Non-invasive brain stimulation for upper extremity dysfunction in children with cerebral palsy: a systematic review and meta-analysis
Original Article

Non-invasive brain stimulation for upper extremity dysfunction in children with cerebral palsy: a systematic review and meta-analysis

Yage Zhang#, Mengru Zhong#, Tingting Peng, Tingting Chen, Simian Cai, Zhaofang Chen, Kaishou Xu ORCID logo

Department of Rehabilitation, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, China

Contributions: (I) Conception and design: K Xu; (II) Administrative support: K Xu; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: Y Zhang, M Zhong, T Chen, S Cai; (V) Data analysis and interpretation: Y Zhang, M Zhong, T Peng, Z Chen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work as co-first authors.

Correspondence to: Kaishou Xu, PhD. Department of Rehabilitation, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, No. 318 Renmin Middle Road, Guangzhou 510120, China. Email: xksyi@126.com.

Background: Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are the most commonly used non-invasive brain stimulation (NIBS) techniques. However, NIBS for upper extremity dysfunction remains unclear in children with cerebral palsy (CP). Thus, we aim to determine safety and effectiveness of NIBS for upper extremity dysfunction in children with CP.

Methods: Two reviewers conducted literature search on five databases including PubMed, Web of Science, ProQuest, Scopus, and Embase independently. Systematic review and meta-analyses of included studies were conducted. Studies used standardized mean difference (SMD) and 95% confidence interval (CI) to calculate pooled effect size between two groups. The statistics I2 was used to assess the heterogeneity between randomized controlled trials (RCTs).

Results: Fifteen studies were included, with seven of which examined rTMS and eight studied tDCS. Total 366 children with CP were included. Changes in Box and Block Test (BBT) of the affected hand changed significantly in post (SMD =0.68; 95% CI: 0.02 to 1.34; P=0.044; I2=0%) and 90-minute effect (SMD =0.69; 95% CI: 0.02 to 1.36; P=0.04; I2=0%), and Modified Ashworth Scale (MAS) (SMD =−0.51; 95% CI: −0.99 to −0.03; P=0.04; I2=0%) after using tDCS were statistically significant. There was no difference of total number of dropouts between each group. No patients experienced serious adverse events.

Conclusions: NIBS is safe and well tolerated in children with CP. And current evidence suggests that when safety guidelines are followed, NIBS does not induce seizures in pediatric patients with no history of epilepsy or stable epilepsy. tDCS is effective in improving upper extremity dysfunction such as fine motor function especially hand dexterity, and reducing upper extremity spasticity in children with CP. Due to insufficient studies, the effectiveness of rTMS is uncertain.

Keywords: Cerebral palsy (CP); non-invasive brain stimulation (NIBS); transcranial magnetic stimulation; transcranial direct current stimulation (tDCS); upper extremity

Submitted Nov 03, 2024. Accepted for publication Feb 10, 2025. Published online Feb 25, 2025.

doi: 10.21037/tp-24-488

Highlight box

Key findings

• A meta-analysis was conducted on safety and effectiveness of non-invasive brain stimulation (NIBS) in upper extremity dysfunction in children with cerebral palsy (CP).

What is known and what is new?

• NIBS is an emerging technique which mainly uses electric current or magnetic field to regulate the excitability of relevant functional areas of the brain, causing immediate and prolonged modulation of cortex excitability. In clinical setting, NIBS has been used in the treatment of attention deficit hyperactivity disorder, adult stroke, autism, CP, and so on.

• NIBS is safe and well tolerated in improving upper extremity function in CP children. And tDCS is effective in improving upper extremity function and spasticity in CP children.

What is the implication, and what should change now?

• NIBS, especially tDCS, may be used as an adjunct for the clinical rehabilitation of children with CP.

Introduction

Cerebral palsy (CP) is a group of persistent disorders affecting the development of movement and posture (1-3). In addition to motor dysfunction, children with CP often have sensory, perceptual, cognitive, as well as epilepsy and secondary musculoskeletal problems (3,4). CP is the leading cause of disability in children (5,6), with an incidence that approximately ranged from 0.8 and 4.4 per 1,000 newborns (7). Approximately 83% of children with CP suffer from upper extremity dysfunction (8), which significantly impacts their daily activity and quality of life (9), and increases the burden on their caregivers and society (10).

Rehabilitation interventions for upper extremity dysfunction in CP mainly aim to improve extremity function and abnormal posture, promote self-care, and reduce the risk of disability. At present, there are two types of common rehabilitation techniques, with one mainly focusing on the clinical symptoms of CP, improving the function of peripheral organs, regulating the central nervous system indirectly, including constraint-induced movement therapy (CIMT) (11), hand-arm bimanual intensive training (HABIT) (12), virtual reality (VR), and computer-based training (13), mirror therapy (14,15) and so on. And another directly acts on the cerebral cortex, promoting neural plasticity, and improving the clinical symptoms from the center to the periphery, including invasive and non-invasive techniques such as non-invasive brain stimulation (NIBS).

