**4. Discussion**

This is the first systematic review of studies using MBIs in patients with ME/CFS. The MBIs used in these studies were mindfulness-based stress reduction and mindfulness-based cognitive therapy, relaxation, Qigong, and yoga.

The etiology and pathogenesis of ME/CFS are still unknown [1]. Researchers have shown changes in some biological markers [100–103]. Other studies highlight changes in the hypothalamic-pituitary-adrenal (HPA) axis in these patients [104].

It was also suggested that ME/CFS may be a neurophysiological disorder in the brain caused by repeated incidental or unnecessary stimuli in the limbic system, which is known as the threat response/protection center. These stimuli can be emotional, psychological, chemical, and/or physiological and they can keep the threat response center on a continuous high alert [105]. Connections between the amygdala and sympathetic, hypothalamic and other limbic brain systems can initiate a series of stimulations and uncontrolled reactions throughout the whole body, which could be considered as the root cause of CFS symptoms [105].

With increasing knowledge based on neuroplasticity and the impact of limbic function on somatic symptoms, the potential mechanisms of MBIs might be explained. There is growing interest in using MBIs and many programs are being offered directly to the public to assist with mental and physical health. One of these programs developed specifically for ME/CFS (25) has shown modest success in functional ability in a clinical audit. Because patients are accessing MBI programs, there is an urgen<sup>t</sup> need for evidence as to whether these programs are having an impact on the core symptoms of ME/CFS or mainly address the secondary dissatisfaction that comes with having a chronic, poorly understood disease for which there is no cure. In this review, the MBIs used in the included studies were quite heterogenous. Two studies used relaxation techniques, five studies used movement-based therapies including different forms of yoga and Qigong and the remaining ones used various forms of mindfulness and cognitive-based approaches. Table A6 describes these interventions briefly.

In this systematic review, we found the most commonly measured outcomes were fatigue severity, anxiety and depression, and quality of life or its components (e.g., physical and mental functioning). When compared to the control group, fatigue severity, mental functioning and anxiety/depression mostly improved in patients receiving MBIs. However, poor reporting, small sample sizes, different diagnostic criteria, and a high risk of bias may challenge this result. It is also worth noting that these symptoms are not specific and can be found not only in some individuals with ME/CFS but also in individuals with many other physical and mental health conditions.

According to the 2015 Institute of Medicine report [1], impaired function, postexertional malaise and unrefreshing sleep are the core symptoms in ME/CFS patients. None of our included studies, however, measured post-exertional malaise. One study measured sleep using a self-reporting scale which improved after 9 weeks of Qigong exercise [40]. Physical or mental functioning and functional performance were mostly measured using self-report scales and only one study measured performance using objective measures [51].

In contrast, anxiety and depression and some cognitive constructs were commonly measured in the included studies. While these symptoms are important, they are secondary and not the key features of ME/CFS. Reporting secondary outcomes while omitting measurement of the core symptoms of a disease may lead to inaccurate conclusions about treatment effectiveness.

Previous studies have used a variety of definitions for the diagnosis of ME/CFS. Lack of consensus and competing definitions act as a barrier for research in this field. Most of the studies in this systematic review used the 1994 CDC criteria for the diagnosis of ME/CFS and two studies used Oxford criteria.

The Oxford criteria were developed at a consensus meeting [46]. They do not require the presence of any symptom other than disabling fatigue. The presence of other symptoms such as immune, autonomic and mood symptoms differentiate ME/CFS from other common medical and psychiatric conditions including major depression. It has long been suspected that the Oxford criteria may therefore fail to exclude individuals with other fatiguing conditions [14,19].

To address this concern, the Agency for Healthy Research and Quality (AHRQ) in the United States conducted a sensitivity analysis in which the outcomes of treatment studies using the Oxford criteria were compared with studies using other criteria (mostly the 1994 CDC Criteria) [14]. They found that whereas most studies using the Oxford criteria showed some benefits for CBT, studies using the CDC criteria were mixed with no overall benefit. With regards to graded exercise therapy, exclusion of the trials using the Oxford case definition left insufficient evidence about the effectiveness of graded exercise therapy on any outcome. Studies of other therapies were not affected as primary studies had small sample sizes and a high risk of bias. These findings confirm that the choice of inclusion criteria impacts study outcomes. The AHRQ concluded that future research should retire the use of the Oxford case definition. The National Institutes of Health held a consensus workshop to guide the future of ME/CFS research [19]. For similar reasons as the AHRQ, they also recommended that the Oxford Criteria should be retired.

The 1994 CDC criteria also have significant drawbacks. They require four out of eight criteria but none are mandatory. This means two subjects identified with these criteria may have no symptoms in common with each other—one might have four and the other, another four. Moreover, minor symptoms may overlap with the symptoms of psychiatric disorders including major depression [14].

The Institute of Medicine [1] has proposed diagnostic criteria which are very similar to the Canadian Consensus Criteria [88]. They require patients to have moderate, substantial or severe disabling fatigue, post-exertional malaise and unrefreshing sleep for at least half of the time and one of the cognitive impairments or orthostatic intolerance symptoms. Conclusions about the effectiveness of interventions will be possible once studies use the same diagnostic criteria and measure core outcomes using standardized measures.

#### *4.1. Strengths and Limitations*

Assessment of a broad range of mind-body approaches and outcomes in a systematic fashion was one of the main strengths of this systematic review. Engaging patients in the process of designing the review protocol and in reviewing the findings increase the applicability and relevance of the findings of this study.

As we found a diverse range of interventions and outcomes across the included studies; we were not able to perform a meta-analysis. We also may have missed some relevant information by including only studies published in the English language.

## *4.2. Research Implications*


## **5. Conclusions**

In this systematic review, we described the current literature on MBIs for the treatment of ME/CFS. Future clinical trials will benefit from the findings of this study in terms of what outcomes and outcome measures are mostly used in previous studies. We showed that the included studies did not report measuring post-exertional malaise as a core outcome of ME/CFS. On the other hand, fatigue severity, anxiety/depression and mental functioning were shown to be improved in the patients receiving MBIs. However, poor reporting, small sample sizes, different diagnostic criteria, and a high risk of bias may challenge this result. We highlight the need for further research to use objective and standardized outcomes and outcome measures for making definitive conclusions.

**Author Contributions:** Conceptualization, S.V., E.S., and K.O; methodology, S.K.A., M.K., E.S., S.P., D.R.J., T.K., M.P., L.S., K.O. and S.V.; validation, S.K.A., M.K., E.S., D.R.J., S.P. and S.V.; formal analysis, S.K.A.; investigation, S.K.A., M.K., D.R.J. and E.S.; resources, S.V.; data curation, S.K.A.; writing—original draft preparation, S.K.A., M.K. and E.S.; writing—review and editing, S.P., E.S. and S.V.; visualization, S.K.A.; supervision, S.V.; project administration, S.P.; funding acquisition, S.V. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the University of Calgary.

**Acknowledgments:** The authors thank Susanne King-Jones for her help in the search strategy and contributions to the project.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
