Neurophysiology of Fibromyalgia

Investigating the Neurobiological Contributions to Pain in Patients With Fibromyalgia

Fibromyalgia is a syndrome associated with fatigue and chronic pain, leading to significant physical limitations and impaired quality of life. There are several challenges that complicate the diagnosis and management of fibromyalgia. The etiology is not well defined, as there are several proposed factors that may trigger the genesis of pain in fibromyalgia including physical and/or emotional life stressors, and genetic predispositions involving neuromodulator pathways. Chronic pain in fibromyalgia arises in the absence of tissue pathology, and consequently a lack of consensus on reliable diagnostic criteria. Understanding the neurophysiology of fibromyalgia would aid in the discovery of objective biomarkers for diagnosis. Therefore, the goals of this study are to:

1. Compare the neurophysiological responses in fibromyalgia compared to healthy controls.
2. Determine whether a two-week cTMS protocol will alter pain in individuals with fibromyalgia.

Study Overview

• Status: Completed
• Conditions: Fibromyalgia
• Intervention / Treatment: Device: Active Controlled Pulse Parameter Transcranial Magnetic Stimulation (cTMS); Device: Sham Controlled Pulse Parameter Transcranial Magnetic Stimulation (cTMS)

Detailed Description

Fibromyalgia is a syndrome associated with fatigue and chronic pain, leading to significant physical limitations and impaired quality of life. Fibromyalgia affects 1.7% of Canadians, with a higher prevalence in females compared to males at 9:1 [1]. There are several challenges that complicate the diagnosis and management of fibromyalgia. The etiology is not well defined, as there are several proposed factors that may trigger the genesis of pain in fibromyalgia. Chronic pain in fibromyalgia arises in the absence of tissue pathology, and consequently a lack of consensus on reliable diagnostic criteria. Understanding the pathophysiology of fibromyalgia would aid in the identification of objective biomarkers that could be used for diagnosis.

Multiple theories have been posited to explain the genesis of chronic pain. The gate control theory describes the attenuation of pain signals in the spinal cord prior to cortical processing, and it has been hypothesized that loss of this gate control leads to the genesis of chronic pain [2]. Gate control can be observed by reduction of afferent signals during active muscle contraction. For example, the amplitude of the somatosensory-evoked potential (SEP) is attenuated during active contraction [3]. To our knowledge, it is unknown whether such gate control is observed in fibromyalgia. The lack of gate control may contribute to chronic pain in this population.

The sensorimotor theory suggests that incongruency between motor intention and sensory feedback underlies chronic pain where there is an absence of tissue pathology [4]. This may align with the genesis of fibromyalgia, given the findings that those with fibromyalgia have altered tactile and proprioceptive functioning [5]. Corticomuscular coherence (CMC) is a useful tool that uses electroencephalography (EEG) and electromyography (EMG) to probe the synchrony of neural firing between the brain and muscle [6]. To our knowledge, it is unknown how the magnitude of CMC varies in fibromyalgia compared to healthy controls.

Non-invasive brain stimulation in the form of Transcranial Magnetic Stimulation (TMS) has been used to probe the activity of corticospinal and cortical networks in fibromyalgia. When TMS pulses are delivered in a repetitive train, a protocol known as repetitive TMS (rTMS), short-term neuroplasticity can be induced (i.e., a change in the activity of neurons in the brain). In fibromyalgia, Mhalla et al. [7] found that 5 days of 10 Hz rTMS reduced pain intensity and improved quality of life metrics. Controlled pulse parameter transcranial magnetic stimulation (cTMS) is a novel technique that may produce stronger analgesic effects by delivering monophasic pulses that could enhance neuroplasticity compared with conventional rTMS. It is unknown whether a longer intervention period or the use of cTMS could lead to greater analgesic effects.

Finally, central sensitization may explain the widespread chronic pain experienced in fibromyalgia. There are several neuromodulators that contribute to the neurobiology of central sensitization and may be implicated in this condition including serotonin, dopamine, and brain-derived neurotrophic factor (BDNF). Serotonin is linked to pain modulation, such that increased levels of 5-HT are associated with hyperalgesia [8]. BDNF has been implicated in the genesis of neuropathic pain [9]. In fibromyalgia compared to healthy controls, serum BDNF levels have been reported to be higher [10]. Abnormal dopamine function may also be associated with fibromyalgia [11]. Positron-emission tomography (PET) studies show lower cortical dopamine D2/D3 binding availability in fibromyalgia compared to healthy controls [12].

