**1. Introduction**

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic condition distinguished by disabling fatigue associated with multiple symptoms including postexertional malaise, orthostatic intolerance, pain, sleep problems, and impaired cognitive

**Citation:** Khanpour Ardestani, S.; Karkhaneh, M.; Stein, E.; Punja, S.; Junqueira, D.R.; Kuzmyn, T.; Pearson, M.; Smith, L.; Olson, K.; Vohra, S. Systematic Review of Mind-Body Interventions to Treat Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. *Medicina* **2021**, *57*, 652. https://doi.org/10.3390/ medicina57070652

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Academic Editor: Derek F. H. Pheby

Received: 11 May 2021 Accepted: 17 June 2021 Published: 24 June 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

and immune functions [1]. While the true prevalence is unknown, Johnston et al., estimated the pooled prevalence of ME/CFS to be 3.28% and 0.76% according to self-reporting and clinical assessment, respectively [2]. In Canada, 1.4% of people older than 12 years old [3] suffer from ME/CFS. Patients report post-exertional malaise (69–100%), muscle pain (63–95%), impaired memory or concentration (88%), non-restorative sleep (87%), joint pain (55–85%), and sore throat (62%) [1,4]. Health-related quality of life in ME/CFS patients is consistently reported as significantly lower than otherwise healthy populations with regards to physical and mental health, self-care, and ability to perform usual activities [5,6]. Not surprisingly, ME/CFS reduces patients' abilities to carry out normal working activities leading to higher unemployment rates [7]. It is estimated that annual household and labor force productivity of ME/CFS patients are decreased by 37% and 54%, respectively, costing an approximate annual loss of \$9.1 billion in the United States (US) [8]. ME/CFS patients, their families and employers endure a high financial burden estimated to be between \$18 to \$51 billion annually in the US [9].

Despite extensive research, the etiology and pathophysiology of ME/CFS have not ye<sup>t</sup> been fully understood. Disruptions in the autonomic nervous system, hypothalamicpituitary-adrenocortical (HPA) axis, and immune system were shown in several studies [10,11]. Metabolic and mitochondrial dysfunction and abnormal gu<sup>t</sup> microbiota were also shown to be interconnected with the above dysregulation [11]. A recent systematic review of neuroimaging studies showed inconsistent but widespread abnormalities in white matter, functional connectivity, and morphological changes of the autonomic nervous system [12].

With no specific etiology, there is no gold standard method to diagnose ME/CFS to date. A recent systematic review of diagnostic methods by Haney et al., identified nine case definitions [13]. Due to the lack of a biomarker, most of the case definitions require other competing diagnoses to be ruled out [14,15]. In the literature, the term myalgic encephalomyelitis (ME) [16] was used earlier than the term chronic fatigue syndrome (CFS) [17]. The Canadian case definition published in 2003 required post-exertional malaise as an essential symptom in these patients and recommended the umbrella term ME/CFS [18], used in this systematic review.

There is no cure for ME/CFS nor any FDA or Health Canada approved medication to treat it [14,19], therefore the focus tends to be on managing and minimizing the symptoms and improving quality of life. A variety of conventional and complementary therapies have been used to mitigate the symptoms of ME/CFS. As in other chronic conditions, long-term pharmacological interventions may have significant impacts on patients and their families in terms of adverse effects and financial burden [20,21]. Non-pharmacological options are of interest to patients as they may be less expensive and have fewer associated adverse effects.

Systematic reviews have shown low strength of evidence for the effectiveness of different complementary therapies [19], cognitive-behavioral therapy (CBT), counseling and behavioral therapies [14,22], and graded exercise therapy [23] for improvement of fatigue, physical functioning, sleep, and quality of life in patients with ME/CFS.

Mind-body approaches utilize the interactions between the brain, mind, and body, and behavior to improve health and wellbeing [24]. Using these interconnections strengthens self-awareness and self-care and helps to improve mood, quality of life, and increase one's ability to cope. Examples of mind-body therapy interventions (MBIs) include progressive muscle relaxation, guided imagery, hypnosis, meditation, mindfulness, Tai chi, yoga, and biofeedback. Newer approaches are using the brain's ability to change (i.e., neuroplasticity) associated with repeated, purposeful thoughts, feelings or behaviors [25]. The science behind how mind-body therapies work is expanding. It has been shown that the brain and body communicate in multiple directions using neurotransmitters/neuropeptides, hormones, and cytokines and MBIs may be influencing physical health by affecting these interactions [24,26].

Considering the complex nature of ME/CFS and the involvement of psycho-neuroendocrine and immune systems, these patients are an ideal population for evaluating MBIs. Furthermore, by enhancing self-knowledge and patients' abilities to work through their problems and reduce stress, MBIs may improve their quality of life and wellbeing [27].

Several MBIs such as mindfulness-based stress reduction (MBSR), mindfulness-based cognitive therapy (MBCT), yoga, and Qigong have been studied in ME/CFS patients, but to our knowledge, have not ye<sup>t</sup> been included in any systematic review or meta-analysis. There are some promising results to improve anxiety, fatigue, depression, quality of life, and physical functioning [28–32] in ME/CFS. In this systematic review, we evaluated the effectiveness and safety of MBIs that were studied in individuals diagnosed with ME/CFS. The results of this review will inform the design and methodology of future randomized controlled trials.
