How the Brain and Body Recover After a Wrist Fracture

Study Design Prospective cohort Study Participants (1) Patients aged 18 years and older, with an acute fracture of the distal radius within the past 6 weeks, willing and competent to complete the informed consent process. Patients with multiple trauma; have had an open fracture; have a unilateral sensory deficit; significant neurological disease or patients who would be unable to follow trial procedures will be excluded.

(2) Participants with Chronic Complex Regional Pain Syndrome (CRPS), willing and competent to complete the informed consent process.

Planned Size of Sample Total of 250 participants

• 200 with distal radius fractures
• 50 with chronic CRPS Planned Study Period September 2025 - 2029 (4 years) Research Aim The primary aim of this study is to perform multi-domain deep phenotyping of patients following a distal radius fracture, to generate novel hypotheses regarding the biological and physiological mechanisms that predict the transition to chronic pain and Complex Regional Pain Syndrome (CRPS).

Key research questions

• Validate candidate genes and identify molecular biomarkers associated with pain persistence and development of CRPS
• To characterise the neurobiological and bodily representation changes that occur following a wrist fracture and their impact on the patient experience using fMRI
• Investigate autonomic nervous system function as a potential predictor of clinical outcomes using Wearable digital technology
• To assess the feasibility and acceptability of home-based Virtual Reality interventions in body representation disorder and pain persistence patients

Domain level objectives Objectives Outcome measures Time point(s) of evaluation

• Genetic and Molecular biomarkers 1a) Validate candidate genes, previously identified in chronic CRPS cohorts, in a prospective cohort of at-risk patients' post-fracture Frequency of four specific CRPS associated SNPs determined through PCR analysis PCR analysis of genomic DNA extracted from participants whole blood at month 0 n. 200 (DRF patients) 1b) To analyse for molecular biomarkers that may link with development of chronic pain and CRPS Biomarkers (including cytokines TNFα, Il-1 and IL-6, miRNA expression profiles miR-232 and miR-939 and autoantibodies) Biomarker analysis from whole blood samples taken at month 0 for all DRF patients and at month 6 for participants enrolled in sub-studies Month 0 n. 200 (DRF patients) Month 6 n. 50 - 94 (Sub-studies follow up participants) 1c) To compare genetic and molecular biomarker profiles from acute fracture cohort with those from an established chronic CRPS patient cohort Biomarkers (including cytokines TNFα, Il-1 and IL-6, miRNA expression profiles miR-232 and miR-939 and autoantibodies) Biomarker analysis from whole blood samples taken at month 0 n. 50 (chronic CRPS)
• Neurobiology and Body Representation Disturbance (BRD)

2a) To identify predictive neural signatures in hypothesis-driven regions of interest (e.g. insula, parietal cingulate and ventral premotor cortices) Functional MRI Functional connectivity measures and Brain activation patters measured as Blood-Oxygen-Level-Dependent (BOLD) fMRI performed at month 0 and 6 n. 24 DRF

• 2:1 ratio between disturbed and normal body representation (16 BRD Vs 6 non-BRD

2b) To quantify the impact of BRD on pain severity, perception and quality of life in participants following a distal radius fracture Patient reported outcome measures (PROMS)

• Bath CRPS Body Perception Disturbance Scale
• Neglect-Like Questionnaire
• Body disownership scale
• Brief Pain Inventory
• Fear of Pain Questionnaire - Short form
• Pain Catastrophizing Scale
• Pain Self Efficacy Questionnaire
• Quick Disabilities of the Arm, Shoulder and Hand
• Pittsburgh Sleep Quality Index
• Edinburgh Handedness Index - Short Form
• Hospital Anxiety and Depression Scale PROMS performed at month 0 for all DRF patients and at month 6 for participants enrolled in sub-studies Month 0 n. 200 (DRF) Month 6 n. 50 - 94 (Sub-studies follow up participants) 3. Heart rate variability (wearable digital technology) 3a) To analyse heart rate variability captured via remote wearable technology as a biomarker for predicting outcomes in baseline high vs low pain groups and recovery between high and low pain scores (VAS >6 and <3 respectively) Heart rate variability obtained from wearable device worn on non-fractured wrist for 5 days. Months 0 and 6 n. 50
• 1:1 ratio between numerical rating scale <3 and >6 (25 <3 Vs 25 >6) 4. Virtual Reality intervention feasibility 4a) To evaluate the feasibility, acceptability and preliminary influence on pain and body representation of a home-based virtual reality intervention. Self-reported feasibility and subjectivity questionnaire outcomes and digital wearable variables over 7-day regular usage period.

Patient reported outcome measures (PROMS)

• Tampa Scale of Kinesiophobia
• System Usability Scale
• Virtual Reality Subjective Questionnaire
• Subjective Experience Survey Month 6 n. 20 (BRD or pain persistence at 6 months)

Inclusion criteria

Distal radius fracture (DRF) within past 6 weeks 18 and older Willing and competent to complete the informed consent process

Exclusion criteria

Inability to understand the informed consent process (Language, competence) Multiple trauma Significant neurological disease (multiple sclerosis, previous traumatic brain injury, previous stroke or cerebral haemorrhage and substantial tremor - including Parkinson's, significant resting tremor, or other aetiology) Amputation or medical confirmation of unilateral sensory deficit