Advertisement

Mindfulness-based Stress Reduction in Addition to Usual Care Is Associated with Improvements in Pain, Fatigue, and Cognitive Failures Among Veterans with Gulf War Illness

Published:October 28, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.09.015

      Abstract

      Background

      Many Gulf War I veterans report ongoing negative health consequences. The constellation of pain, fatigue, and concentration/memory disturbances is referred to as “Gulf War illness.” Prior research suggests that mindfulness-based stress reduction may be beneficial for these symptoms, but mindfulness-based stress reduction has not been studied for veterans with Gulf War illness. The objective of this trial was to conduct a pilot study of mindfulness-based stress reduction for veterans with Gulf War illness.

      Methods

      Veterans (N = 55) with Gulf War illness were randomly assigned to treatment as usual plus mindfulness-based stress reduction or treatment as usual only. Mindfulness-based stress reduction was delivered in 8 weekly 2.5-hour sessions plus a single 7-hour weekend session. Pain, fatigue, and cognitive failures were the primary outcomes, assessed at baseline, after mindfulness-based stress reduction, and 6 months follow-up. Secondary outcomes included symptoms of posttraumatic stress disorder and depression.

      Results

      In intention-to-treat analyses, at 6-month follow-up, veterans randomized to mindfulness-based stress reduction plus treatment as usual reported greater reductions in pain (f = 0.33; P = .049), fatigue (f = 0.32; P = .027), and cognitive failures (f = 0.40; P < .001). Depressive symptoms showed a greater decline after mindfulness-based stress reduction (f = 0.22; P = .050) and at 6 months (f = 0.27; P = .031) relative to treatment as usual only. Veterans with posttraumatic stress disorder at baseline randomized to mindfulness-based stress reduction plus treatment as usual experienced significantly greater reductions in symptoms of posttraumatic stress disorder after mindfulness-based stress reduction (f = 0.44; P = .005) but not at 6 months follow-up (f = 0.31; P = .082).

      Conclusions

      Mindfulness-based stress reduction in addition to treatment as usual is associated with significant improvements in self-reported symptoms of Gulf War illness, including pain, fatigue, cognitive failures, and depression.

      Keywords

      Clinical Significance
      • Attendance rates for Gulf War I veterans randomized to a mindfulness intervention (mindfulness-based stress reduction) were high.
      • The addition of mindfulness-based stress reduction to usual care was associated with reductions in pain, fatigue, and cognitive failures compared with usual care alone at 6-month follow-up.
      • Veterans with posttraumatic stress disorder at baseline randomized to mindfulness-based stress reduction in addition to usual care reported significant reductions in posttraumatic stress disorder symptoms immediately after mindfulness-based stress reduction and reductions at the level of a trend at 6-month follow-up.
      Approximately 700,000 US military personnel were deployed to the Persian Gulf in 1990 and 1991. At least one fourth have reported negative health consequences,
      Research Advisory Committee on Gulf War Veterans' Illnesses
      Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations.
      including musculoskeletal pain, fatigue, and concentration/memory disturbances, the constellation of which is referred to as “Gulf War syndrome,” “Gulf War illness,” or “chronic multisymptom illness.”
      • Fukuda K.
      • Nisenbaum R.
      • Stewart G.
      • et al.
      Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
      The Iowa Persian Gulf Study Group
      Self-reported illness and health status among Gulf War veterans: a population-based study.
      Institute of Medicine
      Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined.
      For chronic multisymptom illness subsequent to Gulf War deployment, the term “Gulf War illness” is preferred.
      Institute of Medicine
      Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined.
      Chronic multisymptom illness is common among patients in primary care
      • Kroenke K.
      • Price R.K.
      Symptoms in the community. Prevalence, classification and psychiatric comorbidity.
      and in military combat veterans,
      • Fukuda K.
      • Nisenbaum R.
      • Stewart G.
      • et al.
      Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
      • Blanchard M.S.
      • Eisen S.A.
      • Alpern R.
      • et al.
      Chronic multisymptom illness complex in Gulf War I veterans 10 years later.
      but Gulf War I veterans experience higher rates of chronic multisymptom illness than veterans from previous conflicts.
      • Fukuda K.
      • Nisenbaum R.
      • Stewart G.
      • et al.
      Chronic multisymptom illness affecting Air Force veterans of the Gulf War.

      Hunt SC. VA Approaches to the management of chronic multi-symptom illness in Gulf War I veterans. Presentation at the Third Committee Meeting, April 12, 2012, Irvine, California, 2012.

