Elsevier

Brain, Behavior, and Immunity

Volume 61, March 2017, Pages 110-116
Brain, Behavior, and Immunity

Full-length Article
Insomnia symptoms with objective short sleep duration are associated with systemic inflammation in adolescents

https://doi.org/10.1016/j.bbi.2016.12.026Get rights and content

Highlights

  • Adolescent insomnia with short sleep duration is associated with elevated inflammation.

  • This association is of clinically significant magnitude for a population-based sample.

  • Insomnia with short sleep duration is a more biologically severe phenotype.

  • Systemic inflammation may predict adverse health outcomes in this insomnia phenotype.

Abstract

Inflammation has been suggested as a potential pathway by which insomnia and short sleep can affect risk of morbidity in adults. However, few studies have examined the association of insomnia with inflammation in adolescents, despite accumulating evidence that pathophysiologic changes may already occur during this critical developmental period. The present study sought to examine the association of insomnia symptoms with systemic inflammation and the role of objective sleep duration in this association. Participants were 378 adolescents (16.9 ± 2.3 y, 45.8% female) from the Penn State Child Cohort, a population-based sample who underwent 9-h polysomnography (PSG) followed by a single fasting blood draw to assess plasma levels of C-reactive protein (CRP) and other inflammatory markers. Insomnia symptoms were defined by a self-report of difficulties falling and/or staying asleep, while objective sleep duration groups were defined as a PSG total sleep time ⩾8, 8–7, and ⩽7 h. We assessed the association of insomnia symptoms, objective sleep duration, and their interaction with inflammatory markers, while adjusting for multiple potential confounders. Adolescents reporting insomnia symptoms had significantly higher levels of CRP compared to controls and a significant interaction (p < 0.01) showed that objective sleep duration modified this association. Elevated CRP was present in adolescents with insomnia symptoms and ⩽7 h of sleep (1.79 mg/L) as compared to controls or adolescents with insomnia symptoms and ⩾8 h of sleep (0.90 mg/L and 0.98 mg/L, respectively) or controls with ⩽7 h of sleep (0.74 mg/L; all p-values <0.01). In sum, insomnia symptoms with objective short sleep duration are associated with systemic inflammation as early as adolescence. This study suggests that chronic low-grade inflammation may be a common final pathway towards morbidity in adulthood in this insomnia phenotype.

Introduction

Insomnia, particularly in adults with objective short sleep duration, has been associated with increased physiologic indices of hyperarousal, ranging from increased cortisol and norepinephrine levels, whole-body metabolic rate and impaired heart rate variability to increased high-frequency cortical dynamics, cerebral glucose metabolism and decreased gamma-aminobutyric acid levels (Bonnet and Arand, 2010, Riemann et al., 2010, Vgontzas et al., 2013). Furthermore, adults with insomnia and objective short sleep duration have been found to be at increased risk of hypertension, type 2 diabetes, neurocognitive impairment, depression and mortality (Bathgate et al., 2016, Fernandez-Mendoza et al., 2015, Vgontzas et al., 2013). Thus, there is a need to identify biomarkers to target the diagnosis and treatment of these adverse health outcomes early in the life span. Chronic low-grade inflammation has been proposed as one of the potential paths by which insomnia can lead to adverse health outcomes (Irwin, 2015, Vgontzas et al., 2002, Vgontzas et al., 2013). However, little is known about the association of adolescent insomnia with inflammation, despite accumulating evidence that the main pathophysiologic mechanism of insomnia, i.e., hyperarousal, may already be present during this critical developmental period (Fernandez-Mendoza et al., 2014, Fernandez-Mendoza et al., 2016, Ly et al., 2015, Zhang et al., 2014). This period is also when sleep disorders develop and, therefore, marks a point for potential interventions; indeed, the prevalence of insomnia symptoms increases with the onset of puberty (Calhoun et al., 2014), reaching a peak of 40% in adolescence, similar to the prevalence of insomnia symptoms in adults (Ohayon, 2002).

