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PER3 polymorphism predicts cumulative sleep homeostatic but not neurobehavioral changes to chronic partial sleep deprivation.

Goel N, Banks S, Mignot E, Dinges DF - PLoS ONE (2009)

Bottom Line: The PER3 genotypes did not differ significantly at baseline in habitual sleep, physiological sleep structure, circadian phase, physiological sleepiness, cognitive performance, or subjective sleepiness, although during PSD, PER3(5/5) subjects had slightly but reliably elevated sleep homeostatic pressure as measured physiologically by EEG slow-wave energy in non-rapid eye movement sleep compared with PER3(4/4) subjects.PER3 genotypic and allelic frequencies did not differ significantly between Caucasians and African Americans.The comparability of PER3 genotypes at baseline and their equivalent inter-individual vulnerability to sleep restriction indicate that PER3 does not contribute to the neurobehavioral effects of chronic sleep loss.

View Article: PubMed Central - PubMed

Affiliation: Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. goel@mail.med.upenn.edu

ABSTRACT

Background: The variable number tandem repeat (VNTR) polymorphism 5-repeat allele of the circadian gene PERIOD3 (PER3(5/5)) has been associated with cognitive decline at a specific circadian phase in response to a night of total sleep deprivation (TSD), relative to the 4-repeat allele (PER3(4/4)). PER3(5/5) has also been related to higher sleep homeostasis, which is thought to underlie this cognitive vulnerability. To date, no study has used a candidate gene approach to investigate the response to chronic partial sleep deprivation (PSD), a condition distinct from TSD and one commonly experienced by millions of people on a daily and persistent basis. We evaluated whether the PER3 VNTR polymorphism contributed to cumulative neurobehavioral deficits and sleep homeostatic responses during PSD.

Methodology/principal findings: PER3(5/5) (n = 14), PER3(4/5) (n = 63) and PER3(4/4) (n = 52) healthy adults (aged 22-45 y) demonstrated large, but equivalent cumulative decreases in cognitive performance and physiological alertness, and cumulative increases in sleepiness across 5 nights of sleep restricted to 4 h per night. Such effects were accompanied by increasing daily inter-subject variability in all groups. The PER3 genotypes did not differ significantly at baseline in habitual sleep, physiological sleep structure, circadian phase, physiological sleepiness, cognitive performance, or subjective sleepiness, although during PSD, PER3(5/5) subjects had slightly but reliably elevated sleep homeostatic pressure as measured physiologically by EEG slow-wave energy in non-rapid eye movement sleep compared with PER3(4/4) subjects. PER3 genotypic and allelic frequencies did not differ significantly between Caucasians and African Americans.

Conclusions/significance: The PER3 VNTR polymorphism was not associated with individual differences in neurobehavioral responses to PSD, although it was related to one marker of sleep homoeostatic response during PSD. The comparability of PER3 genotypes at baseline and their equivalent inter-individual vulnerability to sleep restriction indicate that PER3 does not contribute to the neurobehavioral effects of chronic sleep loss.

