Functional Magnetic Resonance Imaging Evaluation of Auricular Percutaneous Electrical Neural Field Stimulation for Fibromyalgia: Protocol for a Feasibility Study

Background Fibromyalgia is a chronic pain state that includes widespread musculoskeletal pain, fatigue, psychiatric symptoms, cognitive and sleep disturbances, and multiple somatic symptoms. Current therapies are often insufficient or come with significant risks, and while there is an increasing demand for non-pharmacologic and especially non-opioid pain management such as that offered through complementary and alternative medicine therapies, there is currently insufficient evidence to recommend these therapies. Percutaneous electrical neural stimulation (PENS) is an evidence-based treatment option for pain conditions that involves electrical current stimulation through needles inserted into the skin. Percutaneous electrical neural field stimulation (PENFS) of the auricle is similar to PENS, but instead of targeting a single neurovascular bundle, PENFS stimulates the entire ear, covering all auricular branches of the cranial nerves, including the vagus nerve. The neural mechanisms of PENFS for fibromyalgia symptom relief are unknown. Objective We hypothesize that PENFS treatment will decrease functional brain connectivity between the default mode network (DMN) and right posterior insula in fibromyalgia patients. We expect that the decrease in functional connectivity between the DMN and insula will correlate with patient-reported analgesic improvements as indicated by the Defense and Veterans Pain Rating Scale (DVPRS) and will be anti-correlated with patient-reported analgesic medication consumption. Exploratory analyses will be performed for further hypothesis generation. Methods A total of 20 adults from the Atlanta Veterans Affairs Medical Center diagnosed with fibromyalgia will be randomized into 2 groups: 10 subjects to a control (standard therapy) group and 10 subjects to a PENFS treatment group. The pragmatic, standard therapy group will include pharmacologic treatments such as anticonvulsants, non-steroidal anti-inflammatory drugs, topical agents and physical therapy individualized to patient comorbidities and preferences, prescribed by a pain management practitioner. The PENFS group will include the above therapies in addition to the PENFS treatments. The PENFS subject group will have the Neuro-Stim System placed on the ear for 5 days then removed and replaced once per week for 4 weeks. The primary outcome will be resting functional magnetic resonance imaging connectivity between DMN and insula, which will also be correlated with pain relief and functional improvements. This connectivity will be analyzed utilizing functional connectivity magnetic resonance imaging (fcMRI) and will be compared with patient-reported analgesic improvements as indicated by the DVPRS and patient-reported analgesic medication consumption. Pain and function will be further evaluated using Patient-Reported Outcomes Measurement Information System measures and measures describing a person’s functional status from Activity and Participation section of the International Classification of Functioning Disability and Health. Results This trial has been funded by the Veterans Health Administration Program Office. This study attained approval by the Emory University/Veterans Affairs (VA) institutional review board and VA Research & Development committee. Institutional review board expedited approval was granted on 2/7/17 (IRB00092224). The study start date is 6/1/17 and estimated completion date is 5/31/20. The recruitment started in June 2017. Conclusions This is a feasibility study that is meant to demonstrate the practicality of using fcMRI to study the neural correlates of PENFS outcomes and provide information regarding power calculations in order to design and execute a larger randomized controlled clinical trial to determine the efficacy of PENFS for improving pain and function. Trial Registration ClinicalTrials.gov NCT03008837; https://clinicaltrials.gov/ct2/show/NCT03008837 (Archived by WebCite at http://www.webcitation.org/6wrY3NmaQ).

1 IK1 RX002113-01A2 1 IK1 RX002113-01A2 3 RRD9 WOODBURY, A be stratified based on age and gender and then divided into standard therapy control (medication management and physical therapy)] or PENFS (series of 4, weekly) treatments and assessed for fMRI changes 2 weeks after the final treatment. [Pain and function will also be assessed at the 2 weeks, 6 weeks and 12 weeks] following the final treatment. CLINICAL RELEVANCE: [Auricular PENFS has not been studied with fMRI. Stimulation of the auricle may produce neural changes that differ from traditional therapies. Understanding the underlying neural mechanisms of auricular PENFS could assist in developing targeted treatments for fibromyalgia and chronic pain.] Further, if PENFS can significantly improve pain relief and function over standard therapies, it could decrease the need for opioid analgesics and their associated risks, which is a primary objective of the VA Opioid Safety Initiative. The present investigation will not only serve to elucidate neural changes with PENFS, but could be directly applicable to our Veterans suffering from fibromyalgia by providing evidence regarding the relative effectiveness of this already clinically-employed non-pharmacologic treatment (or lack thereof), and result in evidence-based implementation and potential cost savings to the VA system.

