Motor Unit Abnormalities After Experimentally Induced Sensitization

Study Overview
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Brief Summary
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Central sensitization is a condition that represents a cascade of neurological adaptations, resulting in an amplification of nociceptive responses from noxious and non-noxious stimuli. This phenomenon presents itself in a vast majority of chronic pain syndromes. Previous evidence has shown that central sensitization results in afferent nociceptor and dorsal horn abnormalities; however, a link between whether this abnormality translates into motor output and more specifically, ventral horn abnormalities, needs to be further explored. Twenty participants were recruited and either a topical capsaicin or a placebo topical cream was applied to their back to induce a transient state of sensitization. Surface electromyography(sEMG) and intramuscular electromyography(iEMG) were used to record motor unit activity from the trapezius and infraspinatus muscles before and after application of capsaicin/placebo. Motor unit recruitment and variability were analyzed in the sEMG and iEMG respectively

Detailed Description
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Central sensitization describes a state of neuronal hyper-excitability in the central nervous system that may occur due to malfunction of spinal and supraspinal pain facilitatory and inhibitory circuits resulting in amplification of somatosensorial responses. Beyond somatosensorial changes, alteration in motor function can also be present with pain, and may be a reflex of neuromuscular function impairment. A normal afferent input and normal central processing circuitry is essential to deliver normal efferent output. However, the influence of the changes that occur within the dorsal horn on the ventral horn remain largely ill defined. Motor unit assessment is crucial in evaluating diseases and abnormalities within the ventral horn. Activity of the ventral horn, where anterior horn cells reside, is very important for motor unit activation. Surface EMG (sEMG) and intramuscular EMG (iEMG) can be used to assess the neural drive to muscles, by recording motor units to understand the effects of central sensitization on motor control and the ventral horn. Based on Henneman's size principle, motor units should be recruited in the same order, with smaller units being recruited first. This principle presents an opportunity to investigate if central sensitization creates abnormalities on the motor unit level. Previously, central sensitization has been induced in healthy subjects to examine its neurophysiological effects via capsaicin. Capsaicin, a chilli pepper extract, can be used to effectively induce experimental transient states of central sensitization. The presence of expanded sensorial responses and the involvement of the spinal nociceptive system post capsaicin have been largely tested by means of quantitative sensory testing methods and electromyography (EMG). Despite the usefulness of experimental capsaicin to better understand the sensorial abnormalities, its impact on motor function and motor unit recruitment are lesser studied. Evidence suggests that nociceptive input by peripheral capsaicin exerts a centrally-mediated inhibitory effect on motor function. A decrease in root mean squared (RMS) amplitude during exercise at the time of peak sensitization was measured by needle EMG. However, the effect that capsaicin-induced sensitization has on individual motor units or on their recruitment patterns has not been previously examined. The purpose of this study was to determine whether topical capsaicin-induced sensitization has any influence on ventral horn activity. We hypothesize that capsaicin induces a change in individual motor unit activity, as well as the recruitment pattern of many motor units, and may affect motor unit activity at different segmental levels from the level of capsaicin application. Participants: Twenty-three healthy participants, age between 20-70 years old, with no direct trauma to cervicothoracic region within the past 30 days, no past medical history of inflammatory disorders as rheumatoid arthritis, no neurodegenerative disorders such as Parkinson's disease nor motor neurone diseases as amyotrophic lateral sclerosis, or other neuromuscular disorder were recruited for this study. Also, included subjects had a normal body mass index (18.5 - 24.9) and had a pain visual analogue scale (VAS) below 3 indicating low pain severity. Since prevalence of neck pain in the general population is high, mild pain or aches are not necessarily related to an abnormality of the underlying muscle. Participants had to be able to communicate in English. Participants were excluded if they had persistent pain for more than 3 months. Experimental Protocol: An initial screening was performed to assess eligibility in the study. Each participant was seated upright with their hands comfortably on their lap and asked to relax their neck and shoulder muscles. The physician member of the research team then assessed the patients' pain intensity by visual analogue scale (VAS). VAS ranges from 0 to 100 mm which 0 mm reflecting no pain at all and 100 mm representing the worst imaginable pain. Following this, brush allodynia, a clinical technique used to identify pain due to a stimulus that does not normally provoke pain, was performed to confirm presence of central sensitization. To map out borders of secondary allodynia, subjects were instructed to recognize a distinct alteration in the sensation perception such as increased burning, intense pricking, or an unpleasant sensation, and that location was marked. Brush allodynia score (BAS) was calculated as the distance between the farthest points marked on the superior and inferior axis multiplied by the distance between the farthest points marked on the medial and lateral axis as previously described by Cavallone et. al. The VAS and the presence of central sensitization by means of BAS were assessed at baseline (pre) before the induction of sensitization and twenty minutes after (post). Upon successful screening of inclusion and exclusion criteria, participants had their left side area of skin (overlying the upper trapezius and infraspinatus muscles) cleansed with alcohol preparation pads and water. The skin was abraded with '3M Red Dot' abrasive strips before application of the surface electromyogram (Trigno Galileo sensors, Delsys Inc.). Electrodes were placed in 4 areas: the muscle belly of the upper trapezius, and the infraspinatus, as well as reference electrodes on C7 and the acromion. These electrodes were 4 channel EMG sensors and had their signals filtered from 20 - 450 Hz. The sEMG recordings were wirelessly transmitted to the Trigno base station, which relays and compiles the data to Neuromap (Delsys Inc.) for signal analysis. A monopolar needle electrode was inserted into the upper fibers of trapezius muscle and its reference was placed at the mid-clavicle point. Using this setup intramuscular recordings of single motor units were performed using an Excaliber, Natus Medical clinical electrodiagnostic machine. Electromyograms recordings before application of intervention Participants were instructed to perform horizontal shoulder abductions from 0° to 90° and then from 90° to 0° for 1 minute. The study subject was verbally cued to move their arm every 2 seconds. sEMGs were recorded during this time. Upon completion of this task, a monopolar intramuscular needle electrode was placed directly into the upper trapezius muscle. Participants were then instructed to gently contract their trapezius muscle by shrugging their shoulder, enough to recruit only the first motor unit in that region. Visual feedback of the signal was given to the subject to ensure that only the first motor unit was activated for the movement. The signal from this motor unit was then optimized for initial deflection from baseline and amplitude characteristics before recordings were made. iEMG recordings were recorded for 30 seconds at a sampling frequency of 6 kHz. Application of intervention Participants received either a dose of 2.5 ml (75µg/ml) capsaicin cream (treatment, Zostrix brand) or skin lotion (placebo) which was inert and caused no sensitization effects. Participants were also blinded to the delivered treatment, using concealed containers for the creams. The location of application was a 10 cm by 10 cm square on trapezius muscle which extended from T3 to T8 on the left side that all recordings were conducted. After collection of the baseline sEMG and iEMG recordings, a trained medical professional applied the capsaicin / placebo cream directly to the region of skin in a standardized 10 cm x 10 cm square at the spinal levels T3-T8, to sensitize the nociceptive afferents within that region. A twenty-minute waiting period was used to enable the sensitizing effects of capsaicin to take effect. Electromyograms recordings after application of intervention To confirm the presence of central sensitization, brush allodynia was used to detect mechanical allodynia outside the region of the primary nociception - region of topical placement - which is the region of secondary allodynia. Upon confirmation of central sensitization, in participants with application of topical capsaicin, participants were entered into the experimental arm of the study.