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Neurobehavioral performance at baseline and during chronic partial sleep deprivation for the PER3 groups.Mean (±SEM) (A) PVT lapses (>500 ms reaction times) per trial, (B) total number correct per trial on the Digit Symbol Substitution Task (DSST) and (C) Digit Span (DS) task, and scores per trial on the (D) Karolinska Sleepiness (KSS) and (E) “Fresh-Tired” Visual Analog Scale (VAS) at baseline (B) and each partial sleep deprivation/restriction night (SR1-SR5) for PER34/4 (open circles), PER34/5 (gray triangles) and PER35/5 (closed circles) subjects. Although all genotypes showed increased PVT lapses and variability across chronic PSD, there were no differential responses in lapses nor did one genotype show more lapses than the other groups at baseline or during chronic PSD. PER35/5 subjects had better cognitive throughput than their PER34/4 counterparts, as indicated by significantly higher DSST scores across days; there were no differential changes in DSST scores across chronic PSD or significant changes across days. For all groups, DS total correct scores significantly decreased, and KSS and VAS scores significantly increased across chronic PSD, but there were no differential changes or group differences in these measures during chronic PSD.
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pone-0005874-g001: Neurobehavioral performance at baseline and during chronic partial sleep deprivation for the PER3 groups.Mean (±SEM) (A) PVT lapses (>500 ms reaction times) per trial, (B) total number correct per trial on the Digit Symbol Substitution Task (DSST) and (C) Digit Span (DS) task, and scores per trial on the (D) Karolinska Sleepiness (KSS) and (E) “Fresh-Tired” Visual Analog Scale (VAS) at baseline (B) and each partial sleep deprivation/restriction night (SR1-SR5) for PER34/4 (open circles), PER34/5 (gray triangles) and PER35/5 (closed circles) subjects. Although all genotypes showed increased PVT lapses and variability across chronic PSD, there were no differential responses in lapses nor did one genotype show more lapses than the other groups at baseline or during chronic PSD. PER35/5 subjects had better cognitive throughput than their PER34/4 counterparts, as indicated by significantly higher DSST scores across days; there were no differential changes in DSST scores across chronic PSD or significant changes across days. For all groups, DS total correct scores significantly decreased, and KSS and VAS scores significantly increased across chronic PSD, but there were no differential changes or group differences in these measures during chronic PSD.

Mentions: Chronic PSD induced significant deficits in neurobehavioral performance across days as shown by increases in lapses (>500 ms reaction times) on the Psychomotor Vigilance Test [PVT; 25]–[27], a well-validated vigilant attention task (Figure 1A), and by increasing variability for all 3 groups across chronic PSD days (Figure 1A). Although all genotypes significantly increased the number of lapses across days (F2.46, 310.29 = 55.35, p<0.001), there were no differential responses in PVT lapses (day×genotype: F4.93, 310.29 = 0.31, p = 0.907) nor did one group show more lapses than the other groups across days (genotype: F2,126 = 0.67, p = 0.514). Moreover, PVT lapses showed no significant baseline (F2,126 = 0.63, p = 0.533) or sleep deprivation (F2,126 = 1.23, p = 0.296) differences (Table 2).


PER3 polymorphism predicts cumulative sleep homeostatic but not neurobehavioral changes to chronic partial sleep deprivation.

Goel N, Banks S, Mignot E, Dinges DF - PLoS ONE (2009)

Neurobehavioral performance at baseline and during chronic partial sleep deprivation for the PER3 groups.Mean (±SEM) (A) PVT lapses (>500 ms reaction times) per trial, (B) total number correct per trial on the Digit Symbol Substitution Task (DSST) and (C) Digit Span (DS) task, and scores per trial on the (D) Karolinska Sleepiness (KSS) and (E) “Fresh-Tired” Visual Analog Scale (VAS) at baseline (B) and each partial sleep deprivation/restriction night (SR1-SR5) for PER34/4 (open circles), PER34/5 (gray triangles) and PER35/5 (closed circles) subjects. Although all genotypes showed increased PVT lapses and variability across chronic PSD, there were no differential responses in lapses nor did one genotype show more lapses than the other groups at baseline or during chronic PSD. PER35/5 subjects had better cognitive throughput than their PER34/4 counterparts, as indicated by significantly higher DSST scores across days; there were no differential changes in DSST scores across chronic PSD or significant changes across days. For all groups, DS total correct scores significantly decreased, and KSS and VAS scores significantly increased across chronic PSD, but there were no differential changes or group differences in these measures during chronic PSD.
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Related In: Results  -  Collection