      • Baker D.G.
      • Mendenhall C.L.
      • Simbartl L.A.
      • et al.
      Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans.
      Much of the debate related to the nature of Gulf War illness has centered on the etiologic roles of psychologic stressors and environmental exposures.
      Research Advisory Committee on Gulf War Veterans' Illnesses
      Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations.
      • Hunt S.C.
      • Richardson R.D.
      • McFall M.
      Re: The Gulf War syndrome controversy.
      Research Advisory Committee on Gulf War Veterans Illnesses. 2009-2013.
      • Wessely S.
      Ten years on: what do we know about the Gulf War syndrome? King's College Gulf War Research Unit.
      Although Gulf War illness is often comorbid with posttraumatic stress disorder and depression,
      • Baker D.G.
      • Mendenhall C.L.
      • Simbartl L.A.
      • et al.
      Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans.
      • Proctor S.P.
      • Heeren T.
      • White R.F.
      • et al.
      Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.
      many veterans with Gulf War illness do not have mental health conditions.
      • Wolfe J.
      • Proctor S.P.
      • Erickson D.J.
      • et al.
      Relationship of psychiatric status to Gulf War veterans' health problems.
      Some researchers have noted a link between exposure to neurotoxins encountered during deployment,
      Research Advisory Committee on Gulf War Veterans' Illnesses
      Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations.
      whereas others have not found evidence of an exposure-related cause.
      The Iowa Persian Gulf Study Group
      Self-reported illness and health status among Gulf War veterans: a population-based study.
      • Wessely S.
      Ten years on: what do we know about the Gulf War syndrome? King's College Gulf War Research Unit.
      Centers for Disease Control and Prevention
      Unexplained illness among Persian Gulf War veterans in an air National Guard unit: preliminary report–August 1990-March 1995.
      • Sartin J.S.
      Gulf War illnesses: causes and controversies.
      Institute of Medicine
      Gulf War and Health Volume 4: Health Effects of Serving in the Gulf War.
      Institute of Medicine
      Gulf War and Health Volume 8: Update of Health Effects of Serving in the Gulf War.
      It has been suggested that Gulf War illness emerged as a consequence of multiple insufficiently established causes.
      • Wessely S.
      Ten years on: what do we know about the Gulf War syndrome? King's College Gulf War Research Unit.
      • Sartin J.S.
      Gulf War illnesses: causes and controversies.
      • Hyams K.C.
      • Wignall F.S.
      • Roswell R.
      War syndromes and their evaluation: from the US Civil War to the Persian Gulf War.
      Although there have been numerous attempts to determine the cause of Gulf War illness,
      Institute of Medicine
      Gulf War and Health Volume 4: Health Effects of Serving in the Gulf War.
      Institute of Medicine
      Gulf War and Health Volume 8: Update of Health Effects of Serving in the Gulf War.
      studies of treatment approaches to Gulf War illness remain limited, and thousands of veterans continue to suffer.
      • Ozakinci G.
      • Hallman W.K.
      • Kipen H.M.
      Persistence of symptoms in veterans of the First Gulf War: 5-year follow-up.
      • Smith B.N.
      • Wang J.M.
      • Vogt D.
      • et al.
      Gulf War illness symptomatology among veterans 10 years after deployment.
      • Li B.
      • Mahan C.M.
      • Kang H.K.
      • et al.
      Longitudinal health study of US 1991 Gulf War veterans: changes in health status at 10-year follow-up.
      Treatment models developed for Gulf War illness recommend interventions that are integrative.
      • Hunt S.C.
      • Richardson R.D.
      • Engel C.C.
      Clinical management of Gulf War veterans with medically unexplained physical symptoms.
      • Engel C.C.
      • Roy M.
      • Kayanan D.
      • et al.
      Multidisciplinary treatment of persistent symptoms after Gulf War service.
      To date, one clinical trial for Gulf War illness has evaluated an integrative approach, which showed a modest benefit of cognitive behavioral therapy or exercise on symptoms of Gulf War illness, which declined over time.
      • Donta S.T.
      • Clauw D.J.
      • Engel Jr., C.C.
      • et al.
      Cognitive behavioral therapy and aerobic exercise for Gulf War veterans' illnesses: a randomized controlled trial.
      Also, there was no significant effect of cognitive behavioral therapy on fatigue relative to usual care and limited effects on pain.
      • Donta S.T.
      • Clauw D.J.
      • Engel Jr., C.C.
      • et al.
      Cognitive behavioral therapy and aerobic exercise for Gulf War veterans' illnesses: a randomized controlled trial.
      Additional studies of integrative approaches are needed.
      Mindfulness-based interventions have been applied to symptom-based syndromes.
      • Reiner K.
      • Tibi L.
      • Lipsitz J.D.
      Do mindfulness-based interventions reduce pain intensity? a critical review of the literature.
      • Lakhan S.E.
      • Schofield K.L.
      Mindfulness-based therapies in the treatment of somatization disorders: a systematic review and meta-analysis.
      • Veehof M.M.
      • Oskam M.J.
      • Schreurs K.M.G.
      • et al.
      Acceptance-based interventions for the treatment of chronic pain: a systematic review and meta-analysis.
      Mindfulness has been defined as “the awareness that emerges by way of paying attention on purpose, in the present moment, and nonjudgmentally to the unfolding of experience moment by moment.”
      • Kabat-Zinn J.
      Commentary on Majumdar, et al.: Mindfulness meditation for health.
      Mindfulness-based interventions are intended to foster the ability to attend to thoughts, emotions, and bodily sensations with an attitude of curiosity, openness, acceptance, and love,
      • Siegel D.J.
      The Mindful Brain: Reflection and Attunement in the Cultivation of Well-being.
      which is theorized to promote cognitive and behavioral changes.
      • Baer R.A.
      Mindfulness training as a clinical intervention: a conceptual and empirical review.
      In mindfulness-based interventions, mindfulness skills are usually developed through a daily discipline of meditation and informal mindfulness practices. Evidence indicates that mindfulness-based interventions are associated with small to modest improvements in general symptom severity, pain, depression, and anxiety,
      • Lakhan S.E.
      • Schofield K.L.
      Mindfulness-based therapies in the treatment of somatization disorders: a systematic review and meta-analysis.
      • Hofmann S.G.
      • Sawyer A.T.
      • Witt A.A.
      • et al.
      The effect of mindfulness-based therapy on anxiety and depression: a meta-analytic review.
      • Bohlmeijer E.
      • Prenger R.
      • Taal E.
      • et al.
      The effects of mindfulness-based stress reduction therapy on mental health of adults with a chronic medical disease: a meta-analysis.
      as well as reduced fatigue among individuals with chronic fatigue syndrome.
      • Surawy C.
      • Roberts J.
      • Silver A.
      The effect of mindfulness training on mood and measures of fatigue, activity, and quality of life in patients with chronic fatigue syndrome on a hospital waiting list: a series of exploratory studies.
      Although some studies indicate that mindfulness training influences attentional
      • Chiesa A.
      • Calati R.
      • Serretti A.
      Does mindfulness training improve cognitive abilities? A systematic review of neuropsychological findings.
      and memory
      • Williams J.M.
      • Teasdale J.D.
      • Segal Z.V.
      • et al.
      Mindfulness-based cognitive therapy reduces overgeneral autobiographical memory in formerly depressed patients.
      abilities, extant research on these types of interventions has not specifically assessed their effect on the memory and cognitive deficits commonly found among veterans with Gulf War illness.
      • Hom J.
      • Haley R.W.
      • Kurt T.L.
      Neuropsychological correlates of Gulf War Syndrome.
      • Lange G.
      • Tiersky L.A.
      • DeLuca J.
      • et al.
      Cognitive functioning in Gulf War illness.
      • Sullivan K.
      • Krengel M.
      • Proctor S.P.
      • et al.
      Cognitive functioning in treatment-seeking Gulf War veterans: Pyridostigmine bromide use and PTSD.
      This evidence raises the possibility that mindfulness-based interventions might be particularly well suited for symptom management of Gulf War illness. A widely available clinical method of teaching mindfulness is an 8-week class series called “mindfulness-based stress reduction.”
      • Baer R.A.
      Mindfulness training as a clinical intervention: a conceptual and empirical review.
      We conducted a pilot study to assess the impact of participation in mindfulness-based stress reduction as an adjunct to treatment as usual for veterans with Gulf War illness presenting as chronic multisymptom illness.
      • Fukuda K.
      • Nisenbaum R.
      • Stewart G.
      • et al.
      Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
      It was hypothesized that participation in mindfulness-based stress reduction would be associated with improvement in pain, fatigue, and cognitive impairments for veterans with Gulf War illness, relative to treatment as usual only. As a secondary aim, we sought to assess the influence of mindfulness-based stress reduction on symptoms of depression and posttraumatic stress disorder, which are common among previously deployed veterans.

      Materials and Methods

      The study was approved by the institutional review board at VA Puget Sound Health Care System and registered with clinicaltrials.gov NCT01267045.

      Participants

      Fifty-five participants were randomized to treatment as usual plus mindfulness-based stress reduction or treatment as usual only (Figure 1). Participants met criteria for Gulf War illness, defined as deployment to the Gulf War theater of operations between August 1990 and August 1991 and self-report of at least 2 of the following symptoms that began after August 1990, lasted at least 6 months, and were present at the time of the interview: (1) fatigue that limits usual activity; (2) musculoskeletal pain involving 2 or more regions of the body; and (3) cognitive symptoms (memory, concentration, or attention difficulties).
      • Fukuda K.
      • Nisenbaum R.
      • Stewart G.
      • et al.
      Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
      The flow of subjects is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Participant flow through the trial. GWS = Gulf War Syndrome; MBSR = mindfulness-based stress reduction; NOS = not otherwise specified.

      Exclusion Criteria

      At baseline, the Structured Clinical Interview for DSM-IV Axis I Disorders psychiatric interview
      • First M.B.
      • Spitzer R.L.
      • Gibbon M.
      • et al.
      Structured Clinical Interview for DSM-IV® Axis I Disorders, Clinician Version (SCID-CV), Administration Booklet.
      determined psychiatric exclusion criteria: (1) history of psychosis, (2) current mania, and (3) current suicidal or homicidal ideation. Additional exclusion criteria were prior participation in mindfulness-based stress reduction, active substance/alcohol abuse that posed a safety threat (current drinking and a past-year history of alcohol-related seizures or delirium tremens), or inpatient psychiatric admission within the past month.

