A new behavioral technique for home symptom management in fibromyalgia
Specific Aims
The long-term objective of this proposal is to develop a brief, effective, and low risk non-pharmacological
intervention for the high prevalence condition of fibromyalgia [58] in order to empower patients to better
manage debilitating symptoms. The intervention, as developed by the applicant, is a behavioral technique
termed “bilateral stimulation and desensitization” (BSD). Its core element is bilateral sensory stimulation
delivered with alternating sounds or finger taps (Friedberg, 2001, 2004). The technique is derived from the
psychotherapeutic protocol of Eye Movement Desensitization and Reprocessing (EMDR; Shapiro, 1995)
whose main application is to treat post-traumatic stress. The proposed study is intended to establish the initial
efficacy of BSD as a symptom management technique for fibromyalgia in a randomized trial. The impact of the
findings on pain intervention research would be to substantively advance the development of a new, low effort
and minimal risk technique for symptom management in fibromyalgia.
Specific Aim 1. To test the efficacy of a new home-based behavioral technique, BSD, for the reduction of
clinically significant pain and pain perception (catastrophizing) in patients with fibromyalgia.
Hypothesis 1: BSD, in comparison to a symptom monitoring attention control condition, will be
associated with medium effect sizes and significant reductions in pain and pain perception (catastrophizing) in
fibromyalgia patients at 3- and 12- month follow-up assessments.
Hypothesis 2: BSD, in comparison to a usual care/no treatment control condition, will be associated with
medium effect sizes and significant reductions in pain and pain perception in fibromyalgia patients at 3-and 12month follow-up assessments.
The 2 control groups are intended to control for (i) participants’ time spent doing the active intervention
(attention control) and (ii) passage of time during the study period (usual care) (Friedberg et al; 2013).
Specific Aim 2: To prospectively test a biobehavioral mediation model for the effects of BSD in patients with
fibromyalgia.
Hypothesis 1: The effects of BSD on pain reduction will be mediated by improved parasympathetic activity
and autonomic balance as measured with heart rate variability.
Hypothesis 2: The effects of BSD on pain reduction will be mediated by increased relaxation, distraction,
and cognitive change as assessed with online diary based self-report measures.
Hypothesis 3: Changes in the adjusted direct effect of BSD is reduced when controlled for the indirect
effects of heart rate variability and/or behavioral change.
Specific Aim 3. To assess compliance with weekly assignments and its relation to implementation of BSDrelated symptom management skills.
Hypothesis 1: Online web diary compliance rates (50% average rate of daily completion per subject
anticipated) will be sufficient to assess symptom ratings and their weekly patterns, and usage of specific BSD
techniques over the three month intervention period. Compliance will be associated with improved outcomes,
i.e., BSD dose-response relationships will be tested.
Hypothesis 2: Success of specific BSD techniques will be confirmed with web diary data and in phone
interviews with each participant. Phone interviews will elicit participant preferences and feedback that will
further refine the delivery of the intervention to increase compliance and better target fibromyalgia symptoms.
Exploratory aim: to assess effect sizes for the clinical outcome of pain in order to do a power calculation for a
large follow-up randomized field trial. This home-based program will be set up on a dedicated website
consisting of a BSD demonstration video (also on DVD), a downloadable BSD self-management booklet, a
MP3 audio sounds BSD technique, and an online diary to record pain and stress symptoms and BSD usage.
The proposed research addresses a key area in the NINR’s Strategic Plan: “To improve quality of life by…
management of pervasive symptoms such as pain.[and to] improve knowledge of biological mechanisms.”
This proposal also responds to PA-13-118: “Pain management should engage interdisciplinary teams…with
randomized trials to reduce pain …customized to the group (i.e., targeted), and to the individual (i.e., tailored).”
Finally, BSD represents a potentially new technology to deliver effective pain management to patients with
debilitating pain. The use of BSD for rapid symptom reduction also challenges the current paradigm of
behavioral treatment delivery that requires multiple face to face sessions with a trained interventionist. The
advantage of BSD over face-to-face therapy for fibromyalgia is based on its brevity, entirely home-based
protocol, and potentially greater efficacy for pain reduction. If this initial randomized trial is efficacious, a large
scale follow-up field trial will be proposed to assess the potential of highly usable BSD-based symptom
management to be adapted into medical care.
Significance
Fibromyalgia is an increasingly recognized, but medically underserved, chronic widespread pain condition
(Jensen et al; 2012). It is estimated to affect 1.3–4.8% of the population, of which 80% are women [58].
In a population study of 13 chronic conditions9, FM exhibited the second highest level (after post-stroke
effects) of impact with respect to: pain-related activity limitations, fair-poor self-rated health, and four or more
GP visits in the last year. Newer FDA approved pharmacological treatments for FM have shown clinically
relevant pain reduction for about 40%, but with frequent adverse effects (4, 16;Wiffen etal; 2013). The most
studied non-pharmacological treatment, aerobic exercise (Bidonde et al; 2014; Hauser et al; 2010) can
improve physical functioning if not pain, but is associated with low adherence and high attrition in -15.