PUBLIC HEALTH RELEVANCE
Given recent increasing opioid-related deaths and evidence showing against the use of opioids for nonmalignant chronic pain, there is growing need for non-narcotic pain management. Fibromyalgia is a difficult to treat chronic pain condition that is often treated with opioids despite existing evidence. The prevalence of fibromyalgia is increased among Veterans returning from the gulf war and is already a significant burden in senior Veterans who may have suffered with chronic pain for decades already. Many treatment options for fibromyalgia carry intolerable side effects. PENFS (percutaneous electrical neural field stimulation) is a FDA-approved, non-pharmacologic therapy that is currently utilized within the military and VA system, but sufficient evidence regarding its outcomes and neural mechanisms have not been adequately investigated. An understanding of its neural underpinnings and analgesic effects could lead to 1) improvements in pain management and quality of life, 2) cost-savings and 3) development of new techniques to address pain.

CRITIQUE 1
DESCRIPTION: This is a second resubmission of a CDA-1 grant in which the goal is to examine the feasibility of using functional connectivity MRI (fcMRI) as a biomarker to investigate functionally correlated neural substrates of pain in patients with fibromyalgia who are undergoing auricular percutaneous electrical neural field stimulation (PENFS) for pain reduction and to evaluate whether PENFS leads to improvements in pain and function compared to standard treatment in Veterans with fibromyalgia.

CRITIQUE (Applicant, Mentor, and Training Program):
Applicant: The candidate is a licensed acupuncturist and board certified pain management physician with a special interest in fibromyalgia. She is currently the Division Chief for pain management at the Atlanta VAMC, and uses the two forms of pain treatment PENS and acupuncture in treatment in the management of chronic pain on a regular basis. She is also a faculty member at Emory University where some of the study procedures will take place. She currently has 12 publications, most recently a narrative review on CAM therapies for pain practitioners. She appears highly committed to building evidence around the use of minimally invasive integrative therapies, like acupuncture and PENFS, for use in her patients as well as to understand underpinnings of chronic pain in fibromyalgia.
Mentor/s: There have been changes to the mentor team in response to previous review critiques. Her primary mentor is Dr. Crossen who is the Executive Associate Director in Center for Visual and Neurocognitive Rehabilitation (CVNR) at the Atlanta VAMC and also directs the neuroimaging core. He has a good history of mentoring junior faculty and will teach her fMRI as it relates to this project which is a central skill she hopes to acquire. Dr. Sniecinski is an anesthesiologist at Emory University, has 1 IK1 RX002113-01A2 4 RRD9 WOODBURY, A performed clinical research studies in the field, and is charged with teaching her more practical aspects of clinical trial implementation and learning appropriate statistical analyses. Dr. Napadow is an external mentor from the Boston area who is known for his content expertise in acupuncture and pain management. He is tasked with providing monthly readings and discussion regarding the assessment of acupuncture with fMRI and with helping her with grant writing. He will be an essential mentor in the field of functional connectivity MRI which he pioneered and will be employed in this study. Reviewers requested the addition of a mentor who had particular expertise in clinical trials and now Dr. Lawrence Phillips has been added to the team. He is the Director of the Clinical Studies Center at the Atlanta VAMC as well as a faculty member at Emory in the medicine and physiology departments. Dr. Phillips was a site PI on the Women's Health Initiative, had several R01 grants and is program director of an NIH training grant that has been renewed for the past 20 years. He has extensive experience in training faculty members and fellows in clinical research. Dr. Kalangara, a pain physician who works with Dr. Woodbury, will serve as a collaborator in the project, will place the auricular PENFS devices on patients to maintain blinding of Dr. Woodbury, and will serve as Acting Chief during her dedicated research time. Dr. Garcia and Dr. Huang are two other consultants with expertise in mechanisms of neuromodulation and developing acupuncture protocols respectively. Dr. Guo is a biostatistician who will consult with Dr. Woodbury about the independent component analysis, a method which was suggested by reviewers in the last review. Dr. Krishnamurthy works in Dr. Crossen's neuroimaging core and will also consult on the research project.
All of these team members together depict a strong network of support and mentorship from a variety of sources. The addition of Dr. Phillips was important to round out mentorship in clinical trial design and conduct. In future applications, it would be nice to have letters from all of these people. The letters section had current letters of most senior key personnel (except Dr. Sniecinski) and old letters from previous applications from people no longer on the team (such as Dr. Mackenzie-Brown).
Training Program: The candidate's goals for the CDA-1 are 1) to develop a foundation of knowledge in important tools for neuroimaging for the objective evaluation of pain and analgesia such as fMRI, 2) to develop experience in conducting a clinical trial, and 3) to become well versed in pain and acupuncture research. Her training plan involves targeted mentorship with each of her mentors and to undertake the Masters of Science in Clinical Research Program at Emory. Her coursework will cover neuroimaging and clinical trials development as well as biostatistics and appears to be carefully thought out to address her goals.

