Mechanisms of Neurodynamic Treatments

Study Overview
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Brief Summary
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INTRODUCTION: Carpal tunnel syndrome (CTS) is a relatively common condition caused by compression of one of the main nerves at the wrist, the median nerve. Non-surgical treatments, like steroid injections and physiotherapy, are the first line of treatment for patients with carpal tunnel syndrome. The investigators have previously shown that specific physiotherapeutic exercises (neurodynamic exercises) can reduce the need for carpal tunnel surgery in some patients. Experimental studies in animal models demonstrate that these exercises have an anti-inflammatory effect and can help the nerve to regenerate. However, the exact mechanisms of action of these exercises are not well understood in patients. A better understanding of the mechanisms of action of physiotherapeutic exercises would help clinicians to better target these treatments to those patients who may benefit from them. AIM: To investigate the mechanisms of action of 6 weeks' neurodynamic treatments on nerve function and structure as well as patient-reported outcome measures in patients with CTS compared to a positive control intervention (routine care steroid injection) and a negative control intervention (advice). METHODS AND ANALYSIS: In this single-blind randomised mechanistic trial, patients with confirmed mild to moderate CTS (n=78) and age and gender-matched healthy controls (n=30) will be included. Patients will be randomly allocated to a 6-week neurodynamic exercise group, steroid injection, or advice group. Outcome measures will be explored at baseline (patients and controls), post-intervention (patients), and 6-month follow-up (patients). Outcomes include diffusion-weighted and anatomical MRI of the median nerve at the wrist, quantitative sensory testing, nerve conduction studies, inflammatory markers in blood and skin biopsies, and validated questionnaires for pain, function, and psychological factors. Two-way repeated measures ANCOVAs (factors time and intervention, adjusted for baseline measurements as a continuous covariate) will be performed to identify differences in MRI parameters, clinical assessment, and inflammatory markers between patients in different groups and healthy controls.

Detailed Description
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Follow-up at 6 months will only include outcome measures from questionnaires.

Official Title
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Mechanisms of Neurodynamic Treatments (MONET)

Conditions
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Diffusion MRI, Physiotherapy, Mechanistic Trial, Carpal Tunnel Syndrome, Neurodynamic Treatment, Nerve Mobilisation

Intervention / Treatment
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* Other: Neurodynamic exercises
* Drug: Steroid injection (Depomedrone 40mg)
* Other: Advice


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Patients: Patients who have a diagnosis of mild to moderate carpal tunnel syndrome based on a clinical assessment and confirmed with nerve conduction studies. Male or Female, aged 18 years or above. Patient is willing and able to give informed consent for participation in the study. Healthy participants: Male or female aged 18 years or above. Participant is willing and able to give informed consent for participation in the study. No history of hand or arm symptoms No history of neck pain in the past 3 months No systemic medical condition No strong anticoagulant medication or altered coagulation (e.g., hemophilia) preventing skin biopsies Severe anxiety or depression Participants are required to be age- & sex-matched to patient participants No contraindications for magnetic resonance scanning at 3T Sufficient command of the English language Exclusion Criteria Patients: Patients who already had surgery for their carpal tunnel syndrome (CTS) or are planning to undergo surgery in the next 6 weeks (patients with unilateral surgery who have unoperated CTS on the other hand are eligible to participate) Patients who had a steroid injection for their CTS in the 6 months prior to the study enrolment or who had already more than 1 steroid injection into the study wrist. Patients who have a diagnosis of severe carpal tunnel syndrome based on a clinical assessment and confirmed with electrodiagnostic testing Electrodiagnostic testing revealing abnormalities other than CTS Any other upper limb or neck problem for which they have sought treatment in the past 3 months History of significant trauma to the upper limb or neck Diabetes Hypothyroidism Severe anxiety or depression Patient who is pregnant, lactating, or planning pregnancy during the study. Patients on strong anticoagulant medication or altered coagulation preventing skin biopsies. Contraindications for magnetic resonance imaging (assessed with MRI safety screening questionnaire). Contraindications for steroid injections Insufficient command of the English language

