Musculoskeletal (MSK) pain is a common reason to seek medical treatment. Temporomandibular disorders (TMDs) are MSK disorders that affect the masticatory muscles, the temporomandibular joint, and related structures in the neck and head. Current research showed that people with chronic TMDs have structural and functional brain changes that may contribute to chronic pain development and maintenance. Therapeutic exercise is a central component in treating chronic MSK conditions. New therapies, including exercise, appear to have potential in targeting cortical changes to improve clinical outcomes. However, mechanisms of action are not well understood, and evidence is limited to a few weak studies and specific populations. Evidence from our research group highlights neck exercise as potentially useful in treating TMDs. However, we do not yet know how the brains of women with TMD respond to specific exercise and whether these changes relate to decreased pain, improved function, and quality of life. Evidence linking brain plasticity, pain modulation, and exercise therapy is currently limited, and non-existent for people with TMDs. Objectives: In women with chronic TMD pain, we will:1) determine the impact of motor control training using visual feedback (MCTF) on clinical outcomes such as pain intensity and jaw disability, 2) assess the impact of MCTF on brain structure, using diffusion tensor imaging, 3) assess the impact of MCTF on brain networks, using resting state functional magnetic resonance imaging, and 4) determine the effectiveness of MCTF to restore normal muscular structure, performance and fatigability of neck cervical muscles, using electromyographic analysis. Methods: Women with chronic TMD pain will be randomized to either an intervention arm or a placebo control group. Women in the intervention arm will receive 8 weeks of progressive exercise MCTF of the cervical muscles, twice per week. Women in the placebo arm will receive innocuous transcutaneous electrical nerve stimulation (turn off). Our primary outcomes will be changes in 1) pain, measured with the Visual Analogue Scale, 2) brain structure and networks, measured by fractional anisotropy (brain structure) and the blood-oxygen-level dependent signal (brain networks). Outcomes will be measured at baseline, after 8 weeks of treatment, and 4 months after treatment ends. Results will directly inform and guide clinicians in prescribing more effective interventions for women with TMD

To treat musculoskeletal disorders, looking at the brain is an unusual strategy but one with high potential for effectiveness. Exercise can potentially train the brain if we understand the links between exercise and productive changes in the brain. Given the high prevalence, impact, and burden of musculoskeletal disorders (MSKDs), therapies need to focus on the origin of the problem to be more effective and reduce economic costs. The latest evidence highlights the need for musculoskeletal rehabilitative therapy, including exercise, to look both at local structural and functional abnormalities of the MSK system and at alterations within the central nervous system. These central alterations have been shown to have a crucial role in the pathophysiology and clinical manifestations of MSKDs. People with chronic MSKDs show brain alterations such as decreased regional grey matter volume in brain areas such as the cingulate cortex, the insula, and the superior frontal and temporal gyrus. They also have impairments in pathways related to pain modulation. These brain alterations are visible in people with chronic MSKDs such as low back pain, osteoarthritis, headaches, and chronic temporomandibular disorders (TMDs).

Therapeutic exercise is a cornerstone for MSKD rehabilitation. Although its effects on pain are not fully understood, therapeutic exercise is widely applied in a variety of painful MSK conditions, including TMDs. Maladaptive changes in the motor cortex in MSKDs can improve after specific exercise training through motor control exercises and skilled cognitive practice, through strength and resistance training, and through novel motor training and visual feedback. However, all this evidence comes from preliminary studies with small sample sizes, before-and-after designs, and in specific clinical populations. Expanding this knowledge base to other clinical populations, with stronger study designs such as randomized controlled trials (RCTs), is important to accurately understand the effects of exercise therapy on brain plasticity and determine whether this approach is effective to manage MSKDs.

Our team is interested in managing TMDs through exercise therapy. From our previous studies on neck muscle impairment in people with TMDs and our recent update of a systematic review on therapeutic exercise to manage TMDs, we conclude that motor control exercise is a promising option to treat people with TMDs. However, the evidence is still limited and more high-quality investigations on the effectiveness of novel motor training in TMDs is needed.

OBJECTIVES

1. Determine the impact of motor control training using visual feedback (MCTF) on pain-disability related outcomes such as pain intensity, pain pressure thresholds and jaw disability. We will compare outcomes for people with TMDs who receive MCTF or a placebo treatment after 8 weeks of treatment, and 4 months after treatment ends.
2. Assess the impact of MCTF and explore its mechanisms of action on brain structure using DTI.
3. Assess the impact of MCTF on brain networks using rsfMRI.
4. Determine the effectiveness of MCTF in people with TMDs to restore normal muscular structure, performance and fatigability of the cervical muscles when compared with a placebo group.