CRITIQUE (Scientific Merit-Strengths, Weaknesses, & Recommendations):
Significance: This project is significant for several reasons. It provides evidence in minimally invasive pain treatment for a difficult-to-treat population of people with fibromyalgia, who often receive opioid treatments. Neurostimulation such as PENS is currently being used in Veteran populations and could be feasibly applied. The use of functional connectivity MRI provides an important opportunity for Dr. Woodbury to learn from Dr. Napadow and other mentors in neuroimaging as well as extend the study of the use of fcMRI as a biomarker in fibromyalgia.
Approach: Dr. Woodbury and team have structured the aims to replicate and extend similar research that has been done by a member of her mentor team and others that has established brain connectivity biomarkers to examine acupuncture effects in patients with fibromyalgia.
Data presented in the Preliminary data and feasibility section should not include studies from other researchers (e.g. Roberts and Brown study) that are not part of the team. Data from previous studies in the larger body of knowledge belong in the Background and Significance and is otherwise potentially misleading.
1 IK1 RX002113-01A2 5 RRD9 WOODBURY, A Environment: The environment is strong. The Atlanta VA has an RR&D Center of Excellence in Visual and Neurocognitive rehabilitation. This center has a neuroimaging core which has been utilized to develop methodology for the data analysis as reported by the candidate. In addition, there are new resources being used at Emory with the addition of Dr. Phillips to the team.
Feasibility: The applicant responded well to critiques about the feasibility of the project in this submission. Given the mentorship in place and the discussion of the clinical trial and the fcMRI aims, the feasibility appears strong.

Overall Evaluation (Applicant/Mentor(s)/Training and Scientific Merit):
The applicant responded well to the prior critiques and appears well positioned to pursue this CDA-1. While grant and scientific writing is addressed in the training plan, the applicant should work to publish papers related to topics in the project that are data-driven with her mentors.
Ethical/Safety Issues: None noted.

OTHER CONSIDERATIONS:
Clinical Relevance: This work is highly clinically relevant, as it will help identify whether PENFS may improve pain and functional outcomes in this sample which can lead to larger studies in the area.
Budget: Travel to Dr. Napadow's clinic was reduced and other items questioned in the last critique such as supplies have now been justified.

CRITIQUE 2
DESCRIPTION: Fibromyalgia affects 5-10 million Americans, with 1,451 Veterans carrying a clinical diagnosis of fibromyalgia annually at the Atlanta VAMC alone according to a recent data query. Though this syndrome more often affects females, due to the higher male to female ratio in the Veteran population both gender groups are well represented with this disease. Pain related to fibromyalgia is often difficult to manage and results in increased utilization of healthcare services, lost workdays, and overall disability. A safe and effective treatment for fibromyalgia is needed.
Percutaneous application of electrical neural stimulation (PENS) and auricular PENS have provided evidence for analgesia in clinical trials. The Military Field Stimulator (MFS/Neuro-Stim System), a percutaneous electrical neural field stimulation (PENFS) device evolved from PENS, is currently employed by the United States (US) military and used in the VA (contract number V797D-50453). There is some evidence based on a small trial of 20 postoperative patients that suggests PENS may have greater benefit than acupuncture for acute pain. However, while the effects of acupuncture treatment have been explored with fMRI and correlated with analgesic improvements, such data do not exist for auricular PENS/PENFS. In fibromyalgia patients, decreased intrinsic brain connectivity on fMRI has been correlated with a reduction in pain scores, and analgesic interventions have decreased connectivity between the default mode network (DMN) and various regions of the insula, normalizing towards healthy controls. OBJECTIVE: This investigation intends to examine the feasibility of using resting state functional connectivity MRI (fcMRI) as a biomarker for PENFS-induced changes in the treatment of fibromyalgia. Auricular PENFS shares similarities with auricular acupuncture (in that it utilizes the ear) and PENS (in that it utilizes percutaneous electrical stimulation). While these therapies are currently clinically employed, only acupuncture (not involving the ear) has been studied in fibromyalgia patients using fMRI. Thus, there is a premise for using fMRI as a biomarker in chronic pain patients, but it is possible that the application of stimulation specifically to the ear may result in differential neural effects as compared to acupuncture in fibromyalgia patients.