Ultimately, a combination of events may lead to widespread chronic pain in fibromyalgia. Understanding the neurophysiology of fibromyalgia would aid in the discovery of objective biomarkers for diagnosis. Therefore, the goals of this study are to:

1. Compare the neurophysiological responses in fibromyalgia compared to healthy controls.
2. Determine whether a two-week cTMS protocol will alter pain in individuals with fibromyalgia.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8S4L1
      • McMaster University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• 18-65 years old

Exclusion Criteria:

• contraindications to TMS
• chronic pain associated with diagnoses other than fibromyalgia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active cTMS; Controlled Pulse Parameter Transcranial Magnetic Stimulation (cTMS) will be delivered at 10 Hz, 2000 pulses targeting the hand representation of the left primary motor cortex. cTMS delivery will require ~11 min to complete. In Experiment 1, this intervention will be performed for 1 session (~11min). In Experiment 2, this intervention will be performed approximately 5 days per week for 2 weeks. In addition, participants will experience their standard medical care.	Device: Active Controlled Pulse Parameter Transcranial Magnetic Stimulation (cTMS); cTMS is a non-invasive, non-painful procedure used to relieve chronic pain and promote short-term changes. The first dorsal interosseous (FDI) muscle of the left motor cortex will be targeted using neuronavigation software. 2000 pulses will be delivered at 10 Hz stimulation. Stimulation will be delivered at 80% of the resting motor threshold obtained from the right FDI muscle. The delivery of cTMS requires 11 minutes in total.
Sham Comparator: Sham cTMS; Sham cTMS will be delivered at as a placebo control. It is important to note that from the participant perspective, the sham stimulation will feel and sound identical to active cTMS. In Experiment 2, this intervention will be performed approximately 5 days per week for 2 weeks. In addition, participants will experience their standard medical care.	Device: Sham Controlled Pulse Parameter Transcranial Magnetic Stimulation (cTMS); A sham coil will be utilized for the sham cTMS condition. It is important to note that from the participant perspective, the sham stimulation will feel and sound identical to active. The location and all other parameters of Sham cTMS will be identical to Active cTMS.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in PROMIS-29 v2.0 Profile	Using numerical rating (0 to 5) to assess the change in seven health domains including physical function, anxiety, depression, fatigue, sleep disturbances, ability to participate in social roles and activities, and pain interference. Each category consists of 4 questions. Also uses a numerical rating to asses pain intensity (0-10).	Experiment 1: At baseline pre-intervention, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
Change in Fibromyalgia impact questionnaire (FIQ)	This instrument will be used to assess the patients feeling and emotion related to their pain experience.	Experiment 1: At baseline pre-intervention, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pain catastrophizing scale-EN-SF	Will be used to assess the patients feeling and emotion related to their pain experience	Experiment 1: At baseline pre-intervention, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
Change in Patient Health Questionnaire-4 (PHQ-4)	Will be used to assess for symptoms of for Major Depressive Disorder and Generalized Anxiety Disorder	Experiment 1: At baseline pre-intervention, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
Change in Short-form Posttraumatic Checklist-5 (Short-form PCL-5)	Will be used to screen for symptoms of Posttraumatic Stress Disorder (PTSD)	Experiment 1: At baseline pre-intervention, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
Change in Motor-evoked potentials (MEPs)	This will include an assessments of MEPs obtained using Transcranial Magnetic Stimulation (TMS).	Experiment 1: At baseline pre-intervention and immediately following 1 treatment session, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
Change in Short-Interval Intracortical Inhibition (SICI)	This will include an assessments of SICI obtained using Transcranial Magnetic Stimulation (TMS).	Experiment 1: At baseline pre-intervention and immediately following 1 treatment session, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
Change in performance on sensorimotor tasks	Tasks include tactile localization, temporal order judgement (TOJ), and sequential amplitude discrimination	Experiment 1: At baseline pre-intervention, Experiment 2: At baseline pre-intervention and 2 weeks post-intervention
EEG assessment of Somatosensory-evoked potentials (SEPs)	This will include an assessment of SEPs using EEG electrodes.	Experiment 1: At baseline pre-intervention only
EEG assessment of Pain-related evoked potentials (PREPs)	This will include an assessment of PREPs using EEG electrodes.	Experiment 1: At baseline pre-intervention only
EEG assessment of Corticomuscular coherence (CMC)	This will include an assessment of CMC using EEG electrodes.	Experiment 1: At baseline pre-intervention only
EEG assessment of Event-related desynchronization (ERD)	This will include an assessment of ERD using EEG electrodes.	Experiment 1: At baseline pre-intervention only

