Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men

Abstract

Tolcapone, a brain penetrant selective inhibitor of catechol-O-methyltransferase (COMT) devoid of psychostimulant properties, improves cognition and cortical information processing in rested volunteers, depending on the genotype of the functional Val158Met polymorphism of COMT. The impact of this common genetic variant on behavioral and neurophysiological markers of increased sleep need after sleep loss is controversial. Here we investigated the potential usefulness of tolcapone to mitigate consequences of sleep deprivation on lapses of sustained attention, and tested the hypothesis that dopamine signaling in the prefrontal cortex (PFC) causally contributes to neurobehavioral and neurophysiological markers of sleep homeostasis in humans. We first quantified in 73 young male volunteers the impact of COMT genotype on the evolution of attentional lapses during 40 h of extended wakefulness. Subsequently, we tested in an independent group of 30 young men whether selective inhibition of COMT activity with tolcapone counteracts attentional and neurophysiological markers of elevated sleep need in a genotype-dependent manner. Neither COMT genotype nor tolcapone affected brain electrical activity in wakefulness and sleep. By contrast, COMT genotype and tolcapone modulated the sleep loss-induced impairment of vigilant attention. More specifically, Val/Met heterozygotes produced twice as many lapses after a night without sleep than Met/Met homozygotes. Unexpectedly, tolcapone further deteriorated the sleep loss-induced performance deficits when compared to placebo, particularly in Val/Met and Met/Met genotypes. The findings suggest that PFC dopaminergic tone regulates sustained attention after sleep loss according to an inverse U-shape relationship, independently of neurophysiological markers of elevated sleep need.

Haplotype of the astrocytic water channel AQP4 modulates slow wave energy in human NREM sleep

“…To examine the impact of the genetic haplotype of AQP4 on the sleep EEG, we investigated data from 134 healthy participants of six previously published sleep deprivation studies (28)(29)(30)(31)(32)(33) All studies were conducted under strictly controlled conditions in the sleep lab of the Institute of Pharmacology and Toxicology at the University of Zürich, Switzerland using similar protocols and methodology ( Figure 1E). Two carriers of rare haplotypes as well as 9 older participants with an age above 60 years were excluded from the analysis.…”

“…The No difference in the distribution of the AQP4-haplotype between the six studies was observed (p > 0.21). In studies that included the administration of one or more treatments (28)(29)(30), only data from the placebo-arm were analyzed.…”

“…Continuous all-night polysomnographic recordings were performed on all baseline-and recovery-nights. The EEG, electrooculogram (EOG), submental electromyogram, (EMG) and electrocardiogram (ECG) were recorded using the polysomnographic amplifiers PSA24 (Braintronics Inc., Almere, the Netherlands; n = 16) (28) and Artisan ® from Micromed (Mogliano Veneto, Italy; n = 107) (29)(30)(31)(32)(33). In the recordings obtained with the PSA24 recording system, the analogue EEG signals were conditioned by a high-pass 12/19/19 1:25:00…”

Reassessing the validity of slow-wave dynamics as a proxy for NREM sleep homeostasis

“…We next assessed whether humans showed a similar heterogeneity in the response of δ power to SD. A total of 110 healthy human subjects from four published datasets who underwent wholenight SD amounting a sustained waking period of 40h (Bodenmann et al, 2009, Holst et al, 2017, Valomon et al, 2018, Weigend et al, 2019, were included in the analysis. Here we show only the aggregate results, but similar results were obtained in each study separately.…”

“…All subjects signed informed consent and were compensated financially for participating. For more details see previous publications (Bodenmann et al, 2009, Holst et al, 2017, Valomon et al, 2018, Weigend et al, 2019. Some subjects were removed across 5 studies for signal artifacts, which made time-course analysis of spectral bands difficult.…”