A Randomized, Sham-Controlled Trial of Cranial Electrical Stimulation for Fibromyalgia Pain and Physical Function, Using Brain Imaging Biomarkers

Summary

The current study is a randomized, placebo-controlled trial to determine the efficacy of cranial electrical stimulation (CES) for improving pain and function in fibromyalgia and further develop resting functional connectivity magnetic resonance imaging (rs-fcMRI) as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Abstract

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive disturbances, and other somatic complaints. Available therapies are often insufficient in treating symptoms, with inadequate pain control commonly leading to opioid usage for attempted management. Cranial electrical stimulation (CES) is a promising non-pharmacologic treatment option for pain conditions that uses pulsed electrical current stimulation to modify brain function via transcutaneous electrodes. These neural mechanisms and the applications of CES in fibromyalgia symptom relief require further exploration.

A total of 50 participants from the Atlanta Veterans Affairs Healthcare System (VAHCS) diagnosed with fibromyalgia were enrolled and then block-randomized into either a placebo plus standard therapy or active CES plus standard therapy group. Baseline assessments were obtained prior to the start of treatment. Both interventions occurred over 12 weeks, and participants were assessed at 6 weeks and 12 weeks after treatment initiation. The primary outcome investigated whether pain and functional improvements occur with the application of CES. Additionally, baseline and follow-up resting state functional connectivity magnetic resonance imaging (rs-fcMRI) were obtained at the 6-week and 12-week time points to assess for clinical applications of neural connectivity biomarkers and the underlying neural associations related to treatment effects.

This is a randomized, placebo-controlled trial to determine the efficacy of CES for improving pain and function in fibromyalgia and further develop rs-fcMRI as a clinical tool to assess the neural correlates and mechanisms of chronic pain and analgesic response.

Introduction

Of the many existing states of chronic pain, one of the most notoriously difficult diseases to diagnose, clinically assess, and treat is fibromyalgia. Fibromyalgia is a debilitating chronic pain syndrome that involves chronic widespread pain, decreased physical function, fatigue, psycho-emotional and sleep disturbances, and various somatic complaints affecting approximately 2-3% of the general population in the Americas (about 8 million people in the U.S.)¹. Diagnosis of the disease is heavily reliant on a patient's understanding of their own symptom profile and pain experience, and without that proper understanding by both clinician and pa....

Protocol

The study was conducted under the approval of the Emory University (IRB 112768) and Atlanta VA Institutional Review Boards (1585632-2; Internal Reference Number: 003) as well as the Atlanta VA R&D Committee (Board Reference Number: 3881). All subjects gave their informed consent for inclusion before they participated in this study. For a visual representation of the study protocol timeline, see Figure 1).

Discussion

The methods of the current study provide not only the possibility of a highly effective treatment modality for fibromyalgia but also the opportunity to improve the diagnostic process of fibromyalgia from the first instance of its pain symptom profile. Use of both active CES and sham CES, with discovery of the type of each individual device being dependent upon serial numbers and a separate key, allowed for blinding of both subjects and researchers until the end of participation, thereby protecting internal validity durin.......

Materials

Name	Company	Catalog Number	Comments
3T Siemens MAGNETOM Prisma Scanner	Siemens Healthineers	N/A	From Emory's website: "The Siemens Magnetom Prisma 3T whole-body MR system is equipped with: a state-of-the art gradient system with a maximum (per axis) strength of 80 mT/m and slew rate of 200 T/m/sec 64 independent RF receiver channels capable of 204 receiver connections a 2-channel RF transmitter. Multiple coils are available, including: a 64-channel head/neck coil with 52 channels for imaging of the head region a 32-channel head-only coil a 20-channel head/neck coil with 16 channels for head spine array coil flexible chest coil large and small flexible coil for extremity imaging.
Alpha-Stim AID Kit	Electromedical Products International Inc.	SKU: 500KIT	A total of 50 devices ordered for research purposes. From the site: "A prescription or order from a licensed healthcare professional is required to purchase this device (within the USA). FDA cleared for anxiety, insomnia and pain only, with approval for depression outside of the United States."
CONN Toolbox v21a16 (RRID:SCR_009550)	Whitfield-Gabrieli and Nieto-Castanon	Version v21a16 (RRID:SCR_009550)	CONN is an open-source SPM-based cross-platform software for the computation, display, and analysis of functional connectivity Magnetic Resonance Imaging (fcMRI). CONN is used to analyze resting state data (rsfMRI) as well as task-related designs.
DSI Studio (RRID:SCR_009557)	Fang-Cheng (Frank) Yeh	RRID:SCR_009557	DSI Studio is a tractography software tool that maps brain connections and correlates findings with neuropsychological disorders. It is a collective implementation of several diffusion MRI methods, including diffusion tensor imaging (DTI), generalized q-sampling imaging (GQI), q-space diffeomorphic reconstruction (QSDR), diffusion MRI connectometry, and generalized deterministic fiber tracking.
fMRIPrep 20.2.5 (RRID:SCR_016216)	NiPreps (NeuroImaging PREProcessing tools)	Version 20.2.5. (RRID:SCR_016216)	A functional magnetic resonance imaging (fMRI) data preprocessing pipeline that is designed to provide an easily accessible, state-of-the-art interface that is robust to variations in scan acquisition protocols and that requires minimal user input, while providing easily interpretable and comprehensive error and output reporting. It performs basic processing steps (coregistration, normalization, unwarping, noise component extraction, segmentation, skull-stripping, etc.) providing outputs that can be easily submitted to a variety of group level analyses, including task-based or resting-state fMRI, graph theory measures, and surface or volume-based statistics.
MRIQC	NiPreps (NeuroImaging PREProcessing tools)		MRIQC extracts no-reference IQMs (image quality metrics) from structural (T1w and T2w) and functional MRI (magnetic resonance imaging) data. (not directly used for analyses)
Sammons Preston Jamar Hydraulic Hand Dynamometer	Alpha Med Inc.	SKU SAMP5030J1	From the website: Ideal for routine screening of grip strength and initial and ongoing evaluation of clients with hand trauma and dysfunction. Unit comes with carrying/storage case, certificate of calibration and complete instructions. Warranted for one full year. The warranty does not cover calibration. Latex free.
SPRI 5-Pound Vinyl-Coated Weight	SPRI | Amazon	N/A	Color: (E) Dark Blue | 5-Pound. Appears on Amazon: Dumbbells Hand Weights Set of 2 - Vinyl Coated Exercise & Fitness Dumbbell for Home Gym Equipment Workouts Strength Training Free Weights for Women, Men (1-10 Pound, 12, 15, 18, 20 lb), https://www.amazon.com/stores/SPRI/Weights/page/9D10835A-CFAB-4DA1-BEE9-AE993C6B5BC1
SPRI 8-Pound Vinyl-Coated Weight	SPRI | Amazon	N/A	Color: (H) Black |8-Pound. Appears on Amazon: Dumbbells Hand Weights Set of 2 - Vinyl Coated Exercise & Fitness Dumbbell for Home Gym Equipment Workouts Strength Training Free Weights for Women, Men (1-10 Pound, 12, 15, 18, 20 lb), https://www.amazon.com/stores/SPRI/Weights/page/9D10835A-CFAB-4DA1-BEE9-AE993C6B5BC1