Mechanisms of Neurodynamic Treatments (MONET)

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.

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

The outcomes assessor and the person responsible for the statistical analysis will be blinded to the participants' allocation.

The advice group will receive advice but no additional intervention during the 6 week intervention period (negative control group)

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.

Steroid injection (Depomedrone 40mg) into the carpal tunnel as per standard practice in patients with carpal tunnel syndrome

Fractional anisotropy will be extracted from regions-of-interest in the median nerve and compared to healthy control group

Change in fractional anisotropy extracted from regions-of-interest in the median nerve at post-intervention (after 6-weeks) compared to baseline

Changes in median sensory nerve action potentials (SNAPs) and compound muscle action potentials (CMAPs): amplitudes (mV)

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)

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)

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)

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)

Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean will be calculated

Mechanical detection thresholds will be assessed using a standardised set of von Frey filaments (mN) over the index finger. Geometric mean wil be calculated

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).

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).

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

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

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

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

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

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

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)

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)

Pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)

Change in pressure pain thresholds will be assessed using an algometer (kg) on the thenar eminence and over the contralateral lower limb (tibialis anterior)

Evaluation of nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)

Change in nerve mechanosensitivity in response to mechanical load (increased tension) applied to the nerve. Range of elbow extension at point of symptoms (degrees)

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'

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'

Symptom severity and limitations in hand function as assessed by the Boston carpal tunnel syndrome questionnaire

Patient reported average intensity of pain, paraesthesia and numbness on 10cm visual analogue scales, ranging from no symptoms to worst symptoms ever

Patient reported outcomes on neuropathic pain symptoms as assessed on Neuropathic Pain Symptom Inventory.

Presence of psychological co-morbidities - The Depression, Anxiety, and Positive Outlook Scale (DAPOS)

Participant reported outcomes on depression and anxiety as per short-form Pain Anxiety Symptoms Scale (PASS-20)

Blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery

Change in blood samples coupled with detailed phenotype data will investigate potential gene associations in CTS and recovery

Concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site

Change in concentration of inflammatory markers in skin biopsies. Baseline biopsy will be performed in the most distal part of the ventrolateral side of the proximal phalanx of the index finger. The 6-weeks biopsy will be performed proximally, avoiding the primary biopsy site

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

IPD that underlie results of a publication will be shared upon the final publication of the main manuscripts of this study.

IPD will be shared upon reasonable request and in line with ethical approval with authors contacting the study investigators.