(Bernardy et al; 2013. . 4,16
Current treatments for FM. CBT for FM17 (Giles, 2014; bernardy et al;; 2013) is effective in slightly reducing
the symptoms of fibromyalgia, but is time-consuming as it requires an average of six months of face-to-face
treatment (18, 19). Also CBT is costly and not available to many patients.20 More recent internet-based CBTbased programs in FM (e.g., Williams et al; 2010) may be more accessible, but these interventions are still
potentially burdensome as they involve learning multiple cognitive and behavioral skills. The potentially
negative impact of high subject burden in fibromyalgia patients was suggested by the findings of a recent
controlled study (Solberg et al; 2010) which found that fibromyalgia patients showed significantly less capacity
to persist on consecutive tasks in comparison to healthy controls. In sum, pain and related limitations in FM
continue to pose a significant unmet medical need for millions of patients.10
New intervention. As developed by the applicant (Friedberg, 2001), the proposed symptom management
intervention of BSD is a rapidly acting, low cost and entirely home-based approach to pain management that
offers hope and help to patients with FM. Its advantage over cognitive behavior therapy (CBT; e.g., Friedberg
et al; 2012) is based on its brevity (5-10 min. at home vs. 45 min. in-person visits), its entirely self-administered
protocol, and its potentially greater efficacy for pain reduction and management. The intervention is derived
from EMDR (eye movement desensitization and reprocessing) which encompasses an 8 stage
psychotherapeutic protocol (Shapiro, 1995). Seven literature reviews21-27(listed by number in references)
concluded that EMDR showed efficacy for post-traumatic stress disorder (PTSD), its main application.
In contrast to the standard EMDR protocol for PTSD which involves evocation of traumatic memories by
trained therapists in face-to-face visits (Shapiro, 1995), BSD is a re-purposed, reformulated, and downsized
intervention technique that focuses on management of specific symptoms (Friedberg, 2001; 2004). The field of
pain treatment will be significantly enhanced if the new BSD symptom management protocol is effective
because it offers a technique that is easy-to-use, minimal risk, and much more accessible for fibromyalgia
patients in (and out) of medical care in comparison to standard behavioral interventions.
Biobehavioral mechanisms. Scientific knowledge of biobehavioral mechanisms and mediators of BSD-based
symptom management and its therapeutic effects on FM will also be advanced in this proposal. As a proposed
variant of systematic desensitization (Tallis et al; 1994), BSD uses dual attention bilateral stimulation (i.e.,
alternating sounds or hand taps) in combination with brief pain exposures (Friedberg, 2001, 2004). In this
proposal, such dual attention sensory stimulation, if focused on pain, is hypothesized to trigger painincompatible responses (i.e., relaxation, distraction, cognitive change; see Feasibility Studies below) and
associated autonomic de-arousal that desensitizes the impact of pain-related sensations in FM (Friedberg,
2001; 2004). The consequent psychophysiological de-arousal facilitates the integration of corrective
information about the meaning of pain symptoms and responses (Hekmat et al; 1994) resulting in reduced
levels of sensory pain and pain perception (i.e., catastrophizing). Supportive studies using bilateral stimulation
procedures in trauma patients (Elofsson et al; 2008; Wilson et al; 1996) have found post-stimulation
physiological evidence for autonomic de-arousal including decreased heart rate, reduced skin conductance,
and increased finger temperature. Furthermore, a non-clinical controlled study (Barrowcliff et al; 2003) found
that physiological arousal caused by white noise and measured with skin conductance was significantly
reduced with bilateral stimulation techniques in comparison to a control condition. These findings suggest rapid
within-session autonomic de-arousal during BSD consistent with a desensitization model that is potentially
applicable to pain in patients with FM.
Mediation via autonomic de-arousal. To assess autonomic de-arousal, we will incorporate the measure of heart
rate variability (HRV) utilizing a research-grade multifunction wristwatch monitor with data storage capability
(eMotion Faros 360; three channel ECG; MegaElectronics, Kuopio, Finland). HRV has been utilized in
research studies as a surrogate measure of central autonomic influences (Petzke and Clauw, 2000).
Fluctuations over time in the interval between normal heartbeats are mediated by autonomic inputs to the sinus
node, and thus provide a window onto the autonomic system. These fluctuations can be quantified and
analyzed in either the time or frequency domain (Petzke and Clauw, 2000). High HRV reflects the magnitude of
parasympathetic nervous system (PNS) influence on heart rate associated with breathing, with PNS influence
carried to the heart via the vagus nerve. Research suggests that high HRV has a protective effect and is
associated with good health (Karemager & Lie, 2000) and well-being (Kemp & Quintana, 2013).
In the proposed study, we hypothesize that improved parasympathetic functioning, as indicated by
increased HRV, will be a mediator of pain reduction in FM. In support of this hypothesis, a pilot study of a 10session HRV biofeedback intervention in fibromyalgia (Hassett et al., 2007) found clinically significant
decreases in pain and improvement in functioning at 3 month follow-up. Also, HRV increased during
biofeedback tasks. Positive HRV effects were immediate which is consistent with data on the relationships
among stress, HPA axis activity (the other arm of the stress system in addition to the ANS; Marques et al;
2010) and brain function (e.g., Annerstadt et al., 2013). The immediate HRV effect is also consistent with rapid
symptomatic reduction associated with the use of BSD for symptom management. Furthermore, in a recent
pilot study (Berry et al., 2014) of a 4-session HRV biofeedback treatment in veterans with chronic pain, the
intervention was significantly more effective than a chronic pain control condition in increasing HRV coherence
(power in the upper range of the low frequency band) and in reducing perceived pain, stress, and physical
activity limitation. It has been suggested that changes in HRV could serve as an objective measure of efficacy
for behavioral interventions (Moustafi et al., 2011).