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurodynamic exercises<br>6-weeks home exercise programme of nerve and tendon gliding exercises | Other: Neurodynamic exercises<br>* The neurodynamic exercises will consist of a home-based exercise programme performed over a period of 6 weeks. Patients will attend a single session with an investigator who will instruct them the home exercise programme consisting of nerve and tendon gliding exercises which will be adjusted with pre-specified progressions over the 6 weeks intervention period. Patients will receive a leaflet and a video link detailing these exercises.<br>|
| Active Comparator: Steroid injection Steroid injection (Depomedrone 40mg)<br>Single steroid injection into Carpal Tunnel (positive control group) | Drug: Steroid injection (Depomedrone 40mg)<br>* Steroid injection (Depomedrone 40mg) into the carpal tunnel as per standard practice in patients with carpal tunnel syndrome<br>|
| Other: Advice<br>The advice group will receive advice but no additional intervention during the 6 week intervention period (negative control group) | Other: Advice<br>* Group receiving advice but no additional treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median nerve fractional anisotropy as determined on diffusion weighted imaging | Fractional anisotropy will be extracted from regions-of-interest in the median nerve and compared to healthy control group | Baseline | 
| Change in median nerve fractional anisotropy as determined on diffusion weighted imaging | Change in fractional anisotropy extracted from regions-of-interest in the median nerve at post-intervention (after 6-weeks) compared to baseline | From baseline to post-intervention (after 6-weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nerve markers on diffusion weighted imaging: water diffusivity (mm2/s) | Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data | Baseline | 
| Change to nerve markers on diffusion weighted imaging: water diffusivity (mm2/s) | Measured at the median nerve and cervical dorsal root ganglia. mm2/s; continuous data | From baseline to post-intervention (after 6-weeks) | 
| Nerve markers on anatomical MRI | Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data | Baseline | 
| Change in nerve markers on anatomical MRI | Measured at the median nerve and cervical dorsal root ganglia. ratio/mm2; continuous data | From baseline to post-intervention (after 6-weeks) | 
| Median nerve MRI T2 mapping | ms; continuous data | Baseline | 
| Changes in median nerve MRI T2 mapping | ms; continuous data | From baseline to post-intervention (after 6-weeks) | 
| Median nerve MRI magnetisation transfer ratio (MTR) | ratio; continuous data | Baseline | 
| Changes in median nerve MRI magnetisation transfer ratio (MTR) | ratio; continuous data | From baseline to post-intervention (after 6-weeks) | 
| Changes in median nerve conduction velocities from electrodiagnostic studies (m/s) | m/s; continuous data | From baseline to post-intervention (after 6-weeks) | 
| Changes in median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs): amplitudes (mV) | mV; continuous data | From baseline to post-intervention (after 6-weeks) | 
| Thermal detection thresholds as assessed in Quantitative Sensory testing - warm and cold detection threshold; thermal sensory limen | Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Data is measured in degrees celsius (point at which cold or warm is detected) | Baseline | 
| Change in thermal detection thresholds as assessed in Quantitative Sensory testing- warm and cold detection threshold; thermal sensory limen | Thermal detection thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Data is measured in degrees celsius (point at which cold or warm is detected) | From baseline to post-intervention (after 6-weeks) | 
| Thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold | Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior). Data is measured in degrees celsius (point at which cold or warm is initially detected as painful) | Baseline | 
| Change in thermal pain thresholds as assessed in Quantitative Sensory testing- warm and cold painful threshold | Pain thermal thresholds will be assessed using a thermode over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger) and over the contralateral lower limb (tibial anterior). Data is measured in degrees celsius (point at which cold or warm is initially detected as painful) | From baseline to post-intervention (after 6-weeks) | 
| Mechanical detection thresholds as assessed in Quantitative sensory testing | Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean will be calculated | Baseline | 
| Change in mechanical detection thresholds as assessed in Quantitative sensory testing | Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean wil be calculated | From baseline to post-intervention (after 6-weeks) | 
| Mechanical pain thresholds as assessed in Quantitative sensory testing | Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior). | Baseline | 
| Change in mechanical pain thresholds as assessed in Quantitative sensory testing | Mechanical pain thresholds will be assessed using a series of weighted pin prick stimulators (mN). They will be assessed over the index finger and over the contralateral lower limb (tibial anterior). | From baseline to post-intervention (after 6-weeks) | 
| Mechanical pain sensitivity as assessed in Quantitative sensory testing | Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating no pain, and '100' indicating most intense pain imaginable). Geometric mean of all numerical ratings for pinprick stimuli will be calculated | Baseline | 
| Change in mechanical pain sensitivity as assessed in Quantitative sensory testing | Mechanical pain sensitivity will be assessed using a series of weighted pin prick stimulators (mN) over the index finger. Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating no pain, and '100' indicating most intense pain imaginable). Geometric mean of all numerical ratings for pinprick stimuli will be calculated | From baseline to post-intervention (after 6-weeks) | 
| Dynamic mechanical allodynia as assessed in Quantitative sensory testing | Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating no pain, and '100' indicating most intense pain imaginable). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger | Baseline | 