NIBS is an emerging technique which mainly uses electric current or magnetic field to regulate the excitability of relevant functional areas of the brain, causing immediate and prolonged modulation of cortex excitability (16). And neural plasticity is the primary mechanism of NIBS for improving dysfunction (17). Preclinical animal studies have shown that rTMS promoted long-term synaptic enhancement, neuroprotection, and neurogenesis (18), and tDCS regulated neurogenesis, increased oligodendrocyte precursor recruitment, and polarize microglia (19). In clinical setting, NIBS has been used in the treatment of attention deficit hyperactivity disorder (ADHD) (20), adult stroke (21), autism (22), CP, and so on.

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are the most commonly used NIBS techniques. rTMS treats diseases through the principle of electromagnetic induction (16). A current passes through a coil placed on the skull, creating a magnetic field perpendicular to the coil, which generates an electric current parallel to the coil in the cortex, and regulates the excitability of local brain regions (23,24). tDCS, on the other hand, uses low-amplitude direct current (1–2 mA) to modify neuronal polarization, altering transmembrane electrical potentials to regulate the excitability of local brain regions, by applying a low-amplitude direct current (1–2 mA) through sponge electrodes positioned on the scalp (25,26). In randomized controlled trials (RCTs), the control group is generally treated with sham stimulation. Generally speaking, sham rTMS stimulation mimic the sound and tactile sensation of rTMS by using a sham rTMS coil without stimulation; another sham rTMS is that A therapist orientated the handle pointing at a 90° angle to the sagittal line (a 45° angle for the real rTMS). And sham tDCS is a procedure that applies current 30 seconds to 1 minute after the start and before the end of tDCS. This is mainly to allow participants to experience the current sensation at the beginning and end of tDCS, but does not actually provide long-term current stimulation.

However, the safety and effectiveness of NIBS for upper extremity dysfunction in children with CP is unclear, with only few articles having ever addressed the problem. In 2024, Metelski et al. (27) reported a systematic review of NIBS improving upper extremity function, and the databases were searched up to May 2023, which was classified according to the International Classification of Functioning, Disability and Health (ICF), descriptive analyses of adverse events, feasibility and efficacy were conducted. The article was only systematically reviewed, and no meta-analysis was performed, which imposed methodological limitations. There were few statistically significant improvements in results for efficacy. Our study conducted meta-analysis by integrating the same outcome measures, and analyzed tolerability and safety using the number of dropouts and adverse events. The effectiveness and safety of NIBS were quantitatively analyzed, with based meta-analysis based on RCT provided the highest level of evidence. And compared with systematic reviews, meta-analyses were methodologically able to increase statistical power and accuracy in estimating effect sizes, and to enhance the reliability and objectivity of the results.

In clinical practice, there are no standard parameters of stimulation such as intensity, frequency, site of stimulation determined yet. These parameters are associated with clinical outcomes and safety to some extent (26,28-32). NIBS targets specific localized different brain regions and is non-invasive, thus it is important to understand the feasibility and safety of NIBS in the treatment of upper extremity dysfunction in children with CP. As a promising rehabilitation technique for neurological disorders, impact of NIBS for upper extremity dysfunction in children with CP remains to be further studied. Therefore, this study aims to conduct a systematic review and meta-analysis of existing studies to evaluate the safety and effectiveness of NIBS for upper extremity dysfunction in children with CP. We present this article in accordance with the PRISMA reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-488/rc) (33).

Methods

This systematic review and meta-analysis has been registered in PROSPERO with registration number CRD42023411971.

Search strategy

Two reviewers (Y.Z. and M.Z.) conducted the systematic review search on June 2024. Five databases were searched including PubMed, Web of Science, ProQuest, Scopus, and Embase. Keywords were used in search terms including “cerebral palsy”, “perinatal stroke”, “repetitive transcranial magnetic stimulation”, “transcranial direct current stimulation”, “non-invasive brain stimulation”, “upper extremity”, “hand”, and their synonyms. The keywords matched the appropriate medical subject headings (MeSH) terms. Relevant truncation or wildcard symbols were used to cover all possible variations of keywords. Related search terms were combined with Boolean operators. The terms were adjusted to fit the requirements of each electronic database. Table 1 shows the search strategy used in each database.

