Hacking the functions of sleep: Non-invasive approaches to stimulate sleep neurophysiology

Sleep is essentially contributing to human health and wellbeing through multiple biological functions, including restoration and biosynthesis, brain clearance, energy metabolism, immunological and endocrine processing, synaptic plasticity, memory consolidation, and regulation of cognitive and emotional processes. Sleep disturbances are highly prevalent and are both a symptom and a contributing risk factor for psychiatric, neurological, and somatic disorders. Given the limitations of pharmacological interventions, non-invasive neuromodulation techniques ranging from non-invasive transcranial (TMS, tDCS, tACS, tRNS, tTIS, and TUS) to peripheral sensory (auditory, olfactory, visual, tactile, vestibular) and electrical nerve (galvanic vestibular, transcutaneous vagus nerve, and median nerve) stimulation have gained increasing attention as potential tools to modulate sleep physiology. These techniques offer promising avenues for both therapeutic applications and fundamental research into sleep-dependent neuroplasticity, interregional communication, and oscillatory activity. However, sleep is not a uniform state but a highly complex and dynamic phenomenon, with intricate macrostructural (e.g., NREM-REM sleep balance, sleep efficiency) and microstructural characteristics (e.g., hierarchically nested slow waves and spindles) that contribute to a variety of functions. This complexity necessitates precise targeting strategies, often employing real-time brain-state-de pendent stimulation, to modulate specific sleep-related processes effectively. In this review, we summarise the functions of sleep and the available non-invasive tools for its modulation, addressing key methodological challenges and providing recommendations for best practices in sleep neuromodulation.