      Procedures

      Recruitment sources included flyers in clinics and letters sent to Gulf War I veterans. Informed consent was obtained. After the baseline assessment, participants were stratified by baseline Patient Health Questionnaire-9 depression score ≥10 and randomly assigned (using concealed allocation) to treatment as usual plus mindfulness-based stress reduction or treatment as usual only. Measures were completed at baseline, 8 weeks later (the post–mindfulness-based stress reduction time point), and 6 months after the post–mindfulness-based stress reduction time point. The research assessor was blinded to the randomization arm. Participants continued to receive treatment as usual without intervention from the study team and received a small amount of monetary compensation for the research assessments. No compensation was provided to attend mindfulness-based stress reduction classes.

      Clinical Assessment

      Primary Outcomes

      The following measures of pain, fatigue, and cognitive dysfunction were the primary outcomes: Pain was assessed by the Short-form McGill Pain Questionnaire,
      • Dworkin R.H.
      • Turk D.C.
      • Revicki D.A.
      • et al.
      Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).
      • Lovejoy T.I.
      • Turk D.C.
      • Morasco B.J.
      Evaluation of the psychometric properties of the revised Short-Form McGill Pain Questionnaire.
      a 22-item measure of pain (Cronbach's α = 0.93). The total score, which has been shown to be responsive to patients' global impressions of change,
      • Lange G.
      • Tiersky L.A.
      • DeLuca J.
      • et al.
      Cognitive functioning in Gulf War illness.
      was used. Fatigue was assessed using the General Fatigue subscale of the Multidimensional Fatigue Inventory,
      • Smets E.M.A.
      • Garssen B.
      • Bonke B.
      • et al.
      The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue.
      which been shown to be a valid measure of overall fatigue in multiple prior studies,
      • Thombs B.
      • Bassel M.
      • McGuire L.
      • et al.
      A systematic comparison of fatigue levels in systemic sclerosis with general population, cancer and rheumatic disease samples.
      but had a Cronbach's α = 0.60 in our study. Cognitive failures were assessed using the Cognitive Failures Questionnaire,
      • Broadbent D.E.
      • Cooper P.F.
      • Fitzgerald P.
      • et al.
      The cognitive failures questionnaire (CFQ) and its correlates.
      a 25-item questionnaire that assesses proneness to commit cognitive errors in everyday tasks (Cronbach's α = 0.95).

      Secondary Outcomes

      Posttraumatic stress disorder symptoms were assessed using the Posttraumatic Stress Disorder Symptom Scale-Interview, a 17-item semistructured interview that assesses current posttraumatic stress disorder diagnostic status (Cronbach's α = 0.87).
      • Foa E.B.
      • Riggs D.S.
      • Dancu C.V.
      • et al.
      Reliability and validity of a brief instrument for assessing posttraumatic stress disorder.
      Depression was assessed using the Patient Health Questionnaire-9
      • Kroenke K.
      • Spitzer R.L.
      • Williams J.B.
      The PHQ-9: validity of a brief depression severity measure.
      (Cronbach's α = 0.86). In addition, the extensively validated National Institutes of Health Patient Reported Outcomes Measurement Information System measure for fatigue
      • Cella D.
      • Yount S.
      • Rothrock N.
      • et al.
      The Patient-Reported Outcomes Measurement Information System (PROMIS) progress of an NIH roadmap cooperative group during its first two years.

      Lai JS, Chen WH. Fatigue archival analysis report, 2006. Available at: http://www.nihpromis.org. Accessed November 19, 2015.

      was administered as an ancillary measure and is included here because of the suboptimal psychometric properties of the Multidimensional Fatigue Inventory general fatigue subscale found in our data. Mindfulness Skills were assessed using the Five Facet Mindfulness Questionnaire
      • Baer R.A.
      • Smith G.T.
      • Lykins E.
      • et al.
      Construct validity of the five facet mindfulness questionnaire in meditating and nonmeditating samples.
      (Cronbach's α = 0.87). The total Five Facet Mindfulness Questionnaire score was used.
      At baseline, exposure to traumatic events was assessed by the Life Events Checklist.
      • Blake D.D.
      • Weathers F.W.
      • Nagy L.M.
      • et al.
      The development of a clinician-administered PTSD scale.
      Wartime exposures were assessed using the biological, chemical, and nuclear agents subscale from the Deployment Risk and Resilience Inventory.

      King DW, King LA, Vogt DS, Knight J, Samper RE. Deployment risk and resilience inventory (DRRI): a collection of measures for studying deployment-related experiences of military personnel and veterans, Military Psychology, 18, 2006, 89–120.

      Intervention: Mindfulness-Based Stress Reduction

      The mindfulness-based stress reduction courses closely followed the curriculum developed by the University of Massachusetts.
      • Kabat-Zinn J.
      Full Catastrophe Living. Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness.
      • Santorelli S.
      • Kabat-Zinn J.
      Mindfulness-based stress reduction professional training: MBSR curriculum guide and supporting materials.
      A single experienced instructor led each mindfulness-based stress reduction group of 20 to 25 veterans; the courses were offered for clinical purposes. Within each mindfulness-based stress reduction group, 2 to 6 veterans were participants in the current study. Each mindfulness-based stress reduction class series met once per week (2.5 hours per session) for 8 weeks, plus a 7-hour session on a Saturday between weeks 6 and 7. Participants received instruction on mindfulness meditation practices, including body scan meditation, breathing meditation, gentle yoga, walking meditation, and loving-kindness meditation. The instructions for these practices were intended to foster increased awareness of thoughts, bodily sensations, and emotions, with an attitude of curiosity, openness, and acceptance. Throughout mindfulness-based stress reduction, participants were assigned to practice meditation led by audio CD for 30 to 45 minutes per day, 6 days per week. Homework also included informal mindfulness practices, such as bringing mindful attention to everyday activities such as walking or eating. Each participant was given a workbook and the book Full Catastrophe Living,
      • Kabat-Zinn J.
      University of Massachusetts Medical Center/Worcester
      Stress Reduction Clinic. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness.
      which outlined learning goals and homework assignments, and provided supplemental reading material.

      Statistical Analyses

      Patient characteristics are presented using descriptive statistics. Independent sample t tests and chi-square tests were used to evaluate baseline differences between treatment arms. Mean scores at baseline, post–mindfulness-based stress reduction, and 6-month follow-up were derived from linear mixed-effects models. Mixed-effects models account for within-subject correlation of responses over time and allow use of all available data across all time points to increase statistical efficiency. Randomization arm and time point were treated as fixed effects. Time × treatment interaction was assessed to determine whether subjects randomized to mindfulness-based stress reduction differed from those randomized to usual care with respect to change from baseline to post–mindfulness-based stress reduction and 6-month time points on outcomes; the significance level is presented for the time × treatment interaction. Between-group effect sizes were calculated using linear mixed-effects models as Cohen's f (0.10 small; 0.25 medium; 0.40 large). The primary analysis was conducted on an intention-to-treat basis. For secondary analyses, identical comparisons were conducted limiting the intervention group to those randomized to mindfulness-based stress reduction who attended ≥4 classes (“completer” analyses).
      • Teasdale J.D.
      • Segal Z.V.
      • Williams J.M.G.
      • et al.
      Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy.
      Additional secondary analyses were performed limiting the patient population to those who met symptom criteria for posttraumatic stress disorder at baseline.
      • Foa E.B.
      • Riggs D.S.
      • Dancu C.V.
      • et al.
      Reliability and validity of a brief instrument for assessing posttraumatic stress disorder.
      A 2-sided P value of less than .05 was considered statistically significant. No adjustments were made for multiple comparisons.
      • Bender R.
      • Lange S.
      Adjusting for multiple testing—when and how?.
      All statistical analyses were performed using Stata (Release 11; StataCorp LP, College Station, Tex).