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pone-0005874-g001: Neurobehavioral performance at baseline and during chronic partial sleep deprivation for the PER3 groups.Mean (±SEM) (A) PVT lapses (>500 ms reaction times) per trial, (B) total number correct per trial on the Digit Symbol Substitution Task (DSST) and (C) Digit Span (DS) task, and scores per trial on the (D) Karolinska Sleepiness (KSS) and (E) “Fresh-Tired” Visual Analog Scale (VAS) at baseline (B) and each partial sleep deprivation/restriction night (SR1-SR5) for PER34/4 (open circles), PER34/5 (gray triangles) and PER35/5 (closed circles) subjects. Although all genotypes showed increased PVT lapses and variability across chronic PSD, there were no differential responses in lapses nor did one genotype show more lapses than the other groups at baseline or during chronic PSD. PER35/5 subjects had better cognitive throughput than their PER34/4 counterparts, as indicated by significantly higher DSST scores across days; there were no differential changes in DSST scores across chronic PSD or significant changes across days. For all groups, DS total correct scores significantly decreased, and KSS and VAS scores significantly increased across chronic PSD, but there were no differential changes or group differences in these measures during chronic PSD.
Mentions: Chronic PSD induced significant deficits in neurobehavioral performance across days as shown by increases in lapses (>500 ms reaction times) on the Psychomotor Vigilance Test [PVT; 25]–[27], a well-validated vigilant attention task (Figure 1A), and by increasing variability for all 3 groups across chronic PSD days (Figure 1A). Although all genotypes significantly increased the number of lapses across days (F2.46, 310.29 = 55.35, p<0.001), there were no differential responses in PVT lapses (day×genotype: F4.93, 310.29 = 0.31, p = 0.907) nor did one group show more lapses than the other groups across days (genotype: F2,126 = 0.67, p = 0.514). Moreover, PVT lapses showed no significant baseline (F2,126 = 0.63, p = 0.533) or sleep deprivation (F2,126 = 1.23, p = 0.296) differences (Table 2).

Bottom Line: The PER3 genotypes did not differ significantly at baseline in habitual sleep, physiological sleep structure, circadian phase, physiological sleepiness, cognitive performance, or subjective sleepiness, although during PSD, PER3(5/5) subjects had slightly but reliably elevated sleep homeostatic pressure as measured physiologically by EEG slow-wave energy in non-rapid eye movement sleep compared with PER3(4/4) subjects.PER3 genotypic and allelic frequencies did not differ significantly between Caucasians and African Americans.The comparability of PER3 genotypes at baseline and their equivalent inter-individual vulnerability to sleep restriction indicate that PER3 does not contribute to the neurobehavioral effects of chronic sleep loss.

View Article: PubMed Central - PubMed

Affiliation: Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. goel@mail.med.upenn.edu

ABSTRACT

Background: The variable number tandem repeat (VNTR) polymorphism 5-repeat allele of the circadian gene PERIOD3 (PER3(5/5)) has been associated with cognitive decline at a specific circadian phase in response to a night of total sleep deprivation (TSD), relative to the 4-repeat allele (PER3(4/4)). PER3(5/5) has also been related to higher sleep homeostasis, which is thought to underlie this cognitive vulnerability. To date, no study has used a candidate gene approach to investigate the response to chronic partial sleep deprivation (PSD), a condition distinct from TSD and one commonly experienced by millions of people on a daily and persistent basis. We evaluated whether the PER3 VNTR polymorphism contributed to cumulative neurobehavioral deficits and sleep homeostatic responses during PSD.

Methodology/principal findings: PER3(5/5) (n = 14), PER3(4/5) (n = 63) and PER3(4/4) (n = 52) healthy adults (aged 22-45 y) demonstrated large, but equivalent cumulative decreases in cognitive performance and physiological alertness, and cumulative increases in sleepiness across 5 nights of sleep restricted to 4 h per night. Such effects were accompanied by increasing daily inter-subject variability in all groups. The PER3 genotypes did not differ significantly at baseline in habitual sleep, physiological sleep structure, circadian phase, physiological sleepiness, cognitive performance, or subjective sleepiness, although during PSD, PER3(5/5) subjects had slightly but reliably elevated sleep homeostatic pressure as measured physiologically by EEG slow-wave energy in non-rapid eye movement sleep compared with PER3(4/4) subjects. PER3 genotypic and allelic frequencies did not differ significantly between Caucasians and African Americans.

Conclusions/significance: The PER3 VNTR polymorphism was not associated with individual differences in neurobehavioral responses to PSD, although it was related to one marker of sleep homoeostatic response during PSD. The comparability of PER3 genotypes at baseline and their equivalent inter-individual vulnerability to sleep restriction indicate that PER3 does not contribute to the neurobehavioral effects of chronic sleep loss.

Show MeSH
Related in: MedlinePlus