Scalp acupuncture treatment for motor dysfunction in children with cerebral palsy: study protocol for a multicenter randomized controlled Trial

Abstract Background: Scalp acupuncture has shown a remarkable treatment efficacy on motor dysfunction in children with cerebral palsy, especially when performed on the motor area of Jiao’s scalp acupuncture, which is the most widely used treatment. However, previous studies have summarized that the clinical curative effect of acupuncture treatment for children with cerebral palsy remains uncertain. Meanwhile, no randomized controlled trials on scalp acupuncture have been performed. The aim of this study is to evaluate the efficacy and safety of scalp acupuncture for motor dysfunction in children with cerebral palsy. Methods/design: This is an assessor and analyst blinded, randomized controlled trial. One hundred cerebral palsy patients with motor dysfunction meeting the inclusion criteria will be allocated by a 1:1 ratio into either an acupuncture treatment group or a control group. Cerebral palsy in the control group will receive conventional rehabilitation treatment, whereas a combination of scalp acupuncture and conventional rehabilitation treatment will be applied to the acupuncture group. Thirty-six treatment sessions will be performed over a 12-week period. The Gross Motor Function Measure and the Fine Motor Function Measure Scale will be assessed as the primary outcome measure. The Pediatric Evaluation of Disability Inventory, and the Cerebral Palsy Quality of Life Questionnaire for Children will be selected as secondary outcome measurements. All assessments will be conducted at baseline, week 4 (treatment 12), week 8 (treatment 24), week 12 (treatment 36), and week 24 (follow-up). Discussion: This is the first trial evaluating the efficacy and safety of scalp acupuncture for motor dysfunction in children with cerebral palsy. The results of this trial are expected to provide relevant evidence demonstrating that scalp acupuncture can be used as an effective rehabilitation treatment method for improving motor dysfunction in children with

Many studies [17] have shown that scalp acupuncture treatment has significant clinical effects on motor dysfunction in children with CP in China, and at present, there are many scalp acupuncture schools have been used to treat motor dysfunction for CP in hospitals.
These include schools such as Jiao's, Lin's, Jin's, Tang's and other different scalp acupuncture schools and the China scalp-point program of the international Standardization [18]. Among them, the anterior oblique line of vertextempora of the international standardization scalp partition or the motor area of Jiao's scalp acupuncture is usually chosen as the scalp acupuncture stimulatory region to treat motor dysfunction in CP. Jiao's scalp acupuncture combines a modern understanding of neuroanatomy and neurophysiology with traditional techniques of Chinese acupuncture to develop a radical new tool for affecting the functions of the central nervous system and accepts a central theory that incorporates brain functions into Chinese medicine principles [10]. The motor area of Jiao's scalp acupuncture that is specifically used for treatment of motor dysfunction in CP is the equivalent of the precentral gyrus of the cerebral cortex, on scalp projection [18]. In a preliminary study, we demonstrated the effect of Jiao's scalp acupuncture combined with rehabilitation treatment on cerebral palsy [19]. However, there haven't been any RCTs done to demonstrate the clinical curative effect of the motor area of Jiao's scalp acupuncture treatment on motor dysfunction in children with CP.
Moreover, although acupuncture has become widely accepted as a treatment for CP and showed better clinical curative effect compared with conventional treatments in China, a new Meta-Analysis published in 2018 [20] based on clinical randomized controlled trials concluded that the clinical curative effect of acupuncture treatment in children with CP

Interventions
The study is a randomized clinical trial carried out in outpatient rehabilitation departments of four hospitals. A total of 100 children with CP will be recruited. The patients will be randomly assigned to two different groups: 1) the treatment group and 2) the control group. The treatment group (n=50) will receive routine rehabilitation treatment combined with scalp acupuncture for 3 times per week and last for 12 weeks, and the control group (n=50) will receive routine rehabilitation treatment for 3 times per week and last for 12 weeks. Both groups will be evaluated at baseline, week 4 (treatment 12), week 8 (treatment 24), week12(treatment 36) and week 24(follow-up). Both groups will receive CP routine rehabilitation treatment during the whole 12-week study period.
The routine rehabilitation program was designed according to the Chinese CP rehabilitation treatment guidelines, which include physical therapy (PT) and occupational therapy (OT) for 3 days a week [21]. Chinese herbal medicine and Chinese patent drugs will be prohibited during the trial.