      Results

      The treatment groups did not differ significantly on demographic characteristics, trauma exposure, medication use, baseline prevalence of chronic conditions, disability status, scores on the primary or secondary outcome measures (Table 1), or deployment-related exposures (Table 2). Receipt of other treatments from baseline to 6-month follow-up also did not differ according to randomization arm (Table 1).
      Table 1Baseline Characteristics of Participants
      CharacteristicMBSR (n = 26)Treatment as Usual (n = 29)P Value
      Age (y, mean ± SD)51.3 ± 6.848.6 ± 7.4.16
      Women, n (%)3 (11.5)5 (17.2).55
      Ethnicity, n (%).24
       White17 (72)17 (58.6)
       African American2 (8.0)8 (27.6)
       Asian1 (4)2 (6.9)
       Native American0 (0.0)1 (3.5)
       Other3 (12)1 (3.5)
      Married, n (%)16 (61.5)15 (51.7).52
      McGill Pain Questionnaire scores75.0 ± 32.581.2 ± 41.9.55
      Multidimensional Fatigue Inventory scores
       General fatigue16.0 ± 2.815.5 ± 3.2.53
       Physical fatigue14.4 ± 2.715.3 ± 2.9.28
       Reduced activity14.9 ± 4.114.3 ± 3.8.63
       Reduced motivation11.5 ± 2.411.6 ± 2.4.92
       Mental fatigue15.5 ± 3.615.6 ± 3.2.97
      Cognitive Failures Questionnaire59.6 ± 16.558.3 ± 18.7.78
      PTSD Symptom Scale Interview29.0 ± 11.226.2 ± 10.6.35
      Total No. of traumas4.23 ± 2.84.72 ± 3.7.58
       Direct experience2.76 ± 2.82.65 ± 2.2.79
       Learned about traumatic event0.52 ± 1.10.30 ± .7.88
       Witnessed traumatic event1.72 ± 1.61.65 ± 1.6.40
      Conditions listed in medical record at baseline, n (%)
       Musculoskeletal pain20 (76.9)27 (93.1).48
      1 diagnosis7 (26.9)3 (10.3)
      2-3 diagnoses16 (61.5)5 (17.2)
      ≥4 diagnoses8 (30.8)8 (27.6)
       Neurologic Pain14 (53.9)15 (51.7).06
      1 diagnosis6 (23.1)11 (37.9)
      ≥2 diagnoses8 (30.8)4 (13.8)
       Any chronic pain condition21 (80.8)23 (79.3).89
       Gastrointestinal10 (38.5)19 (65.5).50
       Respiratory10 (38.5)12 (41.4).67
       Depression13 (50.0)20 (69.0).15
       Anxiety disorder other than PTSD5 (19.2)5 (17.2).85
      Baseline medication use, n (%)
       Opiate14 (53.8)5 (17.2).43
       Antidepressant13 (50.0)14 (48.3).68
       Benzodiazepine4 (15.4)4 (13.8).58
       Amphetamine2 (7.7)3 (10.3).55
      Service-connectedness
       None (0%)3 (11.5)2 (6.9).55
       <50%2 (7.7)5 (17.2).29
       50%-100%21 (80.8)22 (75.9).66
      Other treatments received during the study period
       Pain treatment6 (23.1)8 (27.6).70
       Cognitive-behavioral therapy0 (0.0)1 (3.5).34
       Acceptance and commitment therapy0 (0.0)2 (6.9).17
       Prolonged exposure therapy0 (0.0)0 (0.0)
       Addiction treatment1 (3.8)0 (0.0).29
       Psychiatric medication management7 (26.9)10 (34.5).55
       Cognitive processing therapy0 (0.0)1 (3.4).34
       Other/unspecified mental health treatment7 (26.9)11 (37.9).39
      MBSR = mindfulness-based stress reduction; PTSD = posttraumatic stress disorder; SD = standard deviation.
      Table 2Participant Exposure to Biological, Chemical, and Nuclear Agents
      CharacteristicMBSR (n = 26)

      No. (%)
      Treatment as Usual (n = 29)

      No. (%)
      P Value
      Pyridostigmine pills and vaccines20 (77)26 (90).33
      Chemical and biological weapons7 (27)9 (31).81
      Pesticides and insect repellent18 (69)22 (76).75
      Smoke and diesel fume22 (85)28 (97).24
      Depleted uranium10 (38)6 (21).13
      Nonmilitary food19 (73)23 (79).78
      Exploding artillery or missiles14 (54)20 (69).33
      Entering enemy tank, bunker, or facility12 (46)17 (59).45
      Values present the number and percentage of participants responding in the affirmative to items from VA Deployment Risk and Resiliency Inventory 2 Section F.
      MBSR = mindfulness-based stress reduction.
      By using a definition of “completer” as participation in 4 or more mindfulness-based stress reduction classes,
      • Teasdale J.D.
      • Segal Z.V.
      • Williams J.M.G.
      • et al.
      Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy.
      19 of 26 veterans (73%) randomized to mindfulness-based stress reduction were treatment completers. The mean number of mindfulness-based stress reduction class sessions attended was 5.7 (median number of sessions attended = 7; range, 0-9 sessions). Research compliance was high; 85% completed the post-test assessment; 82% completed the 6-month assessment.