Collaborators and Investigators

• Sponsor: McMaster University

Publications and helpful links

General Publications

• Obata K, Noguchi K. BDNF in sensory neurons and chronic pain. Neurosci Res. 2006 May;55(1):1-10. doi: 10.1016/j.neures.2006.01.005. Epub 2006 Mar 3.
• Mhalla A, Baudic S, de Andrade DC, Gautron M, Perrot S, Teixeira MJ, Attal N, Bouhassira D. Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia. Pain. 2011 Jul;152(7):1478-1485. doi: 10.1016/j.pain.2011.01.034. Epub 2011 Mar 11.
• Ovrom EA, Mostert KA, Khakhkhar S, McKee DP, Yang P, Her YF. A Comprehensive Review of the Genetic and Epigenetic Contributions to the Development of Fibromyalgia. Biomedicines. 2023 Apr 7;11(4):1119. doi: 10.3390/biomedicines11041119.
• Chowdhury A, Raza H, Meena YK, Dutta A, Prasad G. An EEG-EMG correlation-based brain-computer interface for hand orthosis supported neuro-rehabilitation. J Neurosci Methods. 2019 Jan 15;312:1-11. doi: 10.1016/j.jneumeth.2018.11.010. Epub 2018 Nov 16.
• Toprak Celenay S, Mete O, Coban O, Oskay D, Erten S. Trunk position sense, postural stability, and spine posture in fibromyalgia. Rheumatol Int. 2019 Dec;39(12):2087-2094. doi: 10.1007/s00296-019-04399-1. Epub 2019 Jul 31.
• Vitterso AD, Halicka M, Buckingham G, Proulx MJ, Bultitude JH. The sensorimotor theory of pathological pain revisited. Neurosci Biobehav Rev. 2022 Aug;139:104735. doi: 10.1016/j.neubiorev.2022.104735. Epub 2022 Jun 12.
• Nakata H, Inui K, Wasaka T, Nishihira Y, Kakigi R. Mechanisms of differences in gating effects on short-and long-latency somatosensory evoked potentials relating to movement. Brain Topogr. 2003 Summer;15(4):211-22. doi: 10.1023/a:1023908707851.
• Melzack R. Evolution of the neuromatrix theory of pain. The Prithvi Raj Lecture: presented at the third World Congress of World Institute of Pain, Barcelona 2004. Pain Pract. 2005 Jun;5(2):85-94. doi: 10.1111/j.1533-2500.2005.05203.x.
• Yunus MB. The role of gender in fibromyalgia syndrome. Curr Rheumatol Rep. 2001 Apr;3(2):128-34. doi: 10.1007/s11926-001-0008-3.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2024
• Primary Completion (Actual): December 31, 2025
• Study Completion (Actual): December 31, 2025

Study Registration Dates

• First Submitted: July 28, 2023
• First Submitted That Met QC Criteria: August 16, 2023
• First Posted (Actual): August 23, 2023

Study Record Updates

• Last Update Posted (Actual): June 4, 2026
• Last Update Submitted That Met QC Criteria: June 2, 2026
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: pain; fibromyalgia; neuroplasticity; transcranial magnetic stimulation
• Additional Relevant MeSH Terms: Neurologic Manifestations; Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Rheumatic Diseases; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Pain; Fibromyalgia
• Other Study ID Numbers: 16482

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No