IKRX002113-01A2
6 RRD9 WOODBURY, A The candidate's goals are: 1) to develop a foundation of knowledge in important tools for neuro-imaging for the objective evaluation of pain and analgesia such as fMRI, which will be of use for subsequent applications, 2) to develop experience in conducting a clinical trial and 3) to become well versed in pain research for nonpharmacologic therapies.

CRITIQUE (Applicant, Mentor, and Training Program):
Applicant: The candidate has broad experience, interest and training in acupuncture and in allopathic medicine (anesthesiology). She has experienced some basic research training through a Foundation for Anesthesia Education and Research (FAER) fellowship, and advanced clinical training through a pain management fellowship in anesthesiology at Emory University. She is now the lead physician for pain management at the Veterans Affairs Medical Center in Atlanta, GA, treating chronic pain with a combination of mainstream and alternative medical techniques ranging from conservative management with heat, ice, and stretching to pharmacological intervention to acupuncture to minimally invasive, fluoroscopically guided, interventional techniques. She is in a good position to recruit participants. Additionally, she is on the Committee on Pain Medicine for the American Society of Anesthesiologists. Although she has some publications, she lacks experience in clinical trials and fMRI. It is expected that the applicant would gain the necessary experience and knowledge through the CDA process.
Mentor/s: Dr. Woodbury is supported by an accomplished mentorship team, led by Dr. Crosson, a wellregarded researcher in the areas of fMRI, neuroimaging and cognitive function. He is currently the primary mentor of a PhD (RR&D CDA-2) and is a secondary mentor for four others. He [will assure that Dr. Woodbury gets assistance in running the clinical trial.] Vitaly Napadow will add his experience in the particular area of functional neuroimaging as it relates to pain and fibromyalgia. Dr. Sniecinski will help with some of the practical aspects of mounting a study such as organization and compliance with IRB requirements. Dr. Lawrence Phillips, MD, Director of the Clinical Studies Center at the Atlanta VAMC has agreed to be a clinical trial design mentor for the applicant and will devote 1% of his time to this. Wei Huang, MD, PhD, is a consultant who physiatrist/acupuncturist, who may provide some rehabilitation perspective to the process.
Training Program: The training program a Master's of Science in Clinical Research degree program from the Atlanta Clinical & Translational Science Institute in the second year. One expects that the candidate would be accepted into the program, although there is not a contingency plan if she is not. The trips to Dr. Napadow's lab have been reduced, which should make the experience more feasible. The plan could be strengthened with the addition of education in behavioral approaches (exercise, cognitive behavioral therapy) to pain/fibromyalgia.

