Structural brain alterations in pain-related areas have been demonstrated in patients with nonspecific neck pain. While manual therapy combined with therapeutic exercise is an effective management for neck pain, its underlying mechanisms are poorly understood. The primary objective of this trial is to investigate the effects of manual therapy combined with therapeutic exercise on brain imaging biomarkers in patients with chronic nonspecific neck pain. The secondary objectives are to assess neurochemical biomarkers, clinical features of neck pain, cervical range of motion and cervical muscle strength.

This study is a single-blinded, randomized controlled trial. Forty-eight participants with chronic nonspecific neck pain will be recruited into the study. Participants will be randomly allocated to either an intervention or control group (1:1 ratio). Participants in the intervention group will receive manual therapy combined with therapeutic exercise for 10 weeks (2 visits per week). The control group will receive routine physical therapy. Primary outcomes are brain imaging biomarkers (cortical gray matter: volume, thickness and area, and white matter: fractional anisotropy and mean diffusivity) in pain-related areas. Secondary outcomes are neurochemical biomarkers (N-acetylaspartate, NAA; creatine, Cr; glutamic acid/glutamine, Glu/Gln; myoinositol, mI; and choline, cho), clinical features (neck pain intensity, duration, neck disability and psychological symptoms), cervical range of motion and cervical muscle strength.

Inclusion Criteria:

• a history of nonspecific neck pain for ≥ 3 months
• an average pain intensity over the past week ≥ 35 mm. on a visual analogue scale (VAS)

Exclusion Criteria:

• a history of head and neck injury or surgery
• known or suspected vestibular pathology or dizziness caused by underlying pathology in the ear, brain and sensory nerve pathways (e.g. benign paroxysmal positional vertigo) and/or vascular disorders
• any neurological or musculoskeletal condition that could affect the outcomes (e.g., scoliosis, torticollis, myofascial pain syndrome, fibromyalgia and rheumatoid arthritis)
• metabolic conditions (e.g., diabetes, obesity (BMI > 30 kg/m2) and hypertension)
• psychological symptoms (e.g., anxiety, depression and schizophrenia)
• contraindications to MRI (e.g., pregnancy/breastfeeding, claustrophobia and ferromagnetic implants)
• receiving physiotherapy treatment for their neck conditions in the past 12 months.