Finally, fibromyalgia patients in comparison to arthritis patients and healthy controls have reported
significantly higher scores on a validated self-report instrument (COMPASS; Methods) for assessment of
autonomic symptoms that provides clinically relevant scores of autonomic symptom severity (Solano et al;
2009). This suggests that autonomic dysfunction may play an important role in the manifestation of FM and
potentially in the mediation of treatment effects.
Innovation
The proposed clinical trial would be the first well-controlled BSD application for symptom management in
FM. The study rationale seeks to shift both research and clinical practice paradigms of behavioral treatment
that usually involve high costs, multi-session face to face visits with a trained professional and relatively high
patient burden. The advantage of BSD over multi-session in-person cognitive-behavior therapy (CBT) [27] for
chronic pain conditions such as fibromyalgia is based on its brevity, entirely home-based protocol, and
potentially greater efficacy for pain reduction. Furthermore, CBT is time-consuming (6-18 visits; [88]) and not
available to many patients [89]. Many communities simply do not have interventionists trained to deliver
behavioral symptom management interventions; thus obtaining such care poses a significant and sometimes
prohibitive travel burden. Recent internet-based CBT may offer increased accessibility, but these programs for
FM remain burdensome as they require learning and scheduling of multiple techniques (e.g., cognitive
restructuring, graded exercise, pacing [10]). By comparison, the rapid results and minimal time investment for
the stand-alone technique of BSD shows promise to reduce pain and improve pain management without the
requirement of learning and carrying out numerous lifestyle changes.
Innovation is also shown in this proposal with our new highly usable delivery technology for pain
management (25-min. BSD demonstration video and MP3 audio device) that replaces the more burdensome
face to face sessions characteristic of behavioral interventions. Our pilot feasibility studies (below) in
fibromyalgia provide supporting qualitative data (direct feedback from patients in interviews) for the advantages
of home-based BSD for symptom management, including high usability, convenience and self-empowerment
to better manage symptoms. Finally, this application proposes a novel and measurable theoretical mechanism
of change in which the rapidly acting behavioral technique of BSD triggers pain-incompatible responses
(relaxation, distraction, and cognitive change) and associated changes in autonomic cardiovascular function
(HRV) that offers an explanatory biobehavioral process to account for reduced pain and improved pain
management [9, 31].
Approach
Preliminary studies. The applicant has conducted 3 feasibility studies of BSD management for pain in
fibromyalgia. These initial studies were intended to verify putative therapeutic effects of BSD and to adjust
clinical protocols to increase compliance, lower dropout rates, and reduce subject burden.
Feasibility study #1. This initial BSD study (Friedberg, 2004) in fibromyalgia (N=6) involved 2 face to face
treatment sessions, wherein patients were taught by the applicant how to do BSD-based symptom
management for home use. The technique was then assigned with log verification for 3 months. At 3 month
follow-up, effect sizes for pain reduction were medium to large with 4/6 subjects considered treatment
responders. In addition, finger temperature measured in session with a thermal sensor was significantly
increased, an indication of autonomic de-arousal and relaxation (Brown, 1977). This pilot study suggested that
brief BSD symptom management can be effectively utilized for pain.
Feasibility study #2. Given the success of study #1 and our goal of reducing subject burden, the second pilot
project eliminated all interventionist contacts and was entirely home-based. During the 3-month study period,
participants (N=24) were sent a BSD instructional booklet and a MP3 player to deliver audio-based BSD.
Participants also completed paper diaries of symptom ratings and BSD usage. Average compliance with the
2x/day diary was 68%, but post-enrollment dropout was 50% -- reportedly due to time constraints, unforeseen
circumstances, and no response. At 3-month follow-up, significant improvements were found for pain severity
(p=.02), pain interference with functioning (p=.004) (Brief Pain Inventory-Short Form) and pain magnification
(Pain Catastrophizing Scale; p = .025). Representative participant comments (n=12) about the use of BSD
included: “now more mindful of pain”; “helps a lot with pain management; “I can be proactive about my pain”.
Transient mild side effects were reported by 21% (N=5) of subjects and included: arm pain, restless legs and
jittery feelings. No subject reported dropping out due to side effects. Qual. feedback
Feasibility study #3. Based on a power analysis of study #2, 29 subjects were recruited and randomized to an
active BSD condition or wait list control condition utilizing a crossover design.With the intention of reducing
attrition in study #3, participant feedback from study #2 resulted in these adjustments: (1) a user-friendly BSD
demonstration video was provided to all subjects and (2) 2x/day paper diaries were replaced by convenient
1x/day online web diaries. Five participants (17.2%) dropped out after enrollment. Completers vs. dropouts did
not differ significantly on any baseline demographic variable. No significant differences on baseline outcome
variables were found between conditions, with the exception of the pain catastrophizing scale (PCS) and the
PCS magnification subscale which showed higher scores in the BSD condition (p = .04 and p = .007,
respectively). The BSD condition evidenced significant reductions on the Pain Catastrophizing Scale (PCS, (t
(24) = -2.24, p = .03; d = .88) and the PCS rumination subscale (t (24) = -2.71, p = .01; d = 1.07) from baseline
to three-month follow-up, in comparison to the wait-list control condition. Within the BSD condition, there was a
significant reduction in PCS rumination subscale (F (1, 24) = 8.43; p = .008; d = .46) and a near-significant
reduction on the full PCS (F (1, 24) = 4.15; p = .053; d = .36). Reductions in pain intensity on the BPI-SF were
not significant (p=.09); however, the effect size was large (d=.94). Significant improvements were also found
on numerical ratings (0-10) for self-reported pain, fatigue, and stress ratings (all p’s < .02) in the BSD
condition.
