Transcutaneous Auricular Vagus Nerve Stimulation as a Treatment for Musculoskeletal Pain in Cerebral Palsy

Musculoskeletal pain severity and pain interference will be assessed using the Brief Pain Inventory (BPI). The BPI pain severity subscale evaluates pain intensity using four 0-10 numeric rating scale items assessing worst, least, average, and current pain. A composite pain severity score will be calculated as the mean of these four items, in accordance with IMMPACT recommendations. Pain interference will be assessed using the BPI interference subscale, which evaluates the extent to which pain interferes with general activity, mood, walking ability, normal work, relationships, sleep, and enjoyment of life using 0-10 numeric rating scales. Higher scores indicate greater pain severity or interference. Assessments will be conducted by trained outcome assessors blinded to group allocation.

Musculoskeletal pain severity will also be assessed using the Numeric Pain Rating Scale (NPRS), a simple and widely used self-report measure of pain intensity. Participants will rate their average pain intensity on an 11-point numeric rating scale ranging from 0 (no pain) to 10 (worst imaginable pain). The NPRS will serve as a complementary, standardized measure of pain intensity to enhance the robustness and interpretability of pain assessment.

All treatment-emergent adverse events occurring during the intervention period will be recorded through weekly phone calls and/or study visits. Adverse events will be summarized by type, frequency, severity, and relationship to the study intervention. The number and proportion of participants experiencing at least one adverse event will be compared between the active taVNS and sham taVNS groups.

Health-related quality of life will be assessed using the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), a validated self-report measure of health status. The EQ-5D-5L assesses five domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, each rated across five levels of severity. Change in health-related quality of life from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups. Higher index values and visual analogue scale scores indicate better health status.

Depressive symptoms will be assessed using the Patient Health Questionnaire-9 (PHQ-9), a validated self-report questionnaire that measures the severity of depressive symptoms experienced over the past two weeks. Total scores range from 0 to 27, with higher scores indicating greater depressive symptom severity. Change in PHQ-9 scores from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups.

Depressive symptoms will be assessed using the Hamilton Depression Rating Scale (HAM-D), a clinician-administered measure of depression severity. The HAM-D will be completed by a trained assessor blinded to group allocation. Higher scores indicate greater depressive symptom severity. Change in HAM-D scores from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups.

Fatigue will be assessed using the Fatigue Impact and Severity Self-Assessment (FISSA), a self-report questionnaire developed for individuals with cerebral palsy. The FISSA includes 31 items assessing fatigue severity, the impact of fatigue on daily activities, and fatigue management behaviors. Items are rated on a five-point Likert scale, with higher scores indicating greater fatigue severity and impact. Change in fatigue from baseline to the end of the 30-day intervention period will be evaluated using the FISSA total score and compared between the active taVNS and sham taVNS groups.

Spasticity will be assessed using a patient-reported Numeric Rating Scale (NRS). Participants will rate the severity of their spasticity over the past 24 hours on an 11-point scale ranging from 0 (no spasticity) to 10 (worst possible spasticity). Higher scores indicate greater spasticity severity. Change in spasticity severity from baseline to the end of the 30-day intervention period will be compared between the active taVNS and sham taVNS groups.

Plasma concentrations of C-reactive protein (CRP) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in milligrams per liter (mg/L), with higher values indicating greater systemic inflammation. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups.

Plasma concentrations of interleukin-1 beta (IL-1β) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups.

Plasma concentrations of interleukin-6 (IL-6) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups.

Plasma concentrations of interferon gamma (IFN-γ) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups.

Plasma concentrations of tumor necrosis factor alpha (TNF-α) will be measured from fasting blood samples collected at baseline and at the end of the intervention. Concentrations will be reported in picograms per milliliter (pg/mL), with higher values indicating greater pro-inflammatory activity. Change values will be calculated as post-intervention values minus baseline values and summarized descriptively between the active taVNS and sham taVNS groups.

Blinding success will be assessed after completion of the intervention by asking participants and investigators to indicate which treatment group they believe the participant was assigned to (active taVNS or sham taVNS). Blinding effectiveness will be quantified using the James Blinding Index, calculated separately for participants and investigators. Blinding outcomes will be summarized descriptively.