TMS Trial Tests New Fibro Protocol
& Evaluates Mechanisms
Principal Investigator: Katherine Martucci, Ph.D.
Duke University, North Carolina, USA
Several clinical trials show TMS relieves fibromyalgia pain by fine tuning the brain’s communication networks. But this AFSA study goes beyond just looking at efficacy. Martucci proposes an accelerated protocol (only four days of treatment) to stimulate the medial prefrontal cortex (MPFC). The MPFC activity is low in fibromyalgia, making it an ideal, yet novel target for TMS treatment.
She will measure how TMS impacts key fibromyalgia symptoms. But it’s also important to better understand how the therapy works in patients. That’s why Martucci is assessing changes in brain and spinal cord function, along with immune substances in the blood. For general information about the technology, check our article on TMS.
MPFC Role in Fibro
Many brain areas are dysfunctional in fibromyalgia, so what makes the MPFC stand out as the ideal TMS treatment target for this disease? Aside from its low activity, this region contains a vast number of connections to other areas. “TMS works by modifying the activity of the networks tied to the stimulated area, more so than the target,” explains Martucci. So, by stimulating the MPFC, one can change multiple brain circuits.
When people are presented with the possibility of winning a monetary reward, their MPFC lights up in anticipation. But Martucci’s lab found dramatically lower responses in the MPFC in people with fibromyalgia.1 “Reward-related activities are tied to pain-related activities in the brain,” explains Martucci. “The MPFC is also involved with expectation and cognition. We believe targeting this region will improve symptoms of pain, fatigue, mood, and cognitive issues.”
The MPFC is linked to important brain circuits that regulate immune system responses. Yet immune cells in both the brain and systemically are activated in fibromyalgia patients, contributing to the persistence of pain. So, stimulating the MPFC should reduce inflammation and its pain-promoting processes.
Upon imaging the spinal cord of fibromyalgia patients, Martucci found an imbalance between the pain-related and non-pain sensory signals.2 Too many pain signals can overwhelm an already burdened brain, but boosting the MPFC activity should help reduce these signals. Martucci is imaging spinal cord activity to see if this is the case.
Stimulating the MPFC using TMS activates dopamine (blue) and serotonin (red) transmitting circuits throughout the brain and down the cord. This should lead to multiple symptom improvements, along with reduced inflammation and improved spinal cord function.
One final note: the MPFC is a large area. Martucci is testing patients in the MRI scanner with a reward task to pinpoint the best spot to treat.
Reward Task
A test to measure the brain’s anticipatory response to a potential reward needs to be very simple, especially for fibromyalgia patients. Otherwise, the results will be obscured by cognitive impairment issues. The monetary incentive delay (MID) task only requires subjects to click a button when a symbol appears (typically a square).
Here’s how it works. Subjects lay down in an MRI scanner looking up at a screen while holding a clicker in their hand. First, they are presented with a dollar amount they can win. Then they wait in anticipation of the square to appear and press the button as soon as possible.
The time between being presented with a dollar amount (reward potential) and seeing the symbol represents the anticipation phase. The greater the reward, the greater the level of brain activity in the MPFC … at least in healthy people.
“It is essential to do the MID task in the scanner because the only difference between fibromyalgia and control subjects is their brain response,” says Martucci. Even though patients click as fast as the controls and are excited about the rewards, their brain activity is muted.
Analyzing each fibromyalgia patient’s MPFC response to the MID task identifies the target region for that participant. After one week of treatment, the activity in the target area is measured again during the MID task. Martucci expects the amount of increased activity will correlate with symptom improvements and other measures.
Before & After Tests
In addition to the MID task, various measures before and after TMS will provide a clearer picture of how this therapy works in fibromyalgia. Functional MRI (fMRI) will measure communication changes in the brain’s neural networks. Spinal cord imaging will determine if the pain transmissions traveling up the cord are reduced. And immune substances in the blood will hopefully reveal the extent to which TMS favorably reduces immune system activation.
All too often, clinical trials involving fibromyalgia patients focus on pain relief. Martucci is assessing pain thresholds and other measures to quantify pain in patients. However, she is also taking a hard look at the ability of TMS to treat fatigue and cognitive impairment (fibrofog). “We expect that rebalancing the pain circuits connected to the MPFC will alleviate fatigue and cognitive deficits,” says Martucci.
How long can the effects of TMS therapy last? To answer this question, subjects will complete symptom questionnaires at three- and six-months post-treatment.
Treatment Protocol
TMS treatments normally involve 30-minute sessions for four to six weeks. It’s time-consuming and particularly difficult for people with widespread pain and exhaustion. But Martucci is using an accelerated protocol that packs the power of a 30-minute session into 3 minutes.3 As a result, five treatment sessions (one per hour) are done each day, for a total of only four days.
Referring to the protocol, Martucci says, “It uses a different type of stimulation pattern that can more efficiently change brain activity. If we did only one 3-minute session prior to an fMRI scan, we would already see alterations in the brain. We are aiming to do 20 sessions total per participant (five each day). This is similar to the amount of neurostimulation that shows longer effects, on the order of months, in other studies.”
In a Class of its Own
This project employs many novel techniques used successfully in other conditions but this will be the first time they are used in fibromyalgia. Examples include the accelerated protocol, using the MID task to precisely identify the stimulation area, and targeting the MPFC. Several studies show the MPFC and its connected circuits are uniquely altered in fibromyalgia patients. As a result, treating the MPFC is expected to produce improvements in all fibromyalgia symptoms, not just pain.
Imaging the spinal cord activity (both pain-related and non-pain sensory signals) is novel. This information will show how the MPFC stimulation improves the pain inhibitory control system in fibromyalgia.
Measuring the central nervous system (using fMRI) and neuroimmune substances in the blood can uncover important treatment mechanisms. Referring to these approaches, Martucci explains, “It provides more evidence of how altered brain circuits are partly responsible for fibromyalgia symptoms and further substantiate this as a real disease. And perhaps more importantly, as a condition distinct from depression.”
Next Steps
This pilot study is expected to take only one year to complete and represents the crucial first step for establishing the feasibility of the protocol. Further studies to refine the protocol and a large-scale sham-controlled trial that includes men are expected to follow. The long-term goal (within 5-10 years) is to work on FDA approval and insurance coverage of TMS treatment for fibromyalgia.
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How TMS Works | Alternative Therapies | Fibrofog & Treatments | Medications | Fibro Flare Study
References for TMS Treatment Trial in Fibromyalgia
- Park SH, Martucci KT, et al. Neuroimage Rep 2(4):100147, 2022. Free Report
- Martucci KT, et al. Arthritis Rheumatol 71(3):441-450, 2019. Free Report
- Roth Y, et al. Psychiatry Res 328:115482, 2023. Free Report