The interplay of stress and sleep impacts BDNF level

Abstract

Background: Sleep plays a pivotal role in normal biological functions. Sleep loss results in higher stress vulnerability and is often found in mental disorders. There is evidence that brain-derived neurotrophic factor (BDNF) could be a central player in this relationship. Recently, we could demonstrate that subjects suffering from current symptoms of insomnia exhibited significantly decreased serum BDNF levels compared with sleep-healthy controls. In accordance with the paradigm indicating a link between sleep and BDNF, we aimed to investigate if the stress system influences the association between sleep and BDNF.

Methodology/principal findings: Participants with current symptoms of insomnia plus a former diagnosis of Restless Legs Syndrome (RLS) and/or Periodic Limb Movement (PLM) and sleep healthy controls were included in the study. They completed questionnaires on sleep (ISI, Insomnia Severity Index) and stress (PSS, Perceived Stress Scale) and provided a blood sample for determination of serum BDNF. We found a significant interaction between stress and insomnia with an impact on serum BDNF levels. Moreover, insomnia severity groups and score on the PSS each revealed a significant main effect on serum BDNF levels. Insomnia severity was associated with increased stress experience affecting serum BDNF levels. Of note, the association between stress and BDNF was only observed in subjects without insomnia. Using a mediation model, sleep was revealed as a mediator of the association between stress experience and serum BDNF levels.

Conclusions: This is the first study to show that the interplay between stress and sleep impacts BDNF levels, suggesting an important role of this relationship in the pathogenesis of stress-associated mental disorders. Hence, we suggest sleep as a key mediator at the connection between stress and BDNF. Whether sleep is maintained or disturbed might explain why some individuals are able to handle a certain stress load while others develop a mental disorder.

Figure 1. Stress experience in subjects suffering from current insomnia.

Correlation between insomnia severity score (indicated by the Insomnia Severity Index (ISI)) and stress perception (indicated by the Perceived Stress Scale (PSS)). Analysis showed a significant correlation between scores on the ISI and the PSS across the whole sample (r_p = 0.548, p<0.001). * Denotes statistical significance at p<0.05.

Figure 2. Correlation between serum BDNF levels and scores on the Perceived Stress Scale (PSS) by insomnia severity groups according to the Insomnia Severity Index (ISI).

Analyses showed a significant correlation (partial correlation controlled for smoking) between BDNF and stress only in subjects with no insomnia (r_p = −0.511, p = 0.013) compared to subjects with sub threshold (r_p = 0.069, p = 0.814) or clinical insomnia (r_p = 0.199, p = 0.608). White squares represent subjects with no insomnia, black circles represent subjects with sub threshold and black triangles represent subjects with clinical insomnia. (Inset) Mean serum BDNF levels of the insomnia severity groups. Plotted means and standard errors estimated by ANCOVA with serum BDNF as dependent variable, insomnia severity group as independent variable and smoking as covariate. For all three insomnia severity groups the overall effect on serum BDNF was not significant (F(2) = 2.67; p = 0.080). Contrasts showed that serum BDNF levels in the group with no insomnia were significantly higher compared to the groups reporting sub threshold and clinical insomnia (F(1) = 5.33; p = 0.026); (no insomnia n = 24; sub threshold insomnia n = 16, clinical insomnia n = 10). * Denotes statistical significance at p<0.05

Figure 3. Mediation models for the interplay between stress, sleep and BDNF.

(A) Stress as a mediator in the relationship between sleep and BDNF. Analyses revealed a significant ‘a’ path (t = 4.36; p<0.001) between sleep and stress. The ‘b’ path between stress and BDNF was not significant (t = −0.92; p = 0.365). The ‘c’ path between sleep and BDNF was significant after inclusion of stress as mediator (t = −2.05; p = 0.046). The indirect ‘ab’ path was not significant (bootstrap 95% confidence intervals: lower  = −0.385, upper  = 0.169, p>0.05). (B) Sleep as mediator in the relationship between stress and BDNF. The ‘a’ path between stress and sleep was significant (t = 4.36; p<0.001), as was the ‘b’ path between sleep and BDNF (t = −2.05; p = 0.046). The ‘c’ path between stress and BDNF was not significant when the mediator sleep was included (t = −0.92; p = 0.365). In this model the indirect ‘ab’ path was significant (bootstrap 95% confidence intervals: lower  = −0.522, upper  = −0.046; p<0.05). Both models explain 27.3% of the variation (adjusted R square) in serum BDNF levels (F(7.45) = 7.013; p<0.001). Smoking was included as covariate in both models. * Denotes statistical significance at p<0.05 and *** p<0.001.