Immunological and Genomic Effects of an Online Mindfulness Program for Stress Management

Chronic psychological stress is becoming increasingly pervasive in modern society, with 59% of working age adults who seek primary health care for any reason suffering from significant levels of stress. With long work hours and every increasing demands, healthcare workers are at an especially high risk of experiencing excessive amounts of stress, with over 50% of U.S. physicians and 34% of nurses now reporting symptoms of burnout. Psychological stress has been shown to have a variety of detrimental effects on the immune system, including an increased susceptibility to infection, a diminished immune response to vaccines, reactivation of chronic infections, and the development of chronic inflammation, which in turn is a contributing factor to the development and exacerbation of a wide variety of chronic conditions. Acute stress activates the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, provoking the release of various hormones such as ACTH, cortisol, and catecholamines, which in turn alter the functions of immune cells and generally lead to increased production of inflammatory cytokines, including, IL-6, IL-1β, IL-10, and TNF-α . The communication between the neuroendocrine system and the immune system is bidirectional as cytokines also influence hormone production and the brain's response to stress. When experienced acutely, this physiologic response is harmless. However, when the stress is chronic it can lead to dysregulation of the immune system, setting the individual up for a host of problems ranging from serious infections to chronic inflammatory diseases like rheumatoid arthritis, heart disease, Alzheimer's and overall accelerated aging.

Various strategies have been used to counteract both the psychological and physiological effects of chronic stress including cognitive behavioral therapy, yoga, meditation, biofeedback, and others. While all of these have shown benefits, meditation, in particular, has recently gained widespread popularity as a simple and effective intervention for reducing stress. An ancient practice associated with many religions and cultures in different forms, meditation generally involves a calm and relaxed state of focus or concentration. Although its purpose has historically been to help the practitioner gain spiritual insight and achieve some form of enlightenment, it is now being studied as a way to improve mental and physical health. The most extensively studied form of meditation in the medical literature is the 8-week Mindfulness-Based Stress Reduction (MBSR) program developed by Jon Kabat Zinn, which has been shown to benefit patients with a wide variety of mental and physical health conditions.

One mechanism by which this and other forms of meditation are thought to exert their beneficial effects is through their anti-inflammatory effects, affecting the immune system at the cellular and molecular level. For example, a randomized controlled trial in older adults that went through the 8-week MBSR course showed a more than 25% pre-post change in 143 genes, including reduced activity of NF-kB target genes, relative to controls. But, similar changes have been observed in less time-intensive programs. Just 12 minutes a day of Kirtan Kriya Meditation for 8 weeks led to changes in 63 genes in a group of dementia caregivers compared to those who only listened to relaxing music. The observed changes included downregulation of inflammatory cytokines and NF-kB related transcripts as well as upregulation of immunoglobulin-related transcripts and interferon response factors.Some changes may even occur in as little as one day. Kaliman and colleagues showed that following an 8-hour meditation retreat experienced meditators showed reduced expression of histone deacetylases, global histone modifications, and downregulation of pro-inflammatory genes compared to a group of non-meditators who spent the same time simply relaxing. A meta-analysis of randomized trials has also shown consistently positive effects of meditation on immune cell telomeres, which is a marker of immune cell aging. As Epel and colleagues recently showed, many of these effects may be due to a non-specific relaxation response, especially in novices.However, when Creswell and colleagues compared the changes in a group of stressed, unemployed adults that went through either a 3-day meditation retreat or a 3-day relaxation retreat at the same center, only the meditation group showed a sustained reduction in IL-6 that could be accounted for, in part, by connectivity changes within the brain.Two recent papers have done an excellent job of summarizing the current knowledge regarding the molecular signature associated with mind-body training, and the reader is referred to these for a more detailed review of the topic.

Despite their effectiveness, a major limitation of MBSR and similar programs is a formidable time commitment and a high dropout rate, limiting its utility as a practical intervention for stress management in the population at large, especially busy healthcare workers. It would be ideal to have a more scalable intervention which economizes on time, adapts to modern lifestyles and is inexpensive. Accordingly, the Cleveland Clinic developed an online mindfulness-based stress reduction program known as Stress Free Now. A 6-week program with short daily online articles with tips and ideas for reducing stress and an accompanying app with guided meditations, Stress Free Now is designed for the modern man or woman and capable of reaching the masses. In 2013, a study showed that participants in this program experienced significant stress reductions and improvement in other psychological measures compared to controls. What remains to be answered is whether this program will exhibit biological effects comparable to those seen with in-person interventions. This is the purpose of this project. Using whole transcriptome sequencing and measurement of circulating cytokines, telomerase activity, and diurnal cortisol rhythms the investigators plan to characterize the molecular and immunological phenotype associated with participating in an internet-based mindfulness meditation program. It is hypothesized that following participation in Stress Free Now for Healers, participants will exhibit downregulation of pro-inflammatory gene pathways as well as reduced circulating levels of inflammatory cytokines, increased telomerase activity and reduced, smoother diurnal cortisol patterns compared to controls. This knowledge would be significant because it would provide, for the first time, mechanistic evidence of the benefits of a brief, internet-based mindfulness-meditation program, supporting the implementation this and similar programs into clinical practice. The present study will be a prospective parallel non-blinded randomized study with two arms, an intervention group and an active control group.

In brief, 60 healthy healthcare workers will be randomly assigned to either participate in a 6-week internet-based mindfulness meditation program produced by the Cleveland Clinic called Stress Free Now for Healers or to listen to relaxing music for at least 5 minutes a day for 6 weeks, and pre-post comparisons will be made for RNA expression profiles, plasma cytokine concentrations, telomerase activity, 6-point salivary cortisol and several self-reported assessments of physical and mental health.