Scalp acupuncture treatment
The acupuncture intervention complies with the Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA) guidelines. Moreover, all the acupuncturists will attend special training to achieve a sound understanding of the scalp acupuncture intervention program and to standardize the practices procedures across different acupuncturists. The trial adheres to the STRICTA guidelines [22,23].
(2) Scalp acupoint location:  The acupuncture direction of Si shencong (EX-HN1) acupoint is toward the Baihui (GV20) acupoint. For treating motor dysfunction, the needles will be rotated for at least 200 revolutions per minute for 1 minute every 20 minutes for a total of 60 minutes. Scalp acupuncture treatment will be performed by an independent certified practitioner (acupuncturist) with 5 years of clinical experience [10].
(3) Treatment course: The scalp acupuncture treatment will be implemented three times a week (once every other day), twelve times per treatment course, with each patient having three treatment courses in total.

Rehabilitation Treatment
The children with CP will receive the routine rehabilitation programs as mentioned above.
The rehabilitation programs will be carried out three times a week (once every other day) for 12 weeks, and each session of the rehabilitation treatment (PT and OT) will last approximately for 1 hour. All rehabilitation treatments will be carried out by qualified therapists.

Follow up
After the 12-week treatment observation, all patients will start an additional 12-week follow-up period. CP patients from both groups will continue to attend rehabilitation treatment in the follow-up period. However, all patients from both groups are free to choose whether to receive scalp acupuncture or not with consent from his/her parents during the follow-up period. During the 12-week follow-up period, all of the CP patients from both groups will be reassessed by GMFM, FMFM, PEDI and CP-QOL at week 24 and asked to fill out forms to record their rehabilitation treatment attendance. All assessment scales and forms will be returned to the researchers for reviewing at the end of the trial.

Outcome measures
Data collection will be performed by a trained assessor who is blind to patients' assignment at baseline, after the intervention (4 weeks, 8 weeks and 12 weeks) and at the end of follow up (24weeks).

Basic characteristic variables
All of the participants' general status demographic information, such as age, sex, clinical type and GMFCS level (Gross Motor Function Classification System, GMCFS) will be attained from baseline questionnaires.

Primary outcome measurement
This study has two primary outcomes, Gross Motor Function Measure (GMFM) and Fine Motor Function Measure Scale (FMFM) will be assessed at baseline, the interventions period (at 4 weeks, 8 weeks, 12 weeks) and the follow-up period (at 24 weeks).

Gross Motor Function Measure, GMFM
The Gross Motor Function Measure-66 (GMFM-66) is a standardized observational instrument designed to assess the gross motor function of children with CP. It is frequently utilised in clinical and research practice to measure change over time or following interventions [24]. It allows the therapist or physician to evaluate a child's gross motor functioning by observing the way a child performs a series of motor skills. It is divided into five sections: Lying and Rolling, Sitting, Crawling and Kneeling, Standing, and Walking, Running and Jumping. Each item has a very specific detailed description whereby the evaluator scores how capable the child is of completing that item on the basis of four levels: 0=does not initiate, 1=initiates, 2=partially completes, 3=completes or NT=not tested [25]. The total score is a summation of the scores in the five areas by the Gross Motor Ability Estimator software (GMAE Version 1.0.). In addition, the Gross Motor Ability Estimator (GMAE-2) Scoring Software for the GMFM-66 can be downloaded from the CanChild website (https://www.canchild.ca/). The greater the number of tasks attempted, the greater the accuracy of the evaluation [25].

