstem which in turn alter the activity of ascending arousal pathways to the cortex. Figure created with BioRender.com.

Fig. 2.

Invasive approaches to modulate sleep and arousal may be warranted in severe neurological and psychiatric disorders. Deep brain stimulation is already in use in basal ganglia degenerative disorders and shows promise in improving sleep. Basic science studies use viral vectors injected into specific brain regions to modulate the activity of neurons by optogenetic, chemogenetic or gene editing techniques. These techniques are being tested in primates for future use in humans. Transplantation techniques for neurodegenerative conditions such as narcolepsy and RBD are also feasible. Figure created with BioRender.com.