Conclusion: These 3 feasibility studies represent the deliberative, methodical development (Rouansville et al;
2001) of a new home-based symptom management intervention that shows potential to reduce pain and painrelated catastrophizing in patients with FM.
Methods
The proposed design (Figure 1) is a randomized controlled clinical trial that compares 3 conditions: (1) the
feasibility-tested BSD symptom management protocol; (2) an attention control group of “symptom monitoring”;
and (3) a usual care control condition. The 2 control groups are intended to control for (i) participants’ time
spent doing the active intervention (attention control) and (ii) passage of time during the study period (usual
care) (Friedberg et al; 2013).
The study sequence begins with a recruitment effort utilizing medical records from a large primary care
practice (support letters attached) that identifies patients with a diagnosis of FM, all of whom will be sent a
letter signed by the PI and practice medical director inviting them to participate in the study. In addition,
recruitment will involve internet advertising to FM patient organizations (e.g., FM Aware, ProHealth), contacting
FM support groups, and presentations to primary care physicians at Stony Brook University Medical Center.
These recruitment methods were used successfully in the PI’s completed behavioral self-management study
(Friedberg et al; 2013) in chronic fatigue patients (2/3 of subjects obtained from the family medicine patient
database; 1/3 from ads/referrals). Based on these recruitment patterns, roughly 50% of prospective FM
patients would be screened into the study (10/20 month), and 50% of those would agree to participate
(5/month; i.e., 5 subjects x 23 months recruitment = 115). To achieve an endpoint sample of 30 participants/
group based on power calculation (below), the baseline enrollment target will be 115 which assumes 20%
post-enrollment attrition (56, 57). Thus, recruitment targets are expected to be easily met.
For prospective subjects who express interest in the study, eligibility will be confirmed in a brief (Appendix 2)
initial phone interview conducted by the nurse clinician/scientist (58) to screen subjects for (1) access to a home
computer with internet (95.6% of potential subjects in the PI’s prior chronic fatigue study had a home
computer); (2) screening for a confirmatory (or putative) diagnosis of FM in accordance with ACR symptom
criteria (2010; Appendix); and (3) assessment for exclusion criteria (Human Subjects and Appendix) including
psychosis or substance abuse in the two years prior to evaluation (58). Patients are also excluded if: (a)
receiving antidepressant drugs (unless dose-stabilized for at least three months); b) at risk of suicide or in need
of urgent psychiatric treatment. Appropriate medical and psychiatric referrals will be given as needed. In
addition to subjects who have a diagnosis of FM on their medical record, we will request from subjects not
recruited through their medical records a written diagnosis of FM from their physician. Participants that screen
in with FM symptoms (e.g., clinically significant widespread pain) will have this assessment confirmed with
validated self-report measures of pain (Widespread Pain Index; below).
Following fully informed and documented written consent from participants, the baseline assessment will be
completed, which includes mailed questionnaires, online web diaries, and HRV physiological monitoring, all
fully explained in written and verbal instructions. Subjects will then be assigned by the statistician to one of the
three study conditions via a computer-generated blocked randomization schedule (obtained before enrollment
of the first participant). This will be followed by a 90 day period of home-based implementation of the BSD
condition and the symptom monitoring attention control condition with daily web diary verification (assessments
only for usual care control condition). Participants who begin a new non-study treatment (60, 61) (Treatment
Questionnaire; Appendix 2) after enrollment will be included in the overall data analysis if neither baseline nor
outcome assessments show significant differences.
Potential participants
assessed for eligibility
Enrollment
Excluded (n = )
Declined (n = )
Randomized
34 Allocated to EMDR
Post-treatment
assessment (n = )
3-Month Follow-Up
assessment (n = 25
33 allocated to Attention Control
33 Allocated to Usual Care
control
Post-treatment
assessment (n = )
3-Month Follow-Up
assessment (n =25)
Figure 1. BSD Self-management Study Flow Chart
Study variables
Table 1. Questionnaires/diary assessments
Measures
Baseline Assessments
Widespread Pain Index
Fatigue Scale
Short Form-36 Physical Function subscale (SF-36PF)
Beck Anxiety Index (BAI)
Composite Autonomic Symptom Score 31 (COMPASS)
Primary Outcome Measure
Brief Pain Inventory-Short Form
Secondary Outcome Measures
The Pain Catastrophizing Scale (PCS)
Domain
musculoskelatal pain
physical and mental fatigue
physical functioning
anxiety
autonomic symptoms
pain intensity and interference
catastrophic thinking
Anxiety
Autonomic functioning
Biobehavioral Mediation
Heart rate variability
Web diary
Autonomic functioning
behavioral change
Compliance
Web diary
in vivo symptom ratings/BSD usage
Program Feasibility/Satisfaction
Telephone feedback
Client Satisfaction Questionnaire (CSQ)
program usability
satisfaction with program
Baseline assessments
Widespread Pain Index (Appendix). The WPI is a brief validated self-report measure of chronic widespread
pain that may be used in the diagnosis of fibromyalgia (Wolfe et al; 2010). The cutoff score for clinically
significant widespread pain is a score of 7 or higher. Prospective subjects will be required to meet this
threshold score for study eligibility.