CRITIQUE (Scientific Merit-Strengths, Weaknesses, & Recommendations):
Significance: Fibromyalgia and related chronic pain syndromes are common, difficult to manage, and not well understood. They cause misery to affected individuals and vex providers. fMRI is one tool to help gain understanding of the neuroanotomic mechanisms underlying the conditions and such insights neurostimulation such as PENFS, are important, and as they hold the promise of symptom relief free of many of the deleterious side effects associated with medicines. This trial would be similar to others of Dr. Napadow studying the intervention of acupuncture, with the major difference being that instead of acupuncture, the intervention would be PENFS. The candidate plans future trials comparing PENFS to battlefield acupuncture, which is important as battlefield acupuncture is likely to rely a similar mechanism of action and is significantly less expensive, and gaining traction as a practice in the VA and DoD.
Approach: The applicant has been responsive to the major concerns of the reviewers. The scope of the trial has been reduced to a more doable feasibility trial. Twenty Veterans with fibromyalgia will be randomized into either a treatment (four weeks of PENFS) or a control group (four weeks of usual 1 IK1 RX002113-01A2 7 RRD9 WOODBURY, A standard of care treatment with the restriction that no new treatments be introduced). The control group will be block randomized, stratified for age, gender, although not by comorbidities. The PENFS units are still being purchased as a clinical item. Although they are being used in a fashion consistent with their manufacture, they are not being used as a treatment of last resort for pain as is the common practice at the Atlanta VA, but as part of a research protocol. This amounts to a donation to the CDA from the clinical prosthetics service. Dr. Kalangara, will perform the interventions, allowing the PI to perform functional assessments and data analyses in a blinded fashion. The trial now closely matches the form of trials of her mentor, Dr. Napadow, which is consistent with the format of a CDA-1. (Napadow, V.; Kim, J.; Clauw, D. J.; Harris, R. E. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum 2012Rheum , 64, 2398Rheum -2403. The imaging portion of the trial now appears strengthened with the addition of independent component analysis and the inclusion of explicit head movement reduction and correction protocols. The inclusion of PROMIS measures should strengthen the application. The ICF is a conceptual model, not a measure in and of itself, which seems to have been missed by the applicant and team. There is a crosswalk between the ICF and the PROMIS measures. The goal of developing an objective measure of pain could use further explanation. While it is easy to accept that imaging techniques can elucidate the physiologic mechanisms of sensations, the experience of pain seems by its nature to be subjective and dependent on multiple factors including the physiologic experience and the context of the experience, as well as the motivations and goals of the individual. It appears that participants are to be excluded if they experience adverse events such as vasovagal syncope, skin irritation, or they remove the device. Assumedly, they will have already enrolled in the study and have gone through the informed consent process. Even if they aren't able to finish the protocol, they should be included in the study. Environment: The environment appears sufficiently strong to support the candidate. The Atlanta VA RR&D Center of Excellence (CoE) includes sufficient office space, laboratories, data support, and mentorship to support the candidate and the project. The candidate's position in the Atlanta Clinic and Atlanta VA Medical Center-Pain Management and Acupuncture Facilities, should present an adequate population of Veterans for recruitment. The Center for Systems Imaging (CSI) and the Neuroimaging Analysis Laboratory are available to Dr. Woodbury to conduct the scanning and analysis as proposed.
Feasibility: The project appears feasible. The proper equipment, mentoring and institutional support is in place. An adequate population should be available. A timeline for the study has been added, which is helpful. The candidate is qualified and motivated, and has assembled a strong team of mentors and reasonable education plan, and has identified an important area in need of investigation. A plan for reduction of clinical responsibilities has been included, and the amount of travel has been reduced.

Overall Evaluation (Applicant/Mentor(s)/Training and Scientific Merit):
The candidate is accomplished, qualified and motivated, and has assembled a strong team of mentors and a reasonable educational plan, and has identified an important area in need of investigation. The applicant has been responsive to the major points of concern of the reviewers, and as a result, the research plan is more realistic and more feasible, and less ambitious. The current design should produce the data necessary to compute the effect size of the intervention, and lay the groundwork for larger, more definitive trials. The applicant/team seems confused about the ICF model and how it interfaces with the PROMIS measures. The goal of establishing an objective measure of pain could use some clarification. Participants who are withdrawn from the trial after consenting should be included in the study, particularly if the withdrawal has to do with adverse events.
Ethical/Safety Issues: No new issues.

OTHER CONSIDERATIONS:
Clinical Relevance: The potential role of acupuncture (including battlefield acupuncture) and neurostimulation in the treatment of fibromyalgia and pain in general are important to the VA and to the 1 IK1 RX002113-01A2 8 RRD9 WOODBURY, A public at large. Rigorous research that helps to establish the effects, limitations, and mechanisms of such approaches are needed to help Veterans and others. This line of work has the potential to help integrate needed treatments more broadly amongst the medical community.
Budget: The budget of the CDA-1 is restricted to exclusively to support the applicant's salary. Running clinical trials is a large undertaking. It is good to know that the RR&D CVNR has staff available to assist. An actual statement of commitment from the RR&D CVNR to support the study with the personnel to assist the conduct of the trial would be even more impressive.
Other Issues:  Data and safety monitoring plan is adequate.  Inclusion of women and minorities: No specific plans to recruit women and minorities.  However, the sample is relatively small, so that representation by of minorities may not be an issue.  Assumedly, the Atlanta VAMC has a large population of African-American Veterans. Since fibromyalgia disproportionately affects women, it should be relatively easy to recruit women.

CRITIQUE 3
DESCRIPTION: No comments.

Strengths:
The applicant has a history of research and publications in pain and alternative therapies. Her career goals and focus align with the mission of the VA. As a VA clinician, she has useful insight to the practice of pain management in Veterans.

Weaknesses:
 No publications with primary mentor.  The applicant seemingly has no experience even as a collaborator on neuroimaging publications.

Strengths:
The addition of a clinical trials mentor has strengthened the mentorship team.
Training Program:

Strengths:
The formal coursework in fMRI and training by collaborators with neuroimaging experience is strong.
Weaknesses:  Simultaneous enrollment in year 2 in the Master's program, fMRI coursework, and conducting research activities is overly ambitious.  The availability of local (CVNR) resources for hands on neuroimaging analysis and data management could be expanded.