      Intention-To-Treat Analyses

      Primary Outcomes

      Table 3 and Figure 2 show the mean scores for outcome measures over time. Veterans randomized to mindfulness-based stress reduction did not report greater reductions in pain at immediate post-test but reported greater reductions at 6 months, with a medium to large effect size (f = 0.33; P = .049). Reductions in cognitive failures were greater for veterans randomized to mindfulness-based stress reduction at both immediate post-test and at 6 months with large effect sizes: f = 0.44 (P = .002) and f = 0.40 (P < .001), respectively. Those randomized to mindfulness-based stress reduction did not report greater reduction in fatigue (Multidimensional Fatigue Inventory) at immediate post-test but reported greater reductions in fatigue at 6 months with a medium to large effect size (f = 0.32; P = .027).
      Table 3Mean Summary Scores and Cohen's f Effect Sizes* for Mindfulness-Based Stress Reduction (n = 26) vs Treatment as Usual (n = 29) for Intention-To-Treat and Completer Analyses
      Summary ScoresIntention-To-Treat AnalysisCompleter Analysis
      Baseline Mean ± SDPost-treatment Mean ± SD6 Months Mean ± SDBaseline Mean ± SDPost-treatment Mean ± SD6 Months Mean ± SD
      Primary Outcomes
       MPQ-2
      MBSR75.0 ± 32.554.0 ± 44.257.1 ± 44.769.6 ± 26.440.9 ± 23.946.6 ± 24.2
      TAU81.2 ± 41.965.5 ± 43.476.6 ± 49.381.2 ± 41.965.5 ± 43.476.6 ± 49.3
      Effect size*0.130.330.280.40
      P value.45.05.12.01
       MFI General Fatigue
      MBSR16.0 ± 2.814.9 ± 3.613.6 ± 3.416.3 ± 2.714.7 ± 3.213.6 ± 3.4
      TAU15.5 ± 3.215.5 ± 2.915.3 ± 3.615.5 ± 3.215.5 ± 2.915.3 ± 3.6
      Effect size*0.180.320.250.33
      P value.27.03.13.02
       CFQ
      MBSR59.6 ± 16.546.9 ± 18.146.6 ± 15.459.3 ± 16.158.3 ± 17.744.1 ± 14.8
      TAU58.3 ± 18.758.6 ± 18.161.9 ± 18.658.3 ± 18.758.6 ± 18.161.9 ± 18.6
      Effect size*0.440.400.640.49
      P value.002<.001<.001<.001
      Secondary Outcomes
       PSS-I
      MBSR29.0 ± 11.220.7 ± 9.121.7 ± 10.828.3 ± 12.119.1 ± 9.120.4 ± 11.5
      TAU26.2 ± 10.624.7 ± 10.223.6 ± 10.726.2 ± 10.624.7 ± 10.223.6 ± 10.7
      Effect size*0.400.270.550.37
      P value.004.08.001.02
       PHQ-9
      MBSR14.4 ± 5.510.2 ± 6.29.5 ± 4.714.5 ± 5.49.2 ± 5.68.9 ± 4.8
      TAU12.8 ± 5.212.4 ± 6.712.3 ± 6.812.8 ± 5.212.4 ± 6.712.3 ± 6.8
      Effect size*0.220.270.310.38
      P value.05.03.01.01
       PROMIS fatigue
      MBSR62.2 ± 5.456.0 ± 8.657.5 ± 9.662.4 ± 5.055.3 ± 9.058.0 ± 10.0
      TAU62.1 ± 8.861.5 ± 9.362.0 ± 10.062.1 ± 8.861.5 ± 9.362.0 ± 10.0
      Effect size*0.350.260.430.23
      P value.02.05.008.07
       FFMQ
      MBSR115.8 ± 17.3126.5 ± 22.7129.4 ± 22.4116.9 ± 18.0129.7 ± 23.3131.3 ± 20.9
      TAU115.1 ± 16.3115.0 ± 15.1114.6 ± 19.6115.1 ± 16.3115.0 ± 15.1114.6 ± 19.6
      Effect size*0.280.380.300.48
      P value.046.005.03.003
      *Cohen's f 0 .10 small; 0.25 medium; 0.40 large.
      Bolded values are statistically significant.
      CFQ = Cognitive Failures Questionnaire; FFMQ = Five Facet Mindfulness Questionnaire; MBSR = mindfulness-based stress reduction; MFI = Multidimensional Fatigue Inventory; MPQ-2 = McGill Pain Questionnaire 2; PHQ-9 = Patient Health Questionnaire-9; PROMIS = Patient Reported Outcomes Measurement Information System; PSS-I = PTSD Symptom Score Interview; SD = standard deviation; TAU = treatment as usual.
      Figure thumbnail gr2
      Figure 2Outcomes over time for mindfulness-based stress reduction compared with treatment as usual for veterans with Gulf War illness (intention-to-treat analyses). CFQ = Cognitive Failures Questionnaire; MFI = Multidimensional Fatigue Inventory; MPQ-2 = McGill Pain Questionnaire 2; PHQ-9 = Patient Health Questionnaire; PSS-I = PTSD Symptom Scale Interview; PTSD = posttraumatic stress disorder. *P ≤ .05, **P ≤ .01 for significance of group × time interaction.

      Secondary Outcomes

      Depressive symptoms showed a greater decline for those randomized to mindfulness-based stress reduction at immediate post-test and at 6 months with a medium effect size: f = 0.22 (P = .050) and f = 0.27 (P = .031), respectively. The National Institutes of Health Patient Reported Outcomes Measurement Information System fatigue measure showed greater reductions for veterans randomized to mindfulness-based stress reduction at both immediate post-test (f = 0.35; P = .015) and at 6 months (f = 0.26; P = .047) relative to treatment as usual only. Veterans randomized to mindfulness-based stress reduction demonstrated a greater increase in mindfulness skills, with a medium to large effect size at immediate post-test (f = 0.28; P = .046) and at 6 months (f = 0.38; P = .005) relative to treatment as usual only.
      Because posttraumatic stress disorder is frequently comorbid with Gulf War illness,
      • Baker D.G.
      • Mendenhall C.L.
      • Simbartl L.A.
      • et al.
      Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans.
      • Proctor S.P.
      • Heeren T.
      • White R.F.
      • et al.
      Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.
      analyses were conducted on the subset of veterans who met symptom criteria for posttraumatic stress disorder at baseline (n = 45).
      • Foa E.B.
      • Riggs D.S.
      • Dancu C.V.
      • et al.
      Reliability and validity of a brief instrument for assessing posttraumatic stress disorder.
      For veterans with posttraumatic stress disorder at baseline who were randomized to mindfulness-based stress reduction plus treatment as usual, there were greater reductions in symptoms of posttraumatic stress disorder at the immediate post-test (with a large effect size, f = 0.44; P = .005), whereas at 6 months there was a trend toward greater reduction in posttraumatic stress disorder symptoms (f = 0.31; P = .082) compared with treatment as usual only.

      Completer Analyses

      Veterans randomized to mindfulness-based stress reduction who attended at least 4 classes (completers) were compared with veterans randomized to treatment as usual (Table 3). Analyses of primary outcome measures were similar to the intention-to-treat results. For secondary outcomes, mindfulness-based stress reduction completer results were similar to those of intention-to-treat analyses. For the National Institutes of Health Patient Reported Outcomes Measurement Information System fatigue measure, compared with usual care, mindfulness-based stress reduction completers reported greater reductions in fatigue at the post–mindfulness-based stress reduction time point (f = 0.43; P = .008), whereas at 6 months there was a trend toward significance (f = 0.23; P = .073).