Fatigue Scale(Appendix). The 11-item fatigue scale contains the factorially distinct dimensions of mental and
physical fatigue (Wessely & Powell, 1989; Chalder et al., 1993). The fatigue scale has been validated in
chronic fatigue syndrome and medical outpatients and shows adequate internal consistency (Chalder et al.,
1993). Fatigue is a common symptom in FM (Vincent et al; 2013) and therefore will be evaluated to obtain a more
complete assessment of somatic symptoms in this illness.
Short Form-36 Physical Function subscale (SF-36PF; appendix)). To ascertain physical functioning in
relation to health status at baseline, the SF-36PF will be used. Limitations of ill health are measured on a
scale of 0 (limited in all activities, including basic self-care) to 100 (no limitations, able to carry out
vigorous activities). Test construction studies for the SF-36 (25, 26) have shown high internal consistency
for the physical function subscale (α =.91-.94) and substantial differences in scores between patient
and non-patient populations.
Composite Autonomic Symptom Score 31 (COMPASS 31; Sletten et al; 2012; Appendix). This is a 31 item
self-report instrument, concise and statistically robust, intended to assess autonomic symptoms and provide
clinically relevant scores of autonomic symptom severity. Fibromyalgia patients in comparison to arthritis
patients and healthy controls reported significantly higher scores on the COMPASS (Solano et al; 2009).
Several independent groups of investigators have shown that fibromyalgia patients evidence heart rate
variability changes consistent with sympathetic hyperactivity (Solano et al; 2014). The COMPASS measure is
expected to confirm high levels of autonomic symptoms in our cohort consistent with identified autonomic
dysfunction in fibromyalgia (Reyes del Paso et al; 2010).
Primary outcome measure
Brief Pain Inventory-Short Form (BPI-SF): This is a validated 9 item self-administered questionnaire used to
evaluate the severity of a patient's pain and the impact of this pain on the patient's daily functioning. The
patient is asked to rate their worst, least, average, and current pain intensity, list current treatments and their
perceived effectiveness, and rate the degree that pain interferes with general activity, mood, walking ability,
normal work, relations with other persons, sleep, and enjoyment of life on a 10 point scale (Cleeland, 1989).
The BPI-SF has been found to be sensitive to treatment change in published studies in FM (Arnold et al; 2010;
Jones et al; 2012; Kroenke et al; 2009) and in our pilot BSD studies.
Secondary Outcome Measures
Pain Catastrophizing Scale (PCS). The PCS (Sullivan et al; 1995) is a 13-item instrument that evaluates
catastrophic thinking, a cognitive-affective process, in the dimensions of rumination, magnification, and
helplessness, in relation to pain. The PCS has demonstrated high internal consistency (Cronbach’s α = 0.91),
and high test-retest reliability over a 6 week period (r = 0.75; Thorn et al; 1995). Construct validity of the PCS
has been demonstrated both in experimental cold pressor studies (Thorn et al; 1995) and in clinical patient
samples undergoing painful procedures. The PCS has also shown sensitivity to treatment change (Thorn et al;
2007). The PCS outcome data in our pilot study in fibromyalgia showed a significant positive response to the
BSD intervention. The literature on catastrophizing provides strong evidence that catastrophizing shapes emotional, functional
and physiological responses to pain (Quartana et al; 2009) and that its amelioration contributes to the effectiveness of behavioral pain
treatments (99,100).
Beck Anxiety Inventory (BAI). The BAI is a 21-item self-report measure of anxiety and psychological distress
with high internal consistency (a = .92) and established and replicated construct validity (Hewitt et al; 1993;
Steer et al; 1995). Short-term behavioral intervention for FM in routine care has shown efficacy in reducing
anxiety (Vazquez-Rivera et al; 2009). This assessment of psychological distress may also be associated with HRV
(Moustafi et al., 2011), a measure of autonomic functioning that is proposed to play a role in mediating clinical
change.
Heart Rate Variability (HRV). To assess autonomic de-arousal, we will measure HRV utilizing a research-grade
multifunction wristwatch monitor with data storage capability (eMotion Faros 360; three channel ECG;
MegaElectronics, Kuopio, Finland). The HRV measure uses a convenient three lead ECG (one sensor on left
and right collar bone, one sensor on left hip) instead of a chest strap. This model calculates respiration via
either the built in accelerometer or via algorithm analyzing the ECG signal, a preferable way to control for
respiration. Our expectation is that the HRV measure will show a therapeutic improvement associated with
self-report outcomes of reduced pain. Improvements (i.e., increases) in HRV have been associated with pain
reduction in chronic pain conditions (Hassett et al; 2007; Berry et al; 2014). Also a recent study (Reyes del Paso et al;
2010). of
FM patients in comparison to healthy subjects found a link between autonomic cardiovascular regulation
and pain ratings suggesting autonomic dysfunction in FM. Specifically, FM patients showed lower power in the
High Frequency, Low Frequency, and very-low frequency bands of the HRV spectrum, as well as in total HRV,
indicating overall decreased autonomic control of heart rate.