Fine Motor Function Measure Scale, FMFM
The Fine Motor Function Measure (FMFM) assessment scale is used to evaluate the fine motor activities of children with CP, including the upper limb activities and sensory ability. will be performed periodically throughout the study. The original CRFs and all other forms (including the consent forms) will be archived securely in the Clinical Trail Unit (CTU) of the Children's hospital affiliated to Fudan university for 5 years following publication of the last paper or report from the study [10].
The safety of the study will be monitored by a Data and Safety Monitoring Board (DSMB) of the CTU of the Children's hospital affiliated to Fudan university, which consists of independent clinical experts and statisticians with access to unblinded data. The DSMB is independent from the sponsor, the competing interests, and the investigational site and will review the performance and safety of the trial monthly [10].
The criteria for unblinding and discontinuing allocated interventions for a given trial participant include getting severe diseases, having serious complications of CP or experiencing serious acupuncture-related AEs (if any), which have been described previously. The DSMB will reveal a participant's allocated intervention and make the final decision to terminate the trial [10].
The final trial data set will be under the custody of Children's hospital affiliated to Fudan university. The data manager from the CTU of Children's hospital affiliated to Fudan university will have access to the complete, anonymous final data set. Access to the final data set or identifiable data by others will require written requests to be approved by the DSMB of the CTU of Children's hospital affiliated to Fudan university and all study investigators [10].

Sample size calculation
Sample size calculations were performed based on the two primary outcomes. According to our pilot trial, we assume that after 12 weeks of treatment the mean change of GMFM scores in the experimental group will be greater than the control group with the mean differnce of 2.4, with standard deviation of 3.0. At alpha level of 0.025, 40 subjects will be required for each group to ensure a statistical power of 0.9. Considering of 20% drop out, a total of 100 participants will be needed, each group is required to have 50 initial participants.

Participant recruitment
Participants will be recruited in four hospitals (Children's hospital of Fudan university, The 445th hospital of Chinese People's Liberation Army, Huajing Community health service center of Xuhui district and Jiangchuan Community health service center of Minhang district) in Shanghai, China. Prospective participants will be asked to meet with the study coordinator to discuss the study and provide information about the eligibility criteria. If children with CP are eligible and their parents/guardians are interested in participating, they will be invited for a series of rehabilitation assessments after diagnosis by neurologists. One hundred children with CP will be included in the study. When their informed consent has been obtained, children with CP will be randomized into two groups with different treatments [10].

Randomization and allocation concealment
The recruited patients were randomly assigned to experimental group or control group according to a randomization and allocation plan, which was computer-generated, block randomization (block size of 4 and 1:1 allocation) prepared by an independent epidemiologist not otherwise involved in the trial. A computer-generated block randomization process designed by the CTU is used to allocate participants to the treatment group or the control group in a 1:1 ratio (block size =4). The randomization list is kept strictly confidential. Allocation concealment is ensured with the use of sequentially numbered (block number and sequence number), identical, opaque, sealed envelopes.
Computerized randomization preserves allocation concealment and reduces the possibility of selection bias since the research assistant is kept unaware of the group assignments until after the participants are allocated to groups.

Statistical analysis
The Statistical Product and Service Solutions (SPSS) statistical package program (version 20.0, SPSS Inc., Chicago, IL, USA) will be used to analyze data in the CTU of Children's hospital affiliated to Fudan university by statisticians. All analyses will be based on the intention-to-treat principle using the last observation carried forward rule. Baseline information will be collected before randomization and include the gender and age of patients, disease course, clinical type, GMFCS level, primary outcome (GMFM, FMFM), and secondary outcomes (PEDI, CP-QOL). Descriptive statistics will be used to detail baseline participant demographics and general status of patients, such as gender, age, disease course, clinical type and GMFCS level. Variables will be checked for normal distribution and presented as mean +/-standard deviation and compared by Student t test when normally distributed. For not-normally distributed variables, the data will be expressed as median +/-interquartile range, and non-parametric tests will be used. Categorical variables will be expressed as number (%) and analyzed by χ 2 tests or Fisher's exact tests, when appropriate. Mixed effect model will be used to analyze the between-group difference in repeated measured two primary outcomes and other outcomes (GMFM, FMFM, PEDI, and CP-QOL scores) across five testing time points (weeks 0, 4, 8, 12 and 24). Mean group difference and 95% confidence intervals will be reported. Safety analyses will be compared with the incidence of AEs in the two groups using the χ 2 test. A p value of < 0.025 will be considered as statistically significant for the two primary outcomes.