An increasing field of research supports that disturbed sleep may play a role in the modulation of circulating inflammatory molecules such as C-reactive protein (CRP) and interleukin-6 (IL-6). A recent meta-analysis by Irwin et al. (2016) of 72 studies comprising 50,000 primarily middle-aged individuals demonstrated that insomnia symptoms were significantly associated with increased levels of CRP (effect size [ES] = 0.12) and IL-6 (ES = 0.20). To a lesser extent, shorter sleep duration was associated with significantly increased CRP (ES = 0.09) and IL-6 (ES = 0.11) levels. Interestingly, the association of shorter sleep duration with CRP and IL-6 was stronger in studies using objective sleep measures (ES = 0.18 and ES = 0.29, respectively) as compared to studies using subjective sleep measures (ES = 0.04 and ES = 0.03, respectively). Tumor necrosis factor alpha (TNF-α) levels were not significantly associated with either insomnia symptoms or shorter sleep duration in the studies covered by this meta-analysis. Despite this promising evidence, these effect sizes are modest and a potential explanation may be the lack of studies examining the joint effect of insomnia symptoms and objective sleep duration on inflammatory markers, as pointed out by Irwin et al. (2016). Furthermore, few studies have examined these associations across the lifespan, which will provide a better understanding of the association of insomnia symptoms and short sleep duration with inflammation early in the development of sleep disorders and other morbidity.

Indeed, the literature examining the association of insomnia symptoms or short sleep duration with inflammatory markers in adolescents is sparse. For example, a study in 143 adolescents aged 13–18 y found that shorter average sleep duration, as measured by actigraphy, was significantly correlated (r = −0.29) with increasing levels of CRP (Larkin et al., 2005). Another study conducted in 188 healthy adolescents found that shorter sleep duration, as measured by self-report, was significantly correlated (β = −0.17) with increasing CRP levels only after controlling for age, sex and pubertal status (Martinez-Gomez et al., 2011). Another recent study in 244 healthy high school students found that shorter sleep duration on school nights, as measured by actigraphy, was not significantly associated with increasing CRP levels (β = −0.04) but rather with greater likelihood (odds ratio = 0.62) of having CRP levels >3  mg/L (Hall et al., 2015). However, there are no studies examining the association of insomnia symptoms with inflammation in adolescents and the role of objective sleep duration in this age group.

The overall aim of the present study is to gain a better understanding of the association between adolescent insomnia symptoms and objective short sleep duration with systemic inflammation. CRP was the primary outcome in the present study, while we also examined IL-6, TNF-α, leptin and adiponectin levels as secondary outcomes. We hypothesized that adolescents with insomnia symptoms, as measured by self-report, would have elevated CRP levels compared to adolescents without insomnia symptoms. We also hypothesized that adolescents with objective short sleep duration, as measured by polysomnography (PSG), would have elevated CRP levels compared to adolescents with normal sleep duration. Finally, we tested whether objective sleep duration modifies that association between insomnia symptoms and increased CRP levels in adolescents.

Section snippets

Participants

The Penn State Child Cohort (PSCC) is a general population sample of 700 children between ages 5–12 years, of whom 421 were followed up 8.4 years later as adolescents (mean age 17.0 ± 2.2 years, 53.9% male, and 21.9% ethnic minority). Baseline demographic characteristics were similar between those who did and did not participate in the follow-up study (Bixler et al., 2016). The study protocol was approved by the Penn State University College of Medicine Institutional Review Board. Written informed

Demographic and clinical characteristics of the sample

Out of the 392 adolescents who provided a fasting blood draw to assay for inflammation, a final sample of 378 had complete data on insomnia symptoms, objective sleep duration and the primary outcome (i.e., CRP). Overall, participants were 16.9 ± 2.3 years old and 45.8% were female. A total of 38% of the sample identified as fully-developed and 46% identified as late pubescent, while less than 16% of the sample identified as mid-pubescent or earlier stages. In terms of race/ethnicity, 6.5%

Discussion

This is the first study to examine the association of insomnia symptoms with objective short sleep duration with inflammation in a population-based sample of adolescents. Consistent with the adult literature, we found that insomnia symptoms and short sleep duration are associated with systemic inflammation in adolescents. Importantly, our study showed that elevated CRP levels are primarily present in adolescents who report insomnia symptoms and slept objectively ⩽7 h in the laboratory, and that

Conflict of interest statement

All authors report no biomedical financial interests or any potential conflicts of interest.

Acknowledgments

The authors thank the sleep technicians and staff members of the Sleep Research & Treatment Center and the General Clinical Research Center at the Pennsylvania State University College of Medicine for their support with this project. This research was supported by NIH grants R01 HL63772, R01 HL97165, UL1 RR033184, and C06 RR16499.

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