Sleep reactivity as a novel mechanism in Shift Work Disorder

Project Summary/Abstract All essential 24-hr operations (e.g., first responders, hospital services) rely on nightshift workers who forgo nocturnal sleep for work. Shift workers comprise 20% of the workforce, with 15 million regularly working nights. Most do not adapt to the inverted sleep-wake schedule, resulting in shift work disorder (SWD) characterized by excessive sleepiness and/or insomnia with sleep loss. Furthermore, because nightshifts are critical to safety- sensitive operations, the risk for catastrophic accidents makes SWD a threat to public health and safety. There remain critical gaps in the clinical translation of shift work research into validated treatments for SWD. One gap is a lack of mechanistic research in large clinical samples of SWD that probe pertinent treatment targets. As such, treatments have predominantly focused on symptom management (e.g., stimulants to maintain alertness and hypnotic medications for sleep). Symptom management alone leaves the underlying mechanisms unabated which can continue to cause a myriad of acute and long-term problems and morbidities. To address this gap, the overall objective of this proposal is to elucidate critical and novel mechanisms driving SWD. Our long-term goal is to develop a treatment that identifies and targets the appropriate underlying mechanisms in SWD. Our pilot data indicates that in addition to circadian misalignment (i.e., a mismatch between the body- clock and the sleep-work schedule), one novel and critical mechanism in SWD is sleep reactivity. Sleep reactivity is a trait where sleep is easily disrupted by environmental stimuli and stressors. Our pilot data in a cross-sectional sample suggests that sleep reactivity predicts persistent SWD symptoms even after reducing circadian misalignment. We also show that sleep reactivity can be reduced with Cognitive Behavioral Therapy (CBT). However, sleep reactivity has not been experimentally disassociated from circadian misalignment as an independent causal mechanism of SWD. This research is critical because it would demonstrate that SWD treatment should target sleep reactivity independently from circadian misalignment. To do this, we propose a two-step mechanistic randomized controlled trial in SWD stratified by high and low sleep reactivity (N=150): the first step probes circadian misalignment using timed bright light exposure, and the second step reduces sleep reactivity with Cognitive Behavioral Therapy. Our central hypothesis is that symptoms of SWD will reduce proportionately with circadian realignment in SWD with low sleep reactivity; however, both insomnia (Aim 1) and sleepiness (Aim 2) symptoms will persist in SWD with high sleep reactivity even after experimental reduction of circadian misalignment. In those with persistent symptoms despite reduced circadian misalignment, further reducing sleep reactivity with CBT would result in reductions in symptoms (Aims 3 & 4). Upon completion, results from this study will have established sleep reactivity as a novel causal mechanism of SWD to be inform future precision medicine approaches for this highly prevalent and undertreated disorder.