For all study conditions, a wristwatch device will be worn by participants at home while sitting in a
comfortable chair for 10 minutes ( Hassett et al; 2007; Berry et al; 2014) in the evening preferably between 79pm. HRV data will be collected at these timepoints: the first day of resting baseline, the first day of treatment
termination, and the first day of the 3- and 12-month follow-ups. These time points are intended to be
representative of the intervention period while limiting participant burden.
Measures for Biobehavioral Mediation Model stop
Our biobehavioral mediation model will test the influences of BSD on pain reduction as mediated by an
autonomic indicator (HRV) and behavioral processes (relaxation, distraction, and cognitive change).
Biological measure: Heart Rate Variability (HRV). Specific Aim 2, Hypothesis 1, is intended to determine if
autonomic influences, as measured with HRV, mediate the relationship between the use of BSD and pain
reduction (Hassett et al; 2007; Berry et al; 2014). For the BSD condition only, the HRV wristwatch measure will
be worn before (10 min.), during and after (10 min) the BSD procedures at three time points during the
intervention: initiation (week 1), midpoint (week 6), and termination (week 12). (HRV measurement details
above.) These time points are intended to be representative of the intervention period while limiting participant
burden.
Behavioral measure: Self-report ratings. Specific Aim 2, Hypothesis 2, proposes that the effects of BSD on
pain reduction will be mediated by elevated ratings for distraction, relaxation, and cognitive change as
assessed with self-report measures. Specifically participants in the BSD condition will rate in the online diary
at the end of the day to what extent they experienced the following hypothesized changes during BSD
(Friedberg, 2001) on these items: Distraction: “I couldn’t think about the problem I was focusing on” (0-10);
Relaxation: “I felt more relaxed during the BSD procedure “(0-10); and cognitive change: “I felt better able to
cope with the pain (or other stress) that I was focusing on” (0-10). These ratings will be made at three time
points during the intervention: initiation (week 1), midpoint (week 6), and termination (week 12). These time
points are intended to be representative of the intervention period while limiting participant burden.
Process measure: Web diary
The online web diary will inform the progress of the intervention through daily assessment of symptoms and
BSD usage.
All study conditions. For each one week assessment (baseline; treatment termination, 3- and 12-month followups), a time-stamped web diary (Science Trax; Macon, Georgia) will track average symptom and stress ratings
(0-10 numerical rating scale) at the end of the day. For ratings of pain, pain interference, and stress, responseactivated screens will be displayed, each with a numerical rating scale (0-10). The end point anchors on the
numerical scales will be None (0) and Highest (10).
BSD and attention control conditions only. Daily symptom and stress ratings will be scheduled for the entire 3month intervention period.
BSD condition only. To assess BSD technique(s) used and compliance with BSD assignments, participants will
record at the end of the day: (1) the type of pain used as a BSD target (e.g., neck pain), (2) the BSD
technique(s) used; and (3) behavioral mediation ratings (for distraction, relaxation, and cognitive change
(above)). The PI successfully designed 90-day web diaries in 2 recent CFS behavioral intervention studies
(Friedberg et al; 2013; Friedberg, 2014) to record homework assignments and symptom levels.
Assessment of Program Feasibility/Satisfaction
Program feasibility will be examined with telephone feedback interviews to participants and the Client
Satisfaction Questionnaire.
Feasibility assessment
Participant Feedback by Telephone. To further refine the usability of BSD from our initial feasibility studies
and assess any problems with program implementation (both BSD and symptom monitoring conditions), two
15 minute phone conferences (at the end of weeks 1 and 12) will be held with each participant individually.
Problems will be documented and if necessary program revisions made. The feedback sessions ask subjects
questions about comprehension, interest, relevance, and credibility (62) (Appendix 3) using five point Likert
scale ratings (Shegog et al., 2013). Open-ended participant responses to these items (e.g., what makes the
program credible?) will then be collected as qualitative data.
Client Satisfaction Questionnaire (CSQ). The CSQ, a validated 8 item instrument designed to assess client
satisfaction for human service programs,63 will be administered at the 3-month post-intervention assessment.
The Client Satisfaction Questionnaire (CSQ-8) assesses global client satisfaction with treatments [34]. The 8-item selfreport questionnaire uses scale response options from 1 to 4, with total score ranges from 8 to 32. Previous research has
reported that the CSQ-8 has high internal consistency [35] and was comparable to the Cronbach alpha in this study
(Cronbach alpha=.90). The CSQ has been used to assess participants satisfaction with internet-based cognitive behavior
therapy for deprssion (Donkers et al; 2013) and telephone delivery of psychiatric care (Donke et al; 2002).
Based on the above described telephone feedback and the Client Satisfaction Questionnaire, the PI and
the nurse scientist will jointly assess if receipt of treatment is successful.
Procedure
The study sequence (Figure 3) will involve an initial phone screening by the project director (nurse
clinician/scientist) followed by participant completion and return of: the consent form, baseline questionnaires,
and the HRV monitoring wristwatch device (part of baseline assessment). One week baseline online symptom
diaries are also completed by all subjects. Then group assignments will be made, followed by sending out BSD
pain self-management packages and the HRV wristwatch (for mediation assessment) to the intervention group
only. Following the 3 month intervention period, subjects in all three groups complete and return the 3- and 12month follow-up assessments including: questionnaires, one week web diaries, and HRV monitoring
data/wristwatches. For both BSD and symptom monitoring conditions, two 15 minute phone conferences to
assess feasibility/usability will be held with each participant at the end of weeks 1 and 12. Data analysis will
then be completed.