Official Title
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Evaluation of Motor Unit Abnormalities After Experimentally Induced Sensitization Using Capsaicin: A Randomized, Double-Blinded, Placebo-Controlled Study

Conditions
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Central Sensitisation, Motor Disorders

Intervention / Treatment
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* Drug: Capsaicin Topical Cream (0.075%)
* Device: Delsys Trigno Galileo System
* Device: Excaliber, Natus Medical
* Other: Placebo Cream


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: subject with a normal body mass index (18.5 - 24.9) a pain visual analogue scale (VAS) below 3 indicating low pain severity Exclusion Criteria: medical history of inflammatory disorders as rheumatoid arthritis neurodegenerative disorders such as Parkinson's disease motor neurone diseases as amyotrophic lateral sclerosis, or other neuromuscular disorder

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 70 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized placebo controlled trial using 2 treatments: 1) placebo cream 2) capsaicin cream (0.075%) (Zostrix HP)
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Topical<br>The cream was a lipobase cream, applied topically to the participants upper back, on their left side. | Device: Delsys Trigno Galileo System<br>* A wireless surface EMG device. The sensors will be placed on the trapezius and the infraspinatus muscle, and a recording will be performed.<br>Device: Excaliber, Natus Medical<br>* Intramuscular EMG machine. The intramuscular electrode will be inserted into the trapezius and a recording will be performed.<br>Other: Placebo Cream<br>* Placebo cream will be administered as a topical skin cream<br>|
| Active Comparator: Capsaicin Topical<br>Capsaicin Cream (0.075%), applied topically to the participants upper back, on their left side. | Drug: Capsaicin Topical Cream (0.075%)<br>* Capsaicin cream will be administered as a topical skin cream<br>* Other names: Zostrix HP;Device: Delsys Trigno Galileo System<br>* A wireless surface EMG device. The sensors will be placed on the trapezius and the infraspinatus muscle, and a recording will be performed.<br>Device: Excaliber, Natus Medical<br>* Intramuscular EMG machine. The intramuscular electrode will be inserted into the trapezius and a recording will be performed.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain and Presence of Central Sensitization | Visual Analogue Scale(0-no pain to 10-worst pain imaginable) will measure the amount of burning pain experienced by the intervention | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor Unit Sequence Difference | The recruitment order of the pre motor unit and post motor units will be examined, determining how much the recruitment order changed | 3 months | 
| Variance of Motor Unit Action Potential | The difference in variance within the pre recorded MUAP train and post recorded MUAP train will be examined. | 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Central Sensitization, Surface Electromyography, Intramuscular Electromyography, Motor Unit, Recruitment