Behavioral, electrophysiological, and cerebral correlates of vulnerability to sleep loss : the impact of sleep pressure, circadian phase, and a PER3 polymorphism

Behavioral, electrophysiological, and cerebral correlates of vulnerability to sleep loss:
The impact of sleep pressure, circadian phase, and a PER3 polymorphism.
The impact of sleep loss is highly variable across individuals, and among other influences, genetic factors determine the vulnerability to its detrimental effects. The present thesis aimed to investigate sleep-loss related decrements in subjective and physiological sleepiness, sustained attention, and underlying cerebral correlates by taking into account related genetic vulnerability. Using a candidate-gene approach, we considered a variable-number-tandem-repeat polymorphism in the clock gene PERIOD 3 (PER3), previously related to vulnerability to sleep loss. We compared 14 homozygous long allele carriers (PER35/5) with 14 homozygous short allele carriers (PER34/4). The former genotype was previously reported to be more vulnerable to sleep loss than the latter. In a within-subject design, the sleep homeostatic level was manipulated by two conditions, a 40-h sleep deprivation (SD, high sleep pressure condition) protocol and a 40-h multiple nap protocol (NP, low sleep-pressure condition). We used questionnaires, electrophysiology, hormonal assays, cognitive tasks, and functional magnetic resonance imaging to assess the impact of sleep pressure levels and circadian phase under stringently controlled laboratory conditions.
Our data indicate that sleep loss had more detrimental effects in PER35/5carriers. They were subjectively sleepier and had a greater amount of unintentional sleep episodes. Sustained attention performance was likewise more affected by sleep loss in PER35/5carriers, as evidenced by more intermittent lapses and increasing performance variability with time-on-task during SD. Moreover, nap sleep efficiency tended to be higher in the vulnerable genotype throughout the circadian cycle, which in turn correlated positively with attentional lapses in SD. During the biological night, when performance is usually most compromised due to strongest circadian sleep promotion, higher vulnerability was mirrored in cortical and subcortical deactivation patterns during sustained attention performance under SD. In contrary, resilient participants (PER34/4 carriers) showed increases in task-related brain activity. Likewise, thalamic structures were progressively less recruited with time-on-task and functionally less connected to other arousal-promoting and task-related brain areas in the vulnerable group. Finally, our data suggest that more vulnerable participants are prone to shift into a task-inactive brain default-mode network during the absence of task-relevant stimuli, likely causing the greater “state instability” we observed behaviorally.
In sum, our data show that genetic vulnerability to sleep loss is consistently detectable at the subjective, electrophysiological, and cerebral level. Investigating individual differences in response to sleep loss in combination with basic processes implicated in sleep-wake regulation therefore seems a promising approach to identify phenotypes that allow the prediction of sleep-loss related decrements. A challenging long-term goal is to translate our findings from a controlled laboratory to a field setting with shift workers who face adverse sleep-wake timing and sleep loss on a daily basis.