| Change in dynamic mechanical allodynia as assessed in Quantitative sensory testing | Pain rating for each stimulus on a 0-100 numerical rating scale ('0' indicating no pain, and '100' indicating most intense pain imaginable). Geometric mean (compound measure) of all numerical ratings across light touch stimulators over the index finger | From baseline to post-intervention (after 6-weeks) | 
| Wind-up ratio as assessed in Quantitative sensory testing | Wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continous data | Baseline | 
| Change in wind-up ratio as assessed in Quantitative sensory testing | Change in wind-up ration will be assessed using a pin prick (mN) over the index finger (e.g., ventral aspect of the proximal phalanx of the index finger). Ratio, continuous data | From baseline to post-intervention (after 6-weeks) | 
| Vibration detection thresholds as assessed in Quantitative sensory testing | Vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal) | Baseline | 
| Change in vibration detection thresholds as assessed in Quantitative sensory testing | Change in vibration detection thresholds will be assessed using a tuning fork (64 Hz, 8/8 scale) over a bony prominence over (e.g., palmar side of the distal end of the second metacarpal) | From baseline to post-intervention (after 6-weeks) | 
| Pressure pain thresholds as assessed in Quantitative sensory testing | Pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior) | Baseline | 
| Change in pressure pain thresholds as assessed in Quantitative sensory testing | Change in pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior) | From baseline to post-intervention (after 6-weeks) | 
| Pinch strength test - maximum isometric strength | Pinch grip dynamometry. Continuous data, kg | Baseline | 
| Change in pinch strength test - maximum isometric strength | Pinch grip dynamometry. Continuous data, kg | From baseline to post-intervention (after 6-weeks) | 
| Nerve mechanosensitivity- upper limb neurodynamic test (median nerve) | Evaluation of nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees) | Baseline | 
| Change in nerve mechanosensitivity- upper limb neurodynamic test (median nerve) | Change in nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees) | From baseline to post-intervention (after 6-weeks) | 
| Nerve mechanosensitivity - positive upper limb neurodynamic tests | Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms plus when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative' | Baseline | 
| Change in nerve mechanosensitivity - positive upper limb neurodynamic tests | Upper limb neurodynamic tests will be assessed to determine the presence of increased mechanosensitivity. The neurodynamic test will be graded as 'positive', when there is at least partial reproduction of symptoms and when symptoms can be modified with structural differentiation. Otherwise, the neurodynamic test will be graded as 'negative' | From baseline to post-intervention (after 6-weeks) | 
| Symptom severity and limitations in hand function as assessed by the Boston carpal tunnel syndrome questionnaire | Patient reported symptoms and limitations on the Boston carpal tunnel syndrome questionnaire | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Symptom intensity levels on a Visual Analogue Scale (VAS) | Patient reported average intensity of pain, paraesthesia and numbness on 10cm visual analogue scales, ranging from no symptoms to worst symptoms ever | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Location of symptoms in a body and a hand diagram | Patient reported location of symptoms in a body diagram and a hand diagram. | Baseline, post-intervention (after 6 weeks) | 
| Presence of central sensitisation as assessed with the Central Sensitisation Inventory | Patient reported central sensitisation on the Central Sensitisation Inventory | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Functional deficits- Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire | Participant reported outcomes on ability to perform activities as per quick DASH questionnaire | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Functional deficits- Patient specific functional scale (PSFS) | Participant reported outcomes on the patient specific functional scale | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Presence of neuropathic pain - DN4 | Patient screened for neuropathic pain using DN4 | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Presence of neuropathic pain - pain DETECT | Patient screened for neuropathic pain using pain DETECT | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Neuropathic pain symptoms - Neuropathic Pain Symptom Inventory | Patient reported outcomes on neuropathic pain symptoms as assessed on Neuropathic Pain Symptom Inventory. | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Presence of psychological co-morbidities - The Depression, Anxiety, and Positive Outlook Scale (DAPOS) | Participant reported outcomes on depression and anxiety as per DAPOS | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Presence of psychological co-morbidities - short-form Pain Anxiety Symptoms Scale (PASS-20) | Participant reported outcomes on depression and anxiety as per short-form Pain Anxiety Symptoms Scale (PASS-20) | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Presence of psychological co-morbidities - pain catastrophizing scale (PCS) | Participant reported outcomes on depression and anxiety as per pain catastrophising scale (PCS) | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Assessment of quality of life - EQ-5D-5L | Participant reported outcomes on quality of life as per EQ-5D-5L questionnaire | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Assessment of sleep interference - Insomnia Severity Index | Participant reported outcomes on sleep interference with the Insomnia Severity Index. | Baseline, post-intervention (after 6 weeks), 6-months follow up | 
| Adverse and serious adverse events | Patient self-reported adverse events | From start of intervention until end of intervention (6 weeks) | 
| Exercise adherence to the neurodynamic home-based intervention - number of sessions | Patient self-reported number of sessions per day throughout the intervention in an exercise diary | From start of intervention until end of intervention (6 weeks) |