Quantitative Ultrasound Response of Capsaicin
Condition: Central Sensitisation
Study type: Interventional
Phase: Early Phase 1

Summary: 
      Central Sensitization is an aspect of chronic pain and is associated with over-excitability
      of the central nervous system. Central Sensitization normally presents itself with other
      chronic syndromes such as Myofascial Pain Syndrome, so it is difficult to separate the
      characteristics of the two. The purpose of this study is to determine whether sensitizing
      healthy muscle using capsaicin, a chilli pepper extract, induces a regional change in
      ultrasound texture features of the targeted muscle, or the muscles in that are in close
      proximity. This regional change will be accompanied by electromyography (EMG) recordings to
      confirm the presence of abnormality. Topical capsaicin and injectable capsaicin will be
      applied at three different concentrations, 0ug(placebo effect),50ug and 100ug.

      Research Questions:

      Does sensitization cause a significant regional change in the texture features of the
      targeted muscle or surrounding muscles? Is this regional change confirmed by abnormality of
      motor unit firing rates or EMG amplitudes? Is the response dose dependent? Does the induced
      central sensitization cause a change in force steadiness?

      Experimental Protocol:

      The physician on site will apply surface and intramuscular EMG sensors to the trapezius. A
      goniometer will be placed on the subjects arm to detect position. Following this, an
      ultrasound image of the trapezius, supraspinatus and infraspinatus will be taken.The
      participant will perform an increasing and decreasing contraction.The subject will then have
      capsaicin injected into their trapezius or applied onto their skin. The exercise and
      measurements will then be repeated. The ultrasound will be acquired by the Sonosite
      ultrasound system. The EMG data will be acquired by the Delsys Trigno EMG system for the
      surface EMG and the Cadwell Sierra Wave system for the intramuscular EMG. The data will be
      processed through Delsys EMGworks software and MATLAB. Texture features of the pre and post
      injection ultrasound images will be compared. Decomposition of motor units will allow for the
      analysis of motor unit action potential firing rate and amplitudes. Analysis of force
      steadiness will also be calculated via the goniometer.

      Overall, the findings from this study should present preliminary evidence to inform central
      sensitization's effects on regional muscle structure changes, functional changes and motor
      unit activity.
    

Detailed description: 
      Myofascial pain syndrome (MPS) is a prevalent chronic pain disorder primarily characterized
      by myofascial trigger points (MTrP). There is limited knowledge on the pathophysiology and
      mechanisms underlying MTrP and its development. Ultrasound investigations that have been
      performed on trigger points can differentiate between active and latent trigger points, but
      have not characterized the central sensitization aspect of them. The electromyography (EMG)
      investigations of central sensitization that have been performed mostly use hypertonic saline
      to induce hyperalgesia, and have demonstrated conflicting results. Central sensitization has
      been proposed as the primary mechanism underlying MTrP development. Central sensitization is
      associated with hyperexcitability of neuronal responses to normal or noxious stimuli. There
      is a need for a study that quantifies regional central sensitization using ultrasound to
      measure the changing structure, and electromyography to measure specific motor unit activity
      responses in the muscle.

      Purpose The purpose of this study is to determine whether sensitizing healthy muscle using
      capsaicin induces a change in the structural integrity of the affected muscle, and determine
      if the motor unit frequency and amplitudes change within that region. Central sensitization
      will be induced using topical capsaicin and injectable capsaicin at three different
      concentrations. This is an exploratory trial that aims to provide preliminary evidence on
      whether central sensitization is a direct cause of taut band and MTrP development.

      Our specific research questions are followings:

        1. Does sensitization cause a significant regional change in the texture features of the
           targeted muscle or surrounding muscles?

        2. Does capsaicin induced sensitization elicit a change in motor unit action
           potential(MUAP) amplitude by approximately 20 to 25% within the region of experimentally
           induced central sensitization or in the region of texture feature changes? Our
           hypothesis for this portion of the study is that sensitization modifies the anterior
           horn cell activity which will be measured by the amplitude of the potentials.

        3. Does capsaicin induced sensitization elicit continuous electrical activity as observed
           in MTrPs? This tests the hypothesis that sensitization creates the presence of
           continuous low amplitude action potentials.

        4. Does capsaicin induced sensitization influence the rate of recruitment of motor units in
           the muscle within the region induced? Does this occur within the regions identified by
           the changes in texture features? The recruitment of motor units is normally expected to
           follow the Henneman size principle.[20-23] Our hypothesis for this portion of the study
           is that sensitization will cause an aberration in recruitment. If this is demonstrated,
           then there is modification of the normal processing at both dorsal and ventral horns of
           the spinal cord.

        5. Is there a location dependent EMG response to capsaicin induced sensitization? In other
           words, do the texture features or EMG responses from muscles that lie anatomically
           distant from the location of the site of intramuscular capsaicin injection have changes
           from their baseline calculations? This would test the hypothesis that type III and IV
           afferents have an influence on the anterior horn cells that lie distant to the ones that
           are supplying muscle fibers in the vicinity of the stimulated sensory afferents.

        6. Is there a dose dependent EMG response at motor units to capsaicin induced
           sensitization? Here, the hypothesis of causality will be assessed in a preliminary
           manner. If there is a relationship then further experiments that more thoroughly assess
           causality will be needed.

