Effects of Manual Therapy Combined With Therapeutic Exercise on Brain Biomarkers in Neck Pain

Effects of Manual Therapy Combined With Therapeutic Exercise on Brain Biomarkers in Patients With Chronic Nonspecific Neck Pain: Study Protocol for a Randomized Controlled Trial.

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.

Study Overview

• Status: Completed
• Conditions: Neck Pain
• Intervention / Treatment: Other: Manual therapy combinded with therapeutic exercise; Other: Routine physical therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sureeporn Uthaikhup, PhD.; Phone Number: 6653949249; Email: sureeporn.uthaikhup@cmu.ac.th

Study Locations

• Thailand
  • Chiang Mai, Thailand, 50202
    • Department of Physical Therapy, Faculty of Associated Medical Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 57 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention group; Manual therapy and therapeutic exercise	Other: Manual therapy combinded with therapeutic exercise; The treatment includes cervical mobilization and specific therapeutic exercises: craniocervical and cervical flexors and extensors, axioscapular muscles, and postural correction (30-40 minutes). The participants will attend 20 individual treatment sessions (2 visits per week for 10 weeks).
Experimental: Control group; Routine physical therapy	Other: Routine physical therapy; The treatment includes routine physical therapy (e.g., modalities, range of motion and/or gentle stretching exercise) (30-40 minutes). The participants will attend 20 individual treatment sessions (2 visits per week for 10 weeks).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical gray matter: volume and thickness	Cortical gray matter (volume and thickness) will be measured in pain-related areas (thalamus, prefrontal cortex (PFC), primary somatosensory cortex (S1), primary motor cortex (M1), insula, cingulate cortex, precuneus, temporal lobe and periaqueductal gray matter) using a Magnetic resonance imaging (MRI) machine	At baseline and post-intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
White matter integrity: fractional anisotropy (FA) and mean diffusivity (MD)	White matter in the brain will be quantified using diffusion tensor imaging (DTI) technique.	At baseline and post-intervention
Neurochemical biomarkers: N-acetylaspartate (NAA), creatine (Cr), glutamic acid/glutamine (Glu/Gln), myoinositol (mI), and choline (cho)	Neurochemistry biomarkers will be measured using single-voxel proton magnetic resonance spectroscopy (1H-MRS) in dorsolateral prefrontal cortex (DLPFC), primary somatosensory cortex (S1), anterior cingulate (ACC), insula and thalamus.	At baseline and post-intervention
Neck pain intensity	The average intensity of neck pain will be assessed by using a 0-10 cm visual analogue scale (VAS), with 0 indicating no pain and 10 indicating worst imaginable pain.	At baseline and post-intervention
Neck pain and disability	Neck Disability Index (NDI) will be used to assess how neck pain affects a patient's daily life and to assess the self-rated disability. A total score is 50, which a higher score indicates a higher disability.	At baseline and post-intervention
Anxiety and depression	The symptoms of anxiety and depression will be assessed using Hospital Anxiety and Depression Scale (HADS). It includes two subscales: anxiety (HADS-A) and depression (HADS-D). A total score for each subscale ranges from 0 to 21, with higher scores indicating worse symptoms.	At baseline and post-intervention
Cervical range of motion	Cervical range of motion (degrees) will be measured in flexion, extension, left-right lateral flexion and left-right rotation.	At baseline and post-intervention
Cervical muscle strength	Cervical muscle strength will be measured in a craniocervical flexion action, using a handheld dynamometer (Newtons).	At baseline and post-intervention

Collaborators and Investigators

• Sponsor: Chiang Mai University
• Investigators: Principal Investigator: Sureeporn Uthaikhup, PhD., Department of physical therapy, Chiang Mai university

Publications and helpful links

General Publications

• Jull G, Falla D, Treleaven J, O'Leary S. Management of neck pain disorders: a research informed approach. Edinburgh: Elseiver Limited; 2019.
• Johnston V, O'Leary S, Comans T, Straker L, Melloh M, Khan A, Sjogaard G. A workplace exercise versus health promotion intervention to prevent and reduce the economic and personal burden of non-specific neck pain in office personnel: protocol of a cluster-randomised controlled trial. J Physiother. 2014 Dec;60(4):233; discussion 233. doi: 10.1016/j.jphys.2014.08.007. Epub 2014 Oct 11.
• Sremakaew M, Jull G, Treleaven J, Barbero M, Falla D, Uthaikhup S. Effects of local treatment with and without sensorimotor and balance exercise in individuals with neck pain: protocol for a randomized controlled trial. BMC Musculoskelet Disord. 2018 Feb 13;19(1):48. doi: 10.1186/s12891-018-1964-3.
• Maitland GD, Hengeveld E, Banks K, Anglaise K. Vertebral manipulation. 7th ed. Oxford: Butterworth-Heinemann: Elsevier; 2005.
• de Zoete RMJ, Stanwell P, Weber KA, Snodgrass SJ. Differences in Structural Brain Characteristics Between Individuals with Chronic Nonspecific Neck Pain and Asymptomatic Controls: A Case-Control Study. J Pain Res. 2022 Feb 18;15:521-531. doi: 10.2147/JPR.S345365. eCollection 2022.
• Coppieters I, De Pauw R, Caeyenberghs K, Lenoir D, DeBlaere K, Genbrugge E, Meeus M, Cagnie B. Differences in white matter structure and cortical thickness between patients with traumatic and idiopathic chronic neck pain: Associations with cognition and pain modulation? Hum Brain Mapp. 2018 Apr;39(4):1721-1742. doi: 10.1002/hbm.23947. Epub 2018 Jan 11.
• Didehdar D, Kamali F, Yoosefinejad AK, Lotfi M. The effect of spinal manipulation on brain neurometabolites in chronic nonspecific low back pain patients: a randomized clinical trial. Ir J Med Sci. 2020 May;189(2):543-550. doi: 10.1007/s11845-019-02140-2. Epub 2019 Nov 26.

Study record dates

Study Major Dates

• Study Start (Actual): November 15, 2022
• Primary Completion (Actual): November 28, 2023
• Study Completion (Actual): February 5, 2024

Study Registration Dates

• First Submitted: October 4, 2022
• First Submitted That Met QC Criteria: October 4, 2022
• First Posted (Actual): October 5, 2022

Study Record Updates

• Last Update Posted (Actual): February 7, 2024
• Last Update Submitted That Met QC Criteria: February 6, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Exercise; Magnetic resonance imaging; Magnetic resonance spectroscopy; Neck pain; Manual therapy
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Neck Pain
• Other Study ID Numbers: FF-65 2301484

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No