Recovery sleep after extended wakefulness restores elevated A1 adenosine receptor availability in the human brain

Abstract

Adenosine and functional A₁ adenosine receptor (A₁AR) availability are supposed to mediate sleep-wake regulation and cognitive performance. We hypothesized that cerebral A₁AR availability after an extended wake period decreases to a well-rested state after recovery sleep. [¹⁸F]CPFPX positron emission tomography was used to quantify A₁AR availability in 15 healthy male adults after 52 h of sleep deprivation and following 14 h of recovery sleep. Data were additionally compared with A₁AR values after 8 h of baseline sleep from an earlier dataset. Polysomnography, cognitive performance, and sleepiness were monitored. Recovery from sleep deprivation was associated with a decrease in A₁AR availability in several brain regions, ranging from 11% (insula) to 14% (striatum). A₁AR availabilities after recovery did not differ from baseline sleep in the control group. The degree of performance impairment, sleepiness, and homeostatic sleep-pressure response to sleep deprivation correlated negatively with the decrease in A₁AR availability. Sleep deprivation resulted in a higher A₁AR availability in the human brain. The increase that was observed after 52 h of wakefulness was restored to control levels during a 14-h recovery sleep episode. Individuals with a large increase in A₁AR availability were more resilient to sleep-loss effects than those with a subtle increase. This pattern implies that differences in endogenous adenosine and A₁AR availability might be causal for individual responses to sleep loss.

Keywords: cognitive performance; depression; interindividual differences; sleep deprivation; sleep homeostasis.

Fig. 1.

(A) Study design. Black arrows indicate times of the six hourly neuropsychological testings. Gray arrows indicate time points of PET scans. TIB, time in bed. Average images of anatomy (B, MRI) and A₁AR availability (C and D, PET) after spatial normalization. (Left) Axial, (Middle) sagittal, (Right) coronal views; coordinates according to the Montreal Neurological Institute Brain Atlas were 22, −17, 0 (x, y, z); n = 14.

Fig. 2.

Average relative differences [(SD52 – REC14)/SD52] of A₁AR availability (distribution volume V_T) in brain regions. Error bars indicate SEMs. The asterisks represent significant differences between sleep deprivation and recovery (paired t test, *P < 0.022) (Table 1), n = 14. Ant. cing. ctx., anterior cingulate cortex; Orbitofro., orbitofrontal.

Fig. 3.

Significant correlations (Spearman) and regressions between the difference of A₁AR distribution volumes (V_T) after sleep deprivation and recovery sleep and (A) difference in PVT performance (number of lapses of attention) in the striatum, (B) difference in 3-back performance (number of omissions) in the insula, (C) fraction of slow-wave sleep in the first sleep cycle in the insula, (D) subjective sleepiness rating in the temporal cortex (ctx.).

Fig. 4.

Time course of (A) PVT, (B) 3-back omissions, and (C) KSS-sleepiness during 58 h of sleep deprivation and after 14 h of recovery sleep. Based on high or low A₁AR availability, the subjects were divided into two subgroups. The absolute difference of the test–retest evaluation revealed that in the striatal region the average of the absolute difference between scans was 0.1 (29). This variance was selected as cut-off criterion for selecting groups with high and low receptor availability. The small insets indicate average parametric receptor maps of subgroup high or low A₁AR availability at corresponding time points. Error bars indicate SEM. An asterisk represents significant differences in unpaired t tests between subgroups at corresponding time points. For visualization purposes N-back time courses have been normalized to the respective baseline values at 14 h awake.

Fig. S1.

Distribution volume in relation to the amount of injected (inj.) activity (open circles denote the control group and the filled circles the experimental group).