      This proposed study is a single centered, factorial, randomized placebo-controlled trial with
      two independent variables, depth of capsaicin application(3 levels) and dose of capsaicin(3
      levels), for a total of 6 treatment arms and three control groups.The first between groups
      variable will be topical capsaicin application, injectable(intrafascial) and
      injectable(intramuscular) capsaicin injection. Within each partition, there will be three
      treatments: control, 50 micrograms, 100 micrograms. The control group will receive a topical
      skin lotion that is inert and has no sensitization effect. An equal number of participants
      will be allocated to each of the six treatment groups using an electronic randomization
      generator. Block randomization will be used to ensure equal allotment into each group.

      Capsaicin Application and Injection Capsaicin will be applied directly to the region of the
      innervation zone at the muscle belly to sensitize the neurons within the region of taut band
      development. Topical and intramuscular capsaicin will be used. The capsaicin formula will be
      compounded by a registered pharmacist. Topical capsaicin will be delivered in a cream and
      injectable capsaicin will be intermixed with saline prior to injection. The control group in
      the topical capsaicin arm will be treated with the cream base used during the experiment
      without added capsaicin and the injection arm will be injected with saline. A trained medical
      professional on the research team will apply the topical capsaicin or topical placebo
      treatments. The region of topical application will measure 5cm squared in the dermatome zone
      location to cover an area of approximately 25cm2. A trained physician in physical medicine
      and rehabilitation will deliver injectable capsaicin using a 27-gauge needle at the location
      of the superior fascia of the upper trapezius muscle with ultrasound guidance. Intramuscular
      capsaicin will also be injected using ultrasound guidance to avoid the superior or inferior
      fascia.

      To confirm the presence of central sensitization, brush allodynia will be used to detect
      mechanical hyperalgesia outside the region of primary nociception. The size of the region of
      secondary hyperalgesia will be measured to characterize the extent of central sensitization.
      This will be accomplished using a tape measure and the perpendicular dimensions of the region
      of secondary hyperalgesia will be recorded in square centimeters.

      Experimental Protocol The anatomical location for ultrasound probe and electrode placement
      will be identified for each participant. The ultrasound probe will be placed on 3 muscles:
      the trapezius, the supraspinatus, and the infraspinatus. Two ultrasonic pictures will be
      taken of each. The area will then be cleaned with alcohol and water. The Delsys Galileo
      sensor, and the intramuscular needle electrode will be placed directly on the trapezius'
      identified area. Participants will be asked to gently contract their trapezius muscle. They
      will be instructed to perform a gradually increasing contraction in isometric condition, in a
      controlled manner. They will hold this contraction at 30% of their maximal voluntary
      contraction, and then perform a gradually decreasing contraction to rest. This will be
      performed four times for each type of study intervention and before as well as after each
      intervention, namely topical control cream, topical capsaicin at 50ug and 100 ug, injection
      of the superior aspect of the superior fascia followed by intramuscular injection with these
      two concentrations of capsaicin. The placement of these latter will be verified by ultrasound
      guidance. The intramuscular needle will then be removed and participants will be bandaged and
      cared for appropriately by the expert physician performing the experiment. Participants will
      be re-examined to determine if there were any adverse effects from the experimental
      procedures. If any occurred, then these will be carefully managed by the medical members of
      the research team and recorded. Participants will be asked to remain at the lab for an
      additional 30 minutes to ensure they are well prior to leaving.

      Ultrasound Analysis Texture analysis will be performed using MATLAB and the image and signal
      processing toolbox. Analyses will include first order parameters such as mean and standard
      deviation of the pixel level values, as well as second order parameters, which provide
      details on the spatial distribution of pixel values. These include co-occurance and
      run-length matrices, local binary pattern and blob analysis.

      EMG Analysis The following parameters will be analyzed: the firing times and frequency of
      individual motor units, motor unit action potential amplitude and shapes, the root mean
      square value (RMS) of each channel and of the entire signal, the coefficient of variation for
      force steadiness, and the centroid of the EMG signal in the cranial-caudal and the
      medial-lateral directions. These procedures will be repeated for each contraction.

      The results of this study should provide insight into the structural changes and motor
      changes at the region of sensitization, as well as in adjacent muscles.This will provide
      further insight as to whether structural changes are accompanied by motor changes within the
      same region, and inform further investigations into the pathophysiology of myofascial pain.

      The full study protocol and statistical analysis plan is submitted in the documents section.
    

Intervention name(s): Capsaicin; Delsys Trigno Galileo System; Cadwell Sierra Wave; Sonosite Ultrasound Machine; Goniometer
Intervention type(s): Drug; Device; Device; Device; Device
Intervention description(s): Capsaicin 50ug (low dose), Capsaicin 100ug(high dose) will be administered as a topical skin cream and will be intermixed with saline for the injectable solution.; This device is a wireless surface EMG device.; Intramuscular EMG recording machinery; Ultrasound System; A device to measure angular position
Intervention MeSH terms: Capsaicin
Allocation: Randomized
Intervention model: Factorial Assignment
Intervention model description: A single-centered, factorial, randomized, placebo-controlled trial with two independent variables (dosage and depth of application).
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: MUAP- Motor Unit Action Potential; RMS- Root Mean Square; US-Ultrasound