THE PROPOSED TRIAL: MATERIALS AND METHODS Design: This study will be a randomized controlled trial (RCT). A randomization sequence will be computer-generated by a research assistant (RA) not involved in the study. To ensure concealment, the RA will distribute the results of the sequence to the therapist in consecutively numbered, opaque, and sealed envelopes. Participants will be unaware of the study hypothesis. Assessors (who will measure clinician-assessed tests and analyze imaging outcomes) and the statistician will be blinded to the hypothesis and group allocation, following established guidelines. Participants randomized to the treatment group will receive MCTF as described in the Intervention section. Participants randomized to the placebo group will receive placebo transcutaneous electrical nerve stimulation (TENS) as described in the Intervention section.

Participants: A convenience sample of people who attend the TMD/Orofacial Pain clinic (School of Dentistry, Faculty of Medicine & Dentistry, University of Alberta (UofA)) will be recruited.

Sample Size: This will be a pilot study. Based on data of previous study, using pain intensity as a main outcome and the ANOVA repeated measures within-between interaction (effect size d=0.27) using α=0.05 and β=0.95, a sample size of approximately 18 subjects per each group is required. Due to the possibility of a 10% of dropouts, we will recruit 20 subjects per group. Sample size calculation for the MRI variables was based on values of FA measurements of White Matter (WM) obtained from the WM adjacent to S1/M1 area obtained from Moayedi et al study on subjects with TMD. Based on a moderate difference between groups (effect size d=0.7) using α=0.05 and β=0.20, using an ANOVA analysis for 2 groups, a sample size of approximately 10 subjects per each group is required

PROCEDURES General Considerations: An experienced assessor will determine eligibility of participants and will evaluate them with the standardized forms from the new DC/TMD. REDcap, a password protected web platform (supported by the UofA) will be used to collect all outcomes.

Twenty subjects (10 subjects from the exercise group and 10 subjects from the placebo group) will be randomly allocated to undergo magnetic resonance imaging assessments of their brains at baseline, 2, and 6 months after randomization for both groups (treatment and control groups) if budget permits.

Primary Outcome Variables: The main outcome measures for this study are pain intensity (measured by the VAS) and Fractional Anisotropy (FA) and functional brain networks (evaluated by imaging).

All MRI will be performed in the Peter S. Allen MR Imaging Centre at the UofA by a certified MRI technologist.

Secondary Outcomes: will be discussed in the section of outcomes. The following will be considered secondary outcomes: The Neck Disability Index, Jaw function, Pressure pain threshold (PPT), cervical flexor muscle performance, Neck Extensor Endurance Test (NEET), the Neck Flexor Endurance test (NFET), Neck muscle structure, and Global Rating Scale (GRS)

INTERVENTION Early evidence from our research has shown that participants with TMDs present with abnormalities of the cervical flexor and extensor muscles. Exercises targeting these impairments reduce pain and level of dysfunction in people with cervical involvement. Thus, cervical motor control exercises are one of the most promising choices to treat people with TMDs. Treatment will consist of an 8-week progressive program of neck flexor and extensor exercises, performed for 30-45 min twice a week.

Neck flexor training: Exercise during the first stage will be an incremental craniocervical flexion movement in a relaxed, supine lying position. This exercise targets the deep flexors of the upper cervical region, the longus capitis and colli, rather than the superficial flexors, the sternocleidomastoid and anterior scalene muscles. Participants will be instructed to perform and hold progressively inner range positions of craniocervical flexion, using a pressure biofeedback connected to a screen. This will maximize feedback to the participants as described in Armijo-Olivo et al. Once the correct craniocervical flexion motion is achieved, participants will begin to hold progressively increasing ranges of craniocervical flexion. They will use feedback from the pressure unit placed behind their neck for 5 pressure targets (from 20 mmHg to 30 mmHg). Participants will be asked to hold each level for 10 s and perform 10 repetitions without compensatory movements, with brief rest periods between each contraction (~3-5 s). In the last 2 weeks of the exercise program, participants will perform higher-load exercise with head weight as the load. Numbers of repetitions and sets will be increased as permitted by the participant's response to the exercise. An endurance element will be incorporated by increasing the time the position is held, depending on the participant's progress.