Recruitment/Enrollment
-Recruitment efforts
-Phone screening
-Referral into study
-Mailed standard
questionnaires/consent
form/HRV wristwatches
(N = 100)
Figure 2. Study Timetable
Baseline/Intervention
-1 week baseline
(questionnaires, web
diaries, HRV wristwatch)
-90 day treatment/HRV/ web
diary
- 90 day control conditions
- Web diaries/HRV monitoring
3- and 12-Month Follow-Up
- 1 week web diaries /HRV
wristwatch
-Mailed standard
questionnaires
__________________________
Feedback phone calls: weeks 1
and 12, treatment and attention
control only
Human subjects: after trial, control subjects offered the BSD
Statistical Plan and Data Analysis; recruited=115 at baseline.
Sample size consideration: Jie; This randomized phase II study has three arms: BSD intervention group,
attention control group and usual care control group. Participants will be randomized at a 1:1:1 ratio to these
three arms. Block randomization with randomly chosen block sizes of 6, 9 and 12 will be used to generate the
randomization sequence. All subjects that are randomized will be included in the intent-to-treat analysis. 33-34
subjects will be enrolled to each of the 3 arms at baseline (total N=100) of which it is anticipated that 75 will
complete the study (25% dropout rate). This sample size has 90% power to detect a Cohen’s d of 0.7 (Cohen’s
d is defined as the difference between two means divided by a standard deviation of the data) for the change in
Brief Pain Inventory-Short Form within each arm using a two-sided paired-t test with Type I error at 0.05. For
example, in our previous BSD trial (feasibility study #2), the standard deviation of the change in pain severity
score after three months’ intervention was 6.5 and the estimated pain severity score change was 5.13 points
drop (N=12). Assuming this study has the same variability, then 25 subjects will allow us to detect a 4.55 points
drop with 90% power in the pain severity score after three months’ intervention. The detection power is very
similar if a two-sided Wilcoxon’s signed-rank test is used instead.
25 participants in each group also has 80% power to detect a moderate Cohen’s d of 0.6 in the change in
scores on the Brief Pain Inventory-Short Form (BPI-SF) between the BSD intervention group and attention
control group (or between BSD intervention group and usual care control group) based on a two-sided t-test
with Type I error of 0.20 (Both type I and type II error are generally relaxed in a randomized Phase II trial. This
sample size allows us to detect a Cohen’s d of 0.9 with 90% power and Type I error at 0.05.). The detection
power is boosted to 81% if an F-test based on one-way ANOVA comparing three groups simultaneously is
used instead. Furthermore, 25 subjects in the BSD group will achieve 84% power to detect a positive
Pearson’s correlation coefficient of 0.5 at a significance level of 0.05. Because of the exploratory? nature of
this study, no adjustment for multiple testing problem was implemented in the power estimation and planned in
the statistical analysis. Power estimation was carried out using PASS 12.
Statistical analysis plan
Standard descriptive and summary statistics will be used to characterize the overall study population.
Graphical methods will be used to examine distributions, identify potential influential points, and guide in data
transformations if warranted. To examine associations among various measures, scatterplots and grouped
boxplots will be produced to examine assumptions of linearity, symmetry, and homoscedascity.
Specific aim 1. Efficacy of BSD pain management. The efficacy of BSD in participants with FM will be tested
using two sided paired-t test or Wilcoxon’s signed rank test if the normality assumption is not met. One-way
ANOVA will be used to compare the change in pain (BPI-SF) among the three groups. If the null hypothesis
that three group means are equal is rejected, Dunnett’s procedure will be further used to compare the BSD
group to each of other two control groups. All assumptions such as normality and linearity will be assessed,
and data transformation may be needed to meet these assumptions. If the model assumption cannot be met,
Kruskal-Wallis test will be used to compare three groups and Wilcoxon’s rank sum test will be used to further
test the difference between the BSD group and any control group.
Clinically significant reductions in pain will also be calculated. To assess clinically significant change (Ogles,
1992; Speer et al; 2001) for pain reduction, a patient will be considered clinically improved if his/her 3- and 12month follow-up post-treatment score is more than two standard deviations below the pre-treatment sample
mean on the Brief Pain Inventory-Short Form, the primary outcome measure for pain.
Specific Aim 2. Mediational Analysis. To prospectively test the biobehavioral mediational model for the effects
of BSD pain management in patients with FM, the analysis plan is as follows: In the initial analysis, pair-wise
bivariate correlations will be calculated between pain, treatment assignment and heart rate variability (HRV).
HRV mediation of BSD effects on pain and the adjusted effect of BSD change after controlling for HRV will be
tested with a series of regression analyses. Due to the limited sample size the Preacher & Hayes Bootstrap
method will be used to assess if there is a significant HRV mediation effect. A similar analysis will be
performed to examine the mediation effect of self-reported changes in relaxation, distraction, and cognitive
change as assessed in the daily web diary.
Specific Aim 3. Compliance and outcomes. The correlation between the change in pain in BSD group and
compliance rate will be assessed through Pearson’s correlation coefficient or Spearman’s rank correlation
coefficient if normality assumption is violated. Due to the small sample size, Wilcoxon’s rank sum test will be
used to compare the pain change between these participants and the rest who cannot successfully use any
EMDR techniques.
Specific Aim 3. To assess compliance with weekly assignments and its relation to implementation of BSDrelated symptom management skills.
