Neurophysiology of Fibromyalgia

Study Overview
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Brief Summary
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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: Compare the neurophysiological responses in fibromyalgia compared to healthy controls. Determine whether a two-week rTMS protocol will alter pain in individuals with fibromyalgia.

Detailed Description
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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. It is unknown whether a longer intervention period 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 rTMS protocol will alter pain in individuals with fibromyalgia. M. B. Yunus, The role of gender in fibromyalgia syndrome, Curr Rheumatol Rep, vol. 3, no. 2, pp. 128-134, 2001, doi: 10.1007/S11926-001-0008-3. R. Melzack, 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, vol. 5, no. 2, pp. 85-94, Jun. 2005, doi: 10.1111/J.1533-2500.2005.05203.X. H. Nakata, K. Inui, T. Wasaka, Y. Nishihira, and R. Kakigi, Mechanisms of differences in gating effects on short-and long-latency somatosensory evoked potentials relating to movement, Brain Topogr, vol. 15, no. 4, pp. 211-222, Jun. 2003, doi: 10.1023/A:1023908707851. A. D. Vittersø, M. Halicka, G. Buckingham, M. J. Proulx, and J. H. Bultitude, The sensorimotor theory of pathological pain revisited, Neurosci Biobehav Rev, vol. 139, Aug. 2022, doi: 10.1016/J.NEUBIOREV.2022.104735. S. Toprak Celenay, O. Mete, O. Coban, D. Oskay, and S. Erten, Trunk position sense, postural stability, and spine posture in fibromyalgia, Rheumatol Int, vol. 39, no. 12, pp. 2087-2094, Dec. 2019, doi: 10.1007/S00296-019-04399-1/TABLES/2. A. Chowdhury, H. Raza, Y. K. Meena, A. Dutta, and G. Prasad, An EEG-EMG correlation-based brain-computer interface for hand orthosis supported neuro-rehabilitation, J Neurosci Methods, vol. 312, pp. 1-11, Jan. 2019, doi: 10.1016/J.JNEUMETH.2018.11.010. A. Mhalla et al., Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia, Pain, vol. 152, no. 7, pp. 1478-1485, 2011, doi: 10.1016/J.PAIN.2011.01.034. E. A. Ovrom, K. A. ; Mostert, S. ; Khakhkhar, D. P. ; Mckee, P. ; Yang, and Y. F. A. Her, A Comprehensive Review of the Genetic and Epigenetic Contributions to the Development of Fibromyalgia, Biomedicines 2023, Vol. 11, Page 1119, vol. 11, no. 4, p. 1119, Apr. 2023, doi: 10.3390/BIOMEDICINES11041119. K. Obata and K. Noguchi, BDNF in sensory neurons and chronic pain, Neurosci Res, vol. 55, no. 1, pp. 1-10, May 2006, doi: 10.1016/J.NEURES.2006.01.005. A. Deitos et al., Clinical Value of Serum Neuroplasticity Mediators in Identifying the Central Sensitivity Syndrome in Patients With Chronic Pain With and Without Structural Pathology, Clin J Pain, vol. 31, no. 11, pp. 959-967, 2015, doi: 10.1097/AJP.0000000000000194. P. B. Wood, M. F. Glabus, R. Simpson, and J. C. Patterson, Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism, J Pain, vol. 10, no. 6, pp. 609-618, Jun. 2009, doi: 10.1016/J.JPAIN.2008.12.008. D. S. Albrecht et al., Differential dopamine function in fibromyalgia, Brain Imaging Behav, vol. 10, no. 3, pp. 829-839, Sep. 2016, doi: 10.1007/S11682-015-9459-4/FIGURES/4.

Official Title
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Investigating the Neurobiological Contributions to Pain in Patients With Fibromyalgia

Conditions
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Fibromyalgia

Intervention / Treatment
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* Device: Active Repetitive Transcranial Magnetic Stimulation (rTMS)
* Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18-65 years old Exclusion Criteria: contraindications to TMS chronic pain associated with diagnoses other than fibromyalgia

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Experiment 1: Response to real intervention compared between fibromyalgia and healthy control group Experiment 2: Fibromyalgia participants allocated to real or sham intervention
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active rTMS<br>Repetitive Transcranial Magnetic Stimulation (rTMS) will be delivered at 10 Hz, 1500 pulses targeting the hand representation of the left primary motor cortex. rTMS 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 Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* rTMS is a non-invasive, non-painful procedure used to relieve chronic pain and promote short-term changes. The abductor pollicis brevis (APB) muscle of the left motor cortex will be targeted using neuronavigation software. 1500 pulses will be delivered at 10 Hz stimulation. Stimulation will be delivered at 80% of the resting motor threshold obtained from the right APB muscle. The delivery of rTMS requires 11 minutes in total.<br>|
| Sham Comparator: Sham rTMS<br>Sham rTMS 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 rTMS. 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 Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* A sham coil will be utilized for the sham rTMS 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 rTMS will be identical to Active rTMS.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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fibromyalgia, transcranial magnetic stimulation, neuroplasticity, pain