      Discussion

      In this small trial, we found that veterans with Gulf War illness randomized to mindfulness-based stress reduction plus treatment as usual had significantly greater improvements, compared with treatment as usual alone, on the primary outcome measures of pain, fatigue, and cognitive failures when assessed 6 months after the intervention. We also found improvement in key secondary outcomes for those randomized to mindfulness-based stress reduction, including symptoms of posttraumatic stress disorder (among veterans who met diagnostic criteria for posttraumatic stress disorder at baseline), which improved at immediate post-test in intention-to-treat analyses but diminished somewhat at 6-month follow-up. At both follow-up time points, we found that veterans with Gulf War illness randomized to mindfulness-based stress reduction demonstrated increased mindfulness skills, with large effect sizes, suggesting that they learned the skills intended by the intervention. Overall, this study provides initial evidence to support offering mindfulness-based stress reduction as an intervention for Gulf War illness presenting as chronic multisymptom illness.
      Outcomes of a mindfulness-based intervention have not been previously reported for Gulf War illness. However, our findings are consistent with studies of mindfulness-based interventions on symptoms that occur as a component of Gulf War illness.
      • Lakhan S.E.
      • Schofield K.L.
      Mindfulness-based therapies in the treatment of somatization disorders: a systematic review and meta-analysis.
      For fatigue, evidence suggests that mindfulness-based interventions are associated with improvement in chronic fatigue syndrome.
      • Surawy C.
      • Roberts J.
      • Silver A.
      The effect of mindfulness training on mood and measures of fatigue, activity, and quality of life in patients with chronic fatigue syndrome on a hospital waiting list: a series of exploratory studies.
      • Rimes K.A.
      • Wingrove J.
      Mindfulness-based cognitive therapy for people with chronic fatigue syndrome still experiencing excessive fatigue after cognitive behaviour therapy: a pilot randomized study.
      One mechanism by which mindfulness is theorized to influence fatigue is through reappraisal of thoughts and feelings that contribute to fatigue.
      • Surawy C.
      • Roberts J.
      • Silver A.
      The effect of mindfulness training on mood and measures of fatigue, activity, and quality of life in patients with chronic fatigue syndrome on a hospital waiting list: a series of exploratory studies.
      • Rimes K.A.
      • Wingrove J.
      Mindfulness-based cognitive therapy for people with chronic fatigue syndrome still experiencing excessive fatigue after cognitive behaviour therapy: a pilot randomized study.
      For chronic pain, a meta-analysis of mindfulness-based interventions for chronic pain reported significant effects for pain intensity,
      • Veehof M.M.
      • Oskam M.J.
      • Schreurs K.M.G.
      • et al.
      Acceptance-based interventions for the treatment of chronic pain: a systematic review and meta-analysis.
      and a review found reductions in pain intensity in 6 of 8 randomized controlled trials.
      • Reiner K.
      • Tibi L.
      • Lipsitz J.D.
      Do mindfulness-based interventions reduce pain intensity? a critical review of the literature.
      A meta-analysis of mindfulness-based interventions for symptom-based syndromes also found significant benefit when pain outcomes were assessed.
      • Lakhan S.E.
      • Schofield K.L.
      Mindfulness-based therapies in the treatment of somatization disorders: a systematic review and meta-analysis.
      The pain measure used in our study (McGill Pain Questionnaire 2) can be considered a measure of the distress caused by pain.
      • Dworkin R.H.
      • Turk D.C.
      • Farrar J.T.
      • et al.
      Core outcome measures for chronic pain clinical trials: IMMPACT recommendations.
      It has been postulated that mindfulness allows uncoupling of the cognitive and emotional elements from the sensory experience of chronic pain, which could decrease distress or suffering.
      • Kabat-Zinn J.
      An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results.
      Mindfulness practices also may constitute a form of exposure therapy for people with chronic pain.
      • Baer R.A.
      Mindfulness training as a clinical intervention: a conceptual and empirical review.
      • Shapiro S.L.
      • Carlson L.E.
      • Astin J.A.
      • et al.
      Mechanisms of mindfulness.
      In addition, anxiety decreases pain threshold and lowers pain tolerance,
      • Dersh J.
      • Polatin P.B.
      • Gatchel R.J.
      Chronic pain and psychopathology: research findings and theoretical considerations.
      and interventions that reduce anxiety and reactivity could be especially helpful. Gulf War illness also can include changes in concentration and memory, and our study findings are consistent with a small prior literature that shows a negative correlation between measures of mindfulness and cognitive failures.
      • Lau M.A.
      • Bishop S.R.
      • Segal Z.V.
      • et al.
      The Toronto mindfulness scale: development and validation.
      • Cheyne J.A.
      • Carriere J.S.A.
      • Smilek D.
      Absent-mindedness: lapses of conscious awareness and everyday cognitive failures.
      • Herndon F.
      Testing mindfulness with perceptual and cognitive factors: external vs. internal encoding, and the cognitive failures questionnaire.
      Mood disturbances often occur in chronic multisymptom illness,
      The Iowa Persian Gulf Study Group
      Self-reported illness and health status among Gulf War veterans: a population-based study.
      and as in multiple prior studies of mindfulness-based interventions,
      • Hofmann S.G.
      • Sawyer A.T.
      • Witt A.A.
      • et al.
      The effect of mindfulness-based therapy on anxiety and depression: a meta-analytic review.
      • Bohlmeijer E.
      • Prenger R.
      • Taal E.
      • et al.
      The effects of mindfulness-based stress reduction therapy on mental health of adults with a chronic medical disease: a meta-analysis.
      we found improvements in depressive symptoms. One possibility is that the observed changes in the self-reported primary outcomes could be mediated by the changes in depression or anxiety, but this initial study was not designed to test this hypothesis. Of note, our intention-to-treat analyses included 3 veterans randomized to mindfulness-based stress reduction who attended zero classes. Seventy-three percent of veterans randomized to mindfulness-based stress reduction attended at least 4 classes, which is similar to our prior experience with mindfulness-based stress reduction among veterans.
      • Kearney D.J.
      • McDermott K.
      • Malte C.
      • et al.
      Effects of participation in a mindfulness program for veterans with posttraumatic stress disorder (PTSD): a randomized controlled pilot study.
      • Kearney D.J.
      • McDermott K.
      • Malte C.A.
      • et al.
      Association of participation in a mindfulness program with measures of PTSD, depression and quality of life in a veteran sample.
      The apparent acceptability of mindfulness-based stress reduction is consistent with the larger body of literature that shows that veterans use complementary and alternative medicine at high rates.
      • Micek M.A.
      • Bradley K.A.
      • Braddock C.H.
      • et al.
      Complementary and alternative medicine use among veterans affairs outpatients.
      • Baldwin C.M.
      • Long K.
      • Kroesen K.
      • et al.
      A profile of military veterans in the southwestern United States who use complementary and alternative medicine: implications for integrated care.
      The reduction in symptoms of posttraumatic stress disorder found in our study is generally consistent with prior studies of mindfulness-based interventions for posttraumatic stress disorder. Uncontrolled studies have shown improvement in posttraumatic stress disorder symptoms over time after mindfulness-based stress reduction,
      • Kearney D.J.
      • McDermott K.
      • Malte C.A.
      • et al.
      Association of participation in a mindfulness program with measures of PTSD, depression and quality of life in a veteran sample.
      • Kimbrough E.
      • Magyari T.
      • Langenberg P.
      • et al.
      Mindfulness intervention for child abuse survivors.
      as did a small trial that compared mindfulness-based cognitive therapy with usual care.
      • King A.P.
      • Erickson T.M.
      • Giardino N.D.
      • et al.
      A pilot study of group mindfulness-based cognitive therapy (MBCT) for combat veterans with posttraumatic stress disorder (PTSD).
      A recent well-designed randomized controlled trial (N = 116) compared mindfulness-based stress reduction with an active control and found that those randomized to mindfulness-based stress reduction had greater improvement in posttraumatic stress disorder symptom severity, depression, and quality of life at 2-month follow-up.
      • Polusny M.A.
      • Erbes C.R.
      • Thuras P.
      • et al.
      Mindfulness-based stress reduction for posttraumatic stress disorder among veterans: a randomized clinical trial.
      However, a prior small randomized controlled trial (N = 47) compared mindfulness-based stress reduction with usual care for veterans with posttraumatic stress disorder and did not find a significant overall effect on symptoms of posttraumatic stress disorder, although a subset had clinically meaningful improvement in a post hoc analysis.
      • Kearney D.J.
      • McDermott K.
      • Malte C.
      • et al.
      Effects of participation in a mindfulness program for veterans with posttraumatic stress disorder (PTSD): a randomized controlled pilot study.
      The findings of the current study provide additional evidence to indicate that participation in mindfulness-based stress reduction is associated with reductions in symptoms of posttraumatic stress disorder; this supports the need for additional, more definitive trials.
      This study was not intended to address questions or propose theories regarding the cause or causes of Gulf War illness, but rather to focus on the suffering and health concerns currently experienced by this cohort of veterans. The perspective of the study was that serious health conditions such as Gulf War illness, regardless of original cause, involve symptoms and functional impairments that may be amenable to amelioration by learning and practicing mindfulness.

      Study Limitations

      This study has a number of limitations. This was designed as a pilot study; thus, we did not adjust for multiple comparisons, so that we would not miss potential associations that could lead to additional treatments for Gulf War illness.
      • Bender R.
      • Lange S.
      Adjusting for multiple testing—when and how?.
      Although the treatment as usual arm accounts for changes due to regression to the mean, it does not allow conclusions regarding whether changes occurred because of the mechanism conceptualized by the intervention vs nonspecific effects of group participation. An additional limitation is that we did not track change in medication use over the course of the study, such as opiates, which might influence study results. In addition, the reliability statistic for the Multidimensional Fatigue Inventory general fatigue subscale was suboptimal in our data, but we included a well-validated overlapping measure of fatigue (the National Institutes of Health Patient Reported Outcomes Measurement Information System fatigue measure), which showed improvement, supporting a significant effect of mindfulness-based stress reduction on fatigue.