Hypothesis 1: Online web diary compliance rates (50% average rate of daily completion per subject
anticipated) will be sufficient to assess symptom ratings and their weekly patterns, and usage of specific BSD
techniques over the three month intervention period. Compliance will be associated with improved outcomes,
i.e., BSD dose-response relationships will be tested.
Hypothesis 2: Success of specific BSD techniques will be confirmed with web diary data and in phone
interviews with each participant. Phone interviews will elicit participant preferences and feedback that will
further refine the delivery of the intervention to increase compliance and better target fibromyalgia symptoms.
Exploratory aim. Effect sizes. Effect sizes for the clinical outcomes of pain (BPI-SF) change in the BSD
group will be estimated. We will explore the relationship between the change in pain scores and clinical and
demographical factors such as baseline pain, gender, age and so on. Data from all three groups will be pooled
in order to get the maximal power. Multiple linear regression models will be used with the change in pain
scores as the dependent variable and each factor of interest along with treatment assignment as the
covariates. Due to limited sample size and the exploratory nature of the analysis, this model may not consider
all of the significant factors simultaneously. All assumptions such as normality and linearity will be assessed,
and data transformation may be needed to meet these assumptions. The analysis results in this exploratory
aim will be valuable in guiding further design of a larger confirmatory phase III trial. All statistical analysis will
be performed using SAS 9.3 (SAS Institute Inc., Cary, NC).
Potential challenges and alternative strategies
Placebo effects. New intervention techniques, in particular, carry the potential to produce strong placebo
responses which may obscure treatment efficacy (Hrobjartsson A. Gotzsche,2010). To effectively address this
type of confounding, we are incorporating two control conditions, one to control for participant attention
involved in the active treatment condition (symptom monitoring attention control) and the second condition to
control for passage of time, i.e., no treatment usual care condition. A previous behavioral self-management
trial in unexplained chronic fatigue (Friedberg et al; 2013) conducted by the applicant using these two control
conditions showed clear superiority of active treatment vs. active and inactive control conditions.
Subject burden. The keeping of daily web diaries and physiological monitoring (HRV) during multiple
assessment periods may engender challenges to participant compliance and retention. Our experience with
daily web diaries and the wearing of actigraphs on the beltline or wrist for one week intervals in two previous
self-management trials in unexplained chronic fatigue and chronic fatigue syndrome (Friedberg et al; 2013;
Friedberg et al; , 2014) has shown compliance levels averaging just under 70% for 90 day web diaries and
about 50% for wearing actigraphs. Given a somewhat lower burden in the proposed study, i.e., 90 day web
diary and wristwatch heart rate monitor (worn for 4-5 hours in total over 90 days), we conservatively estimate
50% daily compliance for both the heart rate monitor and for daily diary data entry which is adequate for
analysis of symptom patterns, BSD usage, and HRV analysis. In addition, participant retention in the entirely
home-based previous trial was a high 92.7% at the 12-month follow-up (Friedberg, 2014).
Heart rate variability (HRV) measurement issues. Although the need to control for respiration during HRV
recordings is a contentious issue, converging evidence indicates that controlling for respiration is not
necessary during resting state recordings (Denver et al., 2007; Thayer et al., 2011). However, respiration
changes during assessment periods may influence HRV (Quintana & Heathers, 2014). Thus, we will adopt
algorithms that can provide appropriate surrogate measures of respiration based on ECG signal
morphology (e.g., Park et al., 2008; Langley et al., 2010). Additionally, differences in the prevailing heart rate
can influence HRV both mathematically, due to the inverse curvilinear relationship between HR and RR
interval (i.e., time between beats; Sacha and Pluta, 2008) and physiologically, via the augmenting or
diminishing effect of the autonomic constituent of HRV (Billman, 2013). Consequently, behavioral interventions
that reduce parasympathetic activation could inflate reductions in HRV via heart rate increases that are
independent of changes in cardiac autonomic nerve activity. Nevertheless, it is possible to mathematically
correct for the influence of the prevailing heart rate on HRV (Sacha, 2013), which may also improve the
reproducibility of HRV (Sacha et al., 2013).
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Ross Shegog,
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Recruitment/Enrollment
-Recruitment
efforts
Follow-Up
-Phone screening
-Referral into study
-Mailed standard
questionnaires/consent form
(N = 100)
Baseline/Intervention
-1 week baseline (web
diaries/HRV wristwatch)
-90 day self-EMDR/HRV msmt.
- 90 day control conditions
-EMDR & attn.cntrl: web diaries
Post-Tx and 3-Month
For each assessment period:
- 1 week web diaries /HRV watch
-Mailed standard questionnaires
____________________________
Feedback phone calls: weeks 1, 6,
12, and 12
Figure 2. Study Timetable
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
Abstract
Reference
adults with depressive symptoms: randomized controlled noninferiority trial.

Donker T; Bennett K; Bennett A; Mackinnon A; van Straten A; Cuijpers P; Christensen H; Griffiths KM.
Complete
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[Journal Article. Randomized Controlled Trial. Research Support, Non-U.S. Gov't]
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UI: 23669884
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Full Text

Authors Full Name
Donker, Tara; Bennett, Kylie; Bennett, Anthony; Mackinnon, Andrew; van Straten, Annemieke; Cuijpers,
Pim; Christensen, Helen; Griffiths, Kathleen M.
My Projects
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