Links between stress, sleep, and inflammation : a translational perspective of resilience

Most individuals will experience one or more extremely traumatic events during their lifetime. For the most part, humans are resilient and have a tremendous capacity to bounce back from hardships; however, for a critical minority, trauma can result in debilitating symptoms, including posttraumatic stress disorder (PTSD). Historically, sleep disturbance and inflammation were viewed as symptoms or consequences of PTSD; however, recently there has been a shift towards conceptualizing sleep disturbance and inflammation as early indications of mental health issues to come. This thesis examined the inextricable link between stress, sleep, and inflammation, and how gaining a better understanding of these interconnected systems could be harnessed to develop enhanced treatments for populations with stress-related symptoms and disorders.

Study I investigated the effect of standardized sleep therapy on posttraumatic stress symptoms, as well as the gene expression pathways that may mediate this effect in sleep disturbed military service members with PTSD (n =39) and controls without PTSD (n = 27). At baseline, participants diagnosed with insomnia and/or obstructive sleep apnea received a combination of 4 to 8 biweekly sessions of cognitive behavioral therapy for insomnia (CBT-I), and automatic positive airway pressure therapy. Results indicated that 22.6% of participants with PTSD had clinically meaningful posttraumatic stress symptom reduction following standardized sleep therapy. Posttraumatic stress symptoms were linked to increased expression of genes associated with immune response systems, which were downregulated with symptom reduction at follow-up. In order to investigate alternative interventions that may improve sleep quality and potentially provide additional benefits for stress-related disorders, Study II was a metaanalysis to determine the effect of mindfulness meditation on sleep quality outcomes in sleep disturbed adults with various mental and physical health conditions. To assess for relative efficacy, mindfulness meditation was compared to evidence-based sleep treatments (like CBT-I and medication) and time/attention-matched interventions to control for placebo effects, which were analyzed separately. The results indicated that mindfulness meditation had a similar effect on sleep quality compared to the evidence-based sleep treatments and was superior to the time/attention matched placebo controls. However, the strength of this evidence was low to moderate, so some doubt remains. Stress, Sleep, and Inflammation. Once mindfulness meditation was established as a potential intervention to improve sleep quality, Study III investigated if sleep quality improvements, following a 4-week mindfulness-based integrative medicine program, were associated with reductions in posttraumatic stress, anxiety, depression, and postconcussion symptoms in sleep disturbed military service members with mild traumatic brain injury (n = 93). The secondary aim was to determine if sleep quality improvements were associated with decreases in protein levels of inflammation. Results indicated that sleep quality improvements, following the intervention, were linked to reductions in posttraumatic stress and other neurobehavioral symptoms, but not to inflammation. Moreover, 65.8% of participants with PTSD had clinically meaningful posttraumatic stress symptom reduction at follow-up. While we found some evidence that posttraumatic stress symptoms were reduced following the mindfulness-based integrative medicine program, this program required almost 30 treatment hours. This may be an excessive treatment duration when mindfulness meditation is used in populations with less severe symptoms. As such, Study IV investigated the effect of a brief 5-week (7.5-hour) mindfulness meditation program on perceived stress symptoms in moderately stressed healthcare professionals. Participants were randomized to the mindfulness-based self-care (MBSC) group (n = 43) or the life-as-usual control group (n = 35). Results indicated that the meditation group had larger reductions in perceived stress, and these reductions were maintained two months following the completion of the program.

Taken together, the findings of these four studies led to some important conclusions regarding the link between stress, sleep, and inflammation. While mindfulness research is still in its infancy, these preliminary results suggest that mindfulness meditation is effective in improving sleep in adult populations with various mental and physical health conditions (Study II). Less intense mindfulness meditation programs (7.5 hours) may be beneficial to reduce perceived stress, which could potentially prevent the development of more severe mental health conditions (Study IV). While 22.6% of individuals with PTSD had reduced posttraumatic stress symptoms following standardized sleep therapy (Study I), 65.8% of individuals with PTSD had reduced posttraumatic stress symptoms following the mindfulness-based integrative medicine program (Study III). There was some evidence that a relationship exists between sleep quality improvements, decreases in gene expression levels of inflammation, and reductions in posttraumatic stress symptoms; although the direction of causality cannot be determined (Study I and III). Clinical implications and recommendations for future research will be discussed.

List of scientific papers

I. Rusch, H. L., Robinson, J., Yun, S., Osier, N. D., Brewin, C. R., & Gill, J. M. (2019). Gene expression differences in PTSD are uniquely related to the intrusion symptom cluster: a transcriptome-wide analysis in military service members. Brain, Behavior, and Immunity. 80, 904-908.
https://doi.org/10.1016/j.bbi.2019.04.039

II. Rusch, H. L., Rosario, M., Levison, L. M., Olivera, A., Livingston, W. S., Wu, T., & Gill, J. M. (2018). The effect of mindfulness meditation on sleep quality: a systematic review and meta-analysis of randomized controlled trials. Annals of the New York Academy of Sciences. 1445(1), 5-16.
https://doi.org/10.1111/nyas.13996

III. Rusch, H. L., Jiang, A., Guedes, V. A., Haight, T., Lekander, M., Gill, J. M., DeGraba, T.,* & Lasselin, J.* (2020). Associations between sleep quality, neurobehavioral symptoms, and inflammation among combat-exposed military service members: an observational integrative medicine study. *Contributed equally. [Manuscript]

IV. Ameli, R., Sinaii, N., Luna, M. J., Panahi, S., Zoosman, M., Rusch, H. L., & Berger, A. (2020). The effects of a brief mindfulness-based program on stress in healthcare professionals in a biomedical research institution: a randomized controlled trial. JAMA Network Open. 3(8), 1-12.
https://doi.org/10.1001/jamanetworkopen.2020.13424