Discussion
Chinese scalp acupuncture is a contemporary acupuncture technique integrating traditional Chinese needling methods with Western medical knowledge of representative areas of the cerebral cortex. As acupuncture developed, various physicians began to introduce western neurophysiology into the field of acupuncture and explored correlations between the brain and human body. Dr. Jiao Shun-fa who is the founder of Jiao's scalp acupuncture, a neurosurgeon in Shan Xi province, is also the recognized founder of Chinese scalp acupuncture. Dr. Jiao combined the modern understanding of neurophysiology and neuroanatomy with the traditional concept of acupuncture to develop the new scalp acupuncture to affect the functions of the central nervous system [10]. The motor area of Jiao's scalp acupuncture is frequently used in rehabilitation of paralysis due to stroke, traumatic brain injury, spinal cord injury and multiple sclerosis. It has been demonstrated effective in treating any type of paralysis, especially for motor dysfunction after stroke [34][35][36]. Based on fMRI studies, it has also been shown that scalp acupuncture has effects on movement regulation and the curative effect of scalp acupuncture is correlated to cerebral activating reaction in motor dysfunction with stroke patients [37,38].The motor area of Jiao's scalp acupuncture is divided into five equal parts: and research practice to measure change over time or following interventions [24]. The FMFM assessment scale is used to evaluate the fine motor activities of children with CP, including the upper limb activities and sensory ability [47]. This scale includes five areas, namely audiovisual tracking ability, upper limb joint's ability, grasping ability, and handeye coordina tion, which reflect the fine motor function by a total percentage of ability.
The PEDI was used as an individual level assessment scale to evaluate daily life activities of CP, it responds to the complex activity ability and necessary functional skills of patients in daily environments and is often used to assess the influence degree of motor dysfunction in families and social environments [10,48]. The PEDI has also been recommended as a gold standard in paediatric rehabilitation [28,29]. Quality of life is a very relevant and important construct in the context of children with cerebral palsy because it can provide a broad subjective indication of their well-being across several life domains such as physical health and social and emotional well-being. Quality of life is considered a broad and multidimensional concept that includes subjective evaluations of both the positive and negative aspects of life. In the context of rehabilitation, quality of life has clinical utility as an important health-related outcome measure that can guide practice [33,49,50]. Based on the concept of ICF, this study will evaluate the clinical efficacy of scalp acupuncture treatment for motor dysfunction in children with cerebral palsy in a comprehensive and multidimensional view by using the international assessment scale.
Acupuncture is a frequently used therapy for CP rehabilitation in China, but the evidence of its effect from previous studies seems to be inconclusive. Some Meta-Analysis have been done to study the effect of acupuncture on CP rehabilitation [17,20]. These reviews have drawn consistent conclusions that acupuncture appears to be safe and effective for CP rehabilitation, but the benefits require further confirmation with larger, more transparent and well conducted randomized clinical trials [10]. Thus, the purpose of this research is to observe the therapeutic effect of scalp acupuncture using Jiao's motor area and Si shencong (EX-HN1) acupoint for motor dysfunction in children with CP by international general evaluation scales. Under strict quality control, this study could potentially confirm whether or not scalp acupuncture is an effective adjunct to the standard rehabilitation treatment on motor dysfunction for children with CP.

Trial status
The treatment protocol version number currently in use is NO. 2019.2.15. The date authenticity of the data from the research results in this subject and whether the assessment indicators have been fulfilled.

Availability of data and materials
Not applicable.