      Conclusions

      The findings in this small trial provide initial support for offering mindfulness-based stress reduction to veterans with Gulf War illness and warrant larger randomized controlled trials of mindfulness-based stress reduction for Gulf War illness.

      Acknowledgments

      This material is based on work supported by the US Department of Veterans Affairs, Office of Research and Development, Clinical R&D Program.

      References

        • Research Advisory Committee on Gulf War Veterans' Illnesses
        Gulf War Illness and the Health of Gulf War Veterans: Scientific Findings and Recommendations.
        US Government Printing Office, Washington, DC2008
        • Fukuda K.
        • Nisenbaum R.
        • Stewart G.
        • et al.
        Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
        JAMA. 1998; 280: 981-988
        • The Iowa Persian Gulf Study Group
        Self-reported illness and health status among Gulf War veterans: a population-based study.
        JAMA. 1997; 277: 238-245
        • Institute of Medicine
        Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined.
        National Academies Press, Washington, DC2014
        • Kroenke K.
        • Price R.K.
        Symptoms in the community. Prevalence, classification and psychiatric comorbidity.
        Arch Intern Med. 1993; 153: 2474-2480
        • Blanchard M.S.
        • Eisen S.A.
        • Alpern R.
        • et al.
        Chronic multisymptom illness complex in Gulf War I veterans 10 years later.
        Am J Epidemiol. 2006; 163: 66-75
      1. Hunt SC. VA Approaches to the management of chronic multi-symptom illness in Gulf War I veterans. Presentation at the Third Committee Meeting, April 12, 2012, Irvine, California, 2012.

        • Baker D.G.
        • Mendenhall C.L.
        • Simbartl L.A.
        • et al.
        Relationship between posttraumatic stress disorder and self-reported physical symptoms in Persian Gulf War veterans.
        Arch Intern Med. 1997; 157: 2076-2078
        • Hunt S.C.
        • Richardson R.D.
        • McFall M.
        Re: The Gulf War syndrome controversy.
        Am J Epidemiol. 1999; 150: 216-217
      2. Research Advisory Committee on Gulf War Veterans Illnesses. 2009-2013.
        U.S. Government Printing Office, Washington, D.C2014
        • Wessely S.
        Ten years on: what do we know about the Gulf War syndrome? King's College Gulf War Research Unit.
        Clin Med. 2001; 1: 28-37
        • Proctor S.P.
        • Heeren T.
        • White R.F.
        • et al.
        Health status of Persian Gulf War veterans: self-reported symptoms, environmental exposures and the effect of stress.
        Int J Epidemiol. 1998; 27: 1000-1010
        • Wolfe J.
        • Proctor S.P.
        • Erickson D.J.
        • et al.
        Relationship of psychiatric status to Gulf War veterans' health problems.
        Psychosom Med. 1999; 61: 532-540
        • Centers for Disease Control and Prevention
        Unexplained illness among Persian Gulf War veterans in an air National Guard unit: preliminary report–August 1990-March 1995.
        JAMA. 1995; 274: 16-17
        • Sartin J.S.
        Gulf War illnesses: causes and controversies.
        Mayo Clin Proc. 2000; 75: 811-819
        • Institute of Medicine
        Gulf War and Health Volume 4: Health Effects of Serving in the Gulf War.
        The National Academies Press, Washington, DC2006
        • Institute of Medicine
        Gulf War and Health Volume 8: Update of Health Effects of Serving in the Gulf War.
        The National Academies Press, Washington, DC2010
        • Hyams K.C.
        • Wignall F.S.
        • Roswell R.
        War syndromes and their evaluation: from the US Civil War to the Persian Gulf War.
        Ann Intern Med. 1996; 125: 398-405
        • Ozakinci G.
        • Hallman W.K.
        • Kipen H.M.
        Persistence of symptoms in veterans of the First Gulf War: 5-year follow-up.
        Environ Health Perspect. 2006; 114: 1553-1557
        • Smith B.N.
        • Wang J.M.
        • Vogt D.
        • et al.
        Gulf War illness symptomatology among veterans 10 years after deployment.
        J Occup Environ Med. 2013; 55: 116-122
        • Li B.
        • Mahan C.M.
        • Kang H.K.
        • et al.
        Longitudinal health study of US 1991 Gulf War veterans: changes in health status at 10-year follow-up.
        Am J Epidemiol. 2011; 174: 761-768
        • Hunt S.C.
        • Richardson R.D.
        • Engel C.C.
        Clinical management of Gulf War veterans with medically unexplained physical symptoms.
        Mil Med. 2002; 167: 414-420
        • Engel C.C.
        • Roy M.
        • Kayanan D.
        • et al.
        Multidisciplinary treatment of persistent symptoms after Gulf War service.
        Mil Med. 1998; 163: 202-208
        • Donta S.T.
        • Clauw D.J.
        • Engel Jr., C.C.
        • et al.
        Cognitive behavioral therapy and aerobic exercise for Gulf War veterans' illnesses: a randomized controlled trial.
        JAMA. 2003; 289: 1396-1404
        • Reiner K.
        • Tibi L.
        • Lipsitz J.D.
        Do mindfulness-based interventions reduce pain intensity? a critical review of the literature.
        Pain Med. 2013; 14: 230-242
        • Lakhan S.E.
        • Schofield K.L.
        Mindfulness-based therapies in the treatment of somatization disorders: a systematic review and meta-analysis.
        PLoS One. 2013; 8: e71834
        • Veehof M.M.
        • Oskam M.J.
        • Schreurs K.M.G.
        • et al.
        Acceptance-based interventions for the treatment of chronic pain: a systematic review and meta-analysis.
        Pain. 2011; 152: 533-542
        • Kabat-Zinn J.
        Commentary on Majumdar, et al.: Mindfulness meditation for health.
        J Altern Complement Med. 2002; 8: 731-735
        • Siegel D.J.
        The Mindful Brain: Reflection and Attunement in the Cultivation of Well-being.
        W.W. Norton & Company, Inc, New York, NY2007
        • Baer R.A.
        Mindfulness training as a clinical intervention: a conceptual and empirical review.
        Clin Psychol Sci Prac. 2003; 10: 125-143
        • Hofmann S.G.
        • Sawyer A.T.
        • Witt A.A.
        • et al.
        The effect of mindfulness-based therapy on anxiety and depression: a meta-analytic review.
        J Consult Clin Psychol. 2010; 78: 169-183
        • Bohlmeijer E.
        • Prenger R.
        • Taal E.
        • et al.
        The effects of mindfulness-based stress reduction therapy on mental health of adults with a chronic medical disease: a meta-analysis.
        J Psychosom Res. 2010; 68: 539-544
        • Surawy C.
        • Roberts J.
        • Silver A.
        The effect of mindfulness training on mood and measures of fatigue, activity, and quality of life in patients with chronic fatigue syndrome on a hospital waiting list: a series of exploratory studies.
        Behav Cogn Psychother. 2005; 33: 103-109
        • Chiesa A.
        • Calati R.
        • Serretti A.
        Does mindfulness training improve cognitive abilities? A systematic review of neuropsychological findings.
        Clin Psychol Rev. 2011; 31: 449-464
        • Williams J.M.
        • Teasdale J.D.
        • Segal Z.V.
        • et al.
        Mindfulness-based cognitive therapy reduces overgeneral autobiographical memory in formerly depressed patients.
        J Abnorm Psychol. 2000; 109: 150-155
        • Hom J.
        • Haley R.W.
        • Kurt T.L.
        Neuropsychological correlates of Gulf War Syndrome.
        Arch Clin Neuropsychol. 1997; 12: 531-544
        • Lange G.
        • Tiersky L.A.
        • DeLuca J.
        • et al.
        Cognitive functioning in Gulf War illness.
        J Clin Exp Neuropsychol. 2001; 23: 240-249
        • Sullivan K.
        • Krengel M.
        • Proctor S.P.
        • et al.
        Cognitive functioning in treatment-seeking Gulf War veterans: Pyridostigmine bromide use and PTSD.
        J Psychopathol Behav Assess. 2003; 25: 95-103
        • First M.B.
        • Spitzer R.L.
        • Gibbon M.
        • et al.
        Structured Clinical Interview for DSM-IV® Axis I Disorders, Clinician Version (SCID-CV), Administration Booklet.
        American Psychiatric Press Inc, Washington, DC1996
        • Dworkin R.H.
        • Turk D.C.
        • Revicki D.A.
        • et al.
        Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2).
        Pain. 2009; 144: 35-42
        • Lovejoy T.I.
        • Turk D.C.
        • Morasco B.J.
        Evaluation of the psychometric properties of the revised Short-Form McGill Pain Questionnaire.
        J Pain. 2012; 13: 1250-1257
        • Smets E.M.A.
        • Garssen B.
        • Bonke B.
        • et al.
        The multidimensional fatigue inventory (MFI) psychometric qualities of an instrument to assess fatigue.
        J Psychosom Res. 1995; 39: 315-325
        • Thombs B.
        • Bassel M.
        • McGuire L.
        • et al.
        A systematic comparison of fatigue levels in systemic sclerosis with general population, cancer and rheumatic disease samples.
        Rheumatology. 2008; 47: 1559-1563
        • Broadbent D.E.
        • Cooper P.F.
        • Fitzgerald P.
        • et al.
        The cognitive failures questionnaire (CFQ) and its correlates.
        Br J Clin Psychol. 1982; 21: 1-16
        • Foa E.B.
        • Riggs D.S.
        • Dancu C.V.
        • et al.
        Reliability and validity of a brief instrument for assessing posttraumatic stress disorder.
        J Trauma Stress. 1993; 6: 459-473
        • Kroenke K.
        • Spitzer R.L.
        • Williams J.B.
        The PHQ-9: validity of a brief depression severity measure.
        J Gen Intern Med. 2001; 16: 606-613
        • Cella D.
        • Yount S.
        • Rothrock N.
        • et al.
        The Patient-Reported Outcomes Measurement Information System (PROMIS) progress of an NIH roadmap cooperative group during its first two years.
        Med Care. 2007; 45: S3-S11
      3. Lai JS, Chen WH. Fatigue archival analysis report, 2006. Available at: http://www.nihpromis.org. Accessed November 19, 2015.