Neck extensor training: Initially, participants will perform craniocervical extension and upper cervical rotation in a prone on elbows position while maintaining the cervical spine in a neutral position. They will progress to a 4-pt kneeling position. These exercises are designed to target the sub-occipital muscles. Attention will first be given to the spinal and scapular postures in the prone on elbows or 4-pt kneeling position. In the second phase of the exercise program, participants will perform higher-load exercise with head weight as the load, focusing on training the deep cervical extensors (the semispinalis cervicis/multifidus group). In this stage, they will initially perform up to 15 repetitions of neck extension while maintaining their head in a neutral position during 4-pt kneeling. Numbers of repetitions and sets will be increased as permitted by the participant's response to the exercise. An endurance element will be incorporated by increasing the time the position is held, depending on the participant's progress.

Participants will be asked to refrain from seeking any additional treatment during the study and will be asked to register their compliance with the exercise program in a daily diary using REDCap.

Placebo: The placebo group will receive placebo TENS (switched-off TENS apparatus with no perceptible stimulation). Four electrodes, 50 x 35 mm, will be placed on the neck muscles. The participant will be informed that this therapy is called a "subthreshold current" and they might not be able to feel any sensation underneath the electrodes during the treatment. The placebo treatment will be for 30 min twice a week for 8 weeks, as for the intervention group.

STATISTICAL ANALYSIS The analysis will follow the intention to treat principle. We will test for significant differences in VAS, PPT, TMDs and neck disabilities at baseline, after 8 weeks of treatment, and 4 months after treatment ends (6 months) between participants receiving MCTF and a placebo group. A two-way mixed ANOVA with repeated measures will be used for each outcome (Objective 1); We will test for significant changes in FA at baseline, after 8 weeks of treatment, and 4 months after treatment ends (6 months) between participants receiving MCTF and a placebo group, using a two-way mixed ANOVA with repeated measures. To determine the relationship between FA and the pain-disability and psychological outcomes, a multiple regression analysis will be conducted (Objective 2); We will determine if there are significant changes in rsfMRI networks after 8 weeks of treatment, and 4 months after treatment ends (6 months) between individuals receiving MCTF and a placebo group, using a two-way mixed ANOVA with repeated measures for each outcome. To determine the relationship between rsfMRI and the pain-disability and psychological outcomes, a multiple regression analysis will be conducted (Objective 3); We will determine if there are significant changes in CCFT, NEET, and NEFT, and cervical muscle structure at baseline, after 8 weeks of treatment, and 4 months after treatment ends (6 months) between individuals receiving MCTF and a placebo group, using a two-way mixed ANOVA with repeated measures for each outcome (Objective 4).

Psychological functioning variables (distress, depression, anxiety) will be covariates. The alpha level will be set at α = 0.05. A Bonferroni adjusted p-value will be applied to correct for potential multiple comparisons and a Bonferroni post hoc test will be used to determine the significant difference between pairwise comparisons. Effect sizes and minimal important difference of the outcomes (using the GRS as an anchor measure) will be used to determine the clinical significance of results.

Inclusion Criteria:

1. females 18-60 years of age (TMDs are more prevalent in females);
2. diagnosed with muscle pain disorders as classified by the new Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) or mixed TMD;
3. have had pain in the masticatory muscle for at least 3 months;
4. have chronic masticatory muscle pain not attributable to recent acute trauma, previous infection, or active inflammation; and
5. have a moderate or severe baseline pain score of 30 mm or greater using a 100 mm VAS.

Exclusion Criteria:

1. metabolic, rheumatoid, or vascular diseases;
2. commonly comorbid functional chronic pain disorders (e.g., irritable bowel syndrome, fibromyalgia);
3. psychiatric disorders (e.g., depression, schizophrenia);
4. abnormal neurological examination;
5. contraindication for MRI scanning (e.g., metallic surgical implant);
6. self-report of substance abuse;
7. exercise therapy in the 6 months before entry into the study or current treatment for TMD;
8. previous experience with electrotherapy; or
9. pregnant or planning a pregnancy.

After confirming eligibility to participate in the study, all participants will be asked to sign an informed consent in accordance with the UofA´s policies on research using human participants.

Patients (reporting one of the main outcome for this study - pain) will be unaware of the hypothesis of this study and performance biases will be avoided by telling them that both treatment options have similar effectiveness. Assessors (measuring clinician assessed tests) and Statistician will be blinded to hypothesis and group allocation following established guidelines.