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

We are trying to address two main issues with regards to pain research. The first is the need for non-invasive non-pharmacologic therapies that can be effectively administered to individuals suffering from chronic pain. The second is the development of reliable biomarkers, such as the neuroimaging that we're using, for the purposes of assessing both fibromyalgia pain and treatment response.

The development and access of multiple open source neuro software packages allows for the streamlined use of neurogenic data analysis. Many of these tools such as fMRIPrep allow researchers who are not familiar with the neuro imaging practices to complete critical pre-processing steps. To maintain blinding, we're unable to titrate for effect using the device as we would in a clinical setting.

The stimulation is typically below the perceptual threshold, but we may be underdosing individuals in our study's treatment group, which causes a smaller effect size and difference between the groups. Cranial electrical stimulation is non-invasive, it's low risk, and it's accessible enough to be self-administered by participants in their own home settings. We can also extract usage rates from each of the research devices to properly evaluate compliance with the treatment and resting state functional connectivity MRI allows us to assess changes in the brain that may occur as a result of our treatment.

We anticipate that our research will further guide biomarker development using neuroimaging as a tool. This contributes to a better understanding of the neural basis of pain, and our hope is that these techniques will eventually be used to guide clinical diagnosis and decision-making for individuals suffering from pain. To recruit study participants, adhere to institutional guidelines for distributing study recruitment materials and employing approved methods.

Screen the persons expressing interest over the phone to ensure they meet all inclusion and exclusion criteria. Follow the eligibility criteria displayed on the screen to include participants and exclude individuals if any exclusion criteria are met. Before each baseline visit, prepare the cranial electrical stimulation or CES device for each participant.

To do so, first turn on the device by pressing the top button for about two seconds until the screen lights up. After ensuring the device is working, press the button for about two seconds until the screen goes blank to turn it off. Ensure each case contains the device, extra batteries, a lanyard, a small solution applicator, and ear clips.

Then place one device case in each bag to be given to the participants and ensure each bag also contains a bottle of conducting solution, an extra cap to fill the small solution applicator, and extra ear clip electrode pads. Meet the participant at the magnetic resonance imaging or MRI scanner location for the scheduled appointment with two copies of the consent form, the bag containing the CES device, and other materials, eligibility testing paperwork, and a questionnaire packet. Complete the inclusion testing paperwork with each consenting participant before proceeding to the next step with the eligible participants.

To explain the device usage to them, remove the device from the case and demonstrate how to turn it on and off. Show how to attach the ear clip cord to the side. Next, show how to remove the old electrode pads from the ear clip by pulling up the adhesive that connects it to the clip.

Then attach the new pad by aligning the hole in it with the raised area in the center of the clip while pressing it down firmly. After that, squeeze the green tips of the clip to open it. Demonstrate how to position the ear lobe between the tips and gently close the clip to attach it to the ear lobe.

Have the participant try it once. Show them how to remove the plastic top from the small solution to applicator and attach the alternate cap to the top of the larger solution bottle. Then push up the small nozzle, slide it into the small applicator, and squeeze the large bottle to fill the small applicator.

Inform the participant to add only about 1-2 drops of the solution to each ear clip electrode pad. Instruct when to use the device every day. Give the participant a blank device log and ask to log the necessary details during each use.

Next, have the participant complete three short physical function tests. First, instruct the participant to rise to a full standing position and then sit all the way back down while keeping the back against the chair. Make the participant do this as many times as possible in 30 seconds.

Then have the participant do arm curls with a dumbbell on each side for 30 seconds per side, starting with the right arm first and then moving to the left. After that, let the participant do three grip strength trials with each arm on a dynamometer. Ask to squeeze the dynamometer as hard as possible and then release it.

Next have the participants complete the questionnaire packet using a pen, and check over the packet to ensure all questions were answered. After walking the participant to the MRI scanner, review the screening form with the MRI technicians and ensure the participant has removed all metal accessories. Help MRI technicians get the participant into the scanner comfortably before administering the MRI scan protocol.

Acquire BOLD, resting state fMRI on a 3T MRI scanner with a 32 channel phased array head coil using a gradient EPI sequence. For the anatomical T1-weighted MP RAGE, set RepetitionTime equal to 2, 530 milliseconds, EchoTime equal to 3 milliseconds, FlipAngle equal to 7 degrees, SliceThickness equal to 0.8 millimeters, and PhaseResolution equal to one millimeter. Acquire DWI scans on the 3T MRI scanner using a diffusion spectrum imaging scheme.

Collect a total of 128 diffusion sampling directions with a maximum B value of 3, 000 seconds per square millimeter, an in plain resolution of 2 millimeters by 2 millimeters, and a slice thickness of 2 millimeters. Acquire physiological data simultaneously with the fMRI data. Securely transfer the MRI data from the scanner location to a secure site for pre-processing and analysis.

Analyze the MRI data from the study with two separate pipelines. One to analyze the functional connectivity between participants and another to analyze white matter tractography. Once the setup, pre-processing, and denoising steps have been completed for the pipelines, set the cluster and voxel thresholds to view functional connectivity patterns.

Use correlational tractography to determine longitudinal changes in white matter integrity correlated with the experiment group. Identify tracked bundles and regions associated with the CES treatment.