        • Baer R.A.
        • Smith G.T.
        • Lykins E.
        • et al.
        Construct validity of the five facet mindfulness questionnaire in meditating and nonmeditating samples.
        Assessment. 2008; 15: 329-342
        • Blake D.D.
        • Weathers F.W.
        • Nagy L.M.
        • et al.
        The development of a clinician-administered PTSD scale.
        J Trauma Stress. 1995; 8: 75-90
      4. King DW, King LA, Vogt DS, Knight J, Samper RE. Deployment risk and resilience inventory (DRRI): a collection of measures for studying deployment-related experiences of military personnel and veterans, Military Psychology, 18, 2006, 89–120.

        • Kabat-Zinn J.
        Full Catastrophe Living. Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness.
        Bantam Doubleday Dell Publishing, New York1990
        • Santorelli S.
        • Kabat-Zinn J.
        Mindfulness-based stress reduction professional training: MBSR curriculum guide and supporting materials.
        University of Massachusetts Medical School, Worcester2002
        • Kabat-Zinn J.
        • University of Massachusetts Medical Center/Worcester
        Stress Reduction Clinic. Full Catastrophe Living: Using the Wisdom of Your Body and Mind to Face Stress, Pain, and Illness.
        Delta Trade Paperbacks, New York, NY2005
        • Teasdale J.D.
        • Segal Z.V.
        • Williams J.M.G.
        • et al.
        Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy.
        J Consult Clin Psychol. 2000; 68: 615-623
        • Bender R.
        • Lange S.
        Adjusting for multiple testing—when and how?.
        J Clin Epidemiol. 2001; 54: 343-349
        • Rimes K.A.
        • Wingrove J.
        Mindfulness-based cognitive therapy for people with chronic fatigue syndrome still experiencing excessive fatigue after cognitive behaviour therapy: a pilot randomized study.
        Clin Psychol Psychother. 2013; 20: 107-117
        • Dworkin R.H.
        • Turk D.C.
        • Farrar J.T.
        • et al.
        Core outcome measures for chronic pain clinical trials: IMMPACT recommendations.
        Pain. 2005; 113: 9-19
        • Kabat-Zinn J.
        An outpatient program in behavioral medicine for chronic pain patients based on the practice of mindfulness meditation: theoretical considerations and preliminary results.
        Gen Hosp Psychiatry. 1982; 4: 33-47
        • Shapiro S.L.
        • Carlson L.E.
        • Astin J.A.
        • et al.
        Mechanisms of mindfulness.
        J Clin Psychol. 2006; 62: 373-386
        • Dersh J.
        • Polatin P.B.
        • Gatchel R.J.
        Chronic pain and psychopathology: research findings and theoretical considerations.
        Psychosom Med. 2002; 64: 773-786
        • Lau M.A.
        • Bishop S.R.
        • Segal Z.V.
        • et al.
        The Toronto mindfulness scale: development and validation.
        J Clin Psychol. 2006; 62: 1445-1467
        • Cheyne J.A.
        • Carriere J.S.A.
        • Smilek D.
        Absent-mindedness: lapses of conscious awareness and everyday cognitive failures.
        Conscious Cogn. 2006; 15: 578-592
        • Herndon F.
        Testing mindfulness with perceptual and cognitive factors: external vs. internal encoding, and the cognitive failures questionnaire.
        Pers Individ Dif. 2008; 44: 32-41
        • Kearney D.J.
        • McDermott K.
        • Malte C.
        • et al.
        Effects of participation in a mindfulness program for veterans with posttraumatic stress disorder (PTSD): a randomized controlled pilot study.
        J Clin Psychol. 2012; 69: 14-27
        • Kearney D.J.
        • McDermott K.
        • Malte C.A.
        • et al.
        Association of participation in a mindfulness program with measures of PTSD, depression and quality of life in a veteran sample.
        J Clin Psychol. 2012; 68: 101-116
        • Micek M.A.
        • Bradley K.A.
        • Braddock C.H.
        • et al.
        Complementary and alternative medicine use among veterans affairs outpatients.
        J Altern Complement Med. 2007; 13: 190-193
        • Baldwin C.M.
        • Long K.
        • Kroesen K.
        • et al.
        A profile of military veterans in the southwestern United States who use complementary and alternative medicine: implications for integrated care.
        Arch Intern Med. 2002; 162: 1697-1704
        • Kimbrough E.
        • Magyari T.
        • Langenberg P.
        • et al.
        Mindfulness intervention for child abuse survivors.
        J Clin Psychol. 2010; 66: 17-33
        • King A.P.
        • Erickson T.M.
        • Giardino N.D.
        • et al.
        A pilot study of group mindfulness-based cognitive therapy (MBCT) for combat veterans with posttraumatic stress disorder (PTSD).
        Depress Anxiety. 2013; 30: 638-645
        • Polusny M.A.
        • Erbes C.R.
        • Thuras P.
        • et al.
        Mindfulness-based stress reduction for posttraumatic stress disorder among veterans: a randomized clinical trial.
        JAMA. 2015; 314: 456-465