Table 1

Search strategy

Databases Search strategy
PubMed ((“Cerebral palsy”[MeSH Terms] OR “Cerebral palsy”[All Fields] OR “CP”[All Fields] OR “perinatal stroke”[All Fields] OR “hemiplegi*”[All Fields] OR “monoplegi*”[All Fields] OR “diplegi*”[All Fields] OR “triplegi*”[All Fields] OR “quadriplegi*”[All Fields] OR “tetraplegi*”[All Fields]) AND (“transcranial magnetic stimulation”[MeSH Terms] OR “TMS”[All Fields] OR “transcranial magnetic stimulation*”[All Fields] OR “rTMS”[All Fields] OR “repetitive transcranial magnetic stimulation*”[All Fields] OR “deep transcranial magnetic stimulation”[All Fields] OR (“transcranial direct current stimulation”[MeSH Terms] OR “tDCS”[All Fields] OR “transcranial direct current stimulation*”[All Fields]) OR (“NIBS”[All Fields] OR “non-invasive brain stimulation*”[All Fields] OR “non-invasive brain stimulation*”[All Fields])) AND (“hand function”[All Fields] OR “hand*”[All Fields] OR “upper extremity”[MeSH Terms] OR “upper extremity*”[All Fields] OR “upper limb*”[All Fields] OR “arm”[All Fields])) AND ((english[Filter]) AND (allchild[Filter]))
Web of Science (“cerebral palsy” OR “CP” OR “perinatal stroke” OR “hemiplegi*” OR “monoplegi*” OR “diplegi*” OR “triplegi*” OR “quadriplegi*” OR “tetraplegi*”) AND (“child” OR “children” OR “kid*” OR “neonate” OR “infant*”) AND ((“TMS” OR “transcranial magnetic stimulation*” OR “rTMS” OR “repetitive transcranial magnetic stimulation*” OR “deep transcranial magnetic stimulation”) OR (“tDCS” OR “transcranial direct current stimulation*”) OR (“NIBS” OR “non-invasive brain stimulation*” OR “non-invasive brain stimulation*”)) AND (“hand function” OR “hand*” OR “upper extremity*” OR “upper limb*” OR “arm*”) (Topic) and English (Languages)
Embase (‘cerebral palsy’/exp OR ‘cerebral palsy’ OR ‘cp’/exp OR ‘cp’ OR ‘hemiplegi*’ OR ‘monoplegi*’ OR ‘diplegi*’ OR ‘triplegi*’ OR ‘quadriplegi*’ OR ‘tetraplegi*’) AND (‘transcranial magnetic stimulation’/exp OR ‘tms’ OR ‘transcranial magnetic stimulation*’ OR ‘rtms’ OR ‘repetitive transcranial magnetic stimulation*’ OR ‘deep transcranial magnetic stimulation’ OR ‘tdcs’ OR ‘transcranial direct current stimulation*’ OR ‘nibs’ OR ‘non-invasive brain stimulation*’ OR ‘transcranial direct current stimulation’/exp) AND (‘hand function’ OR ‘hand’ OR ‘upper extremity’/exp OR ‘upper extemity*’ OR ‘upper limb*’ OR ‘arm*’) AND [article]/lim AND [humans]/lim AND [english]/lim AND ([newborn]/lim OR [infant]/lim OR [child]/lim OR [preschool]/lim OR [school]/lim OR [adolescent]/lim)
Scopus (TITLE-ABS-KEY(“cerebral palsy” OR “CP” OR “perinatal stroke” OR “hemiplegi*” OR “monoplegi*” OR “diplegi*” OR “triplegi*” OR “quadriplegi*” OR “tetraplegi*”) AND TITLE-ABS-KEY(“TMS” OR “transcranial magnetic stimulation*” OR “rTMS” OR “repetitive transcranial magnetic stimulation*” OR “deep transcranial magnetic stimulation” OR “tDCS” OR “transcranial direct current stimulation*” OR “NIBS” OR “non-invasive brain stimulation*” OR “non-invasive brain stimulation*”) AND TITLE-ABS-KEY (“hand function” OR “hand*” OR “upper extremity*” OR “upper limb*” OR “arm*”) AND NOT TITLE-ABS-KEY(“stroke” OR “apoplexy” OR “autism” OR “ASDs”) AND TITLE-ABS-KEY(“child” OR “children” OR “kid*” OR “neonate” OR “infant*”) AND NOT TITLE-ABS-KEY(“adult*” OR “mice” OR “mouse”)) AND (LIMIT-TO (PUBSTAGE, “final”)) AND (LIMIT-TO (DOCTYPE, “ar”)) AND (LIMIT-TO (LANGUAGE, “English”))
ProQuest (((“cerebral palsy” OR “CP” OR “perinatal stroke” OR “hemiplegi*” OR “monoplegi*” OR “diplegi*” OR “triplegi*” OR “quadriplegi*” OR “tetraplegi*”) NOT (“stroke” OR “apoplexy” OR “autism” OR “ASDs”)) AND ((“child” OR “children” OR “kid*” OR “neonate” OR “infant*”) NOT (“adult*” OR “mice” OR “mouse”)) AND ((“TMS” OR “transcranial magnetic stimulation*” OR “rTMS” OR “repetitive transcranial magnetic stimulation*” OR “deep transcranial magnetic stimulation”) OR (“tDCS” OR “transcranial direct current stimulation*” NOT (“FES” OR “functional electrical stimulation”)) OR (“NIBS” OR “non-invasive brain stimulation*” OR “non-invasive brain stimulation*”)) AND (“hand function” OR “hand*” OR (“upper extremity”) OR (“upper limb” OR “upper limbs”) OR “arm*”)) AND (stype.exact(“Scholarly Journals” OR “Dissertations & Theses”) AND la.exact(“ENG”))

ASDs, autism spectrum disorders; CP, cerebral palsy; FES, functional electrical stimulation; MeSH, medical subject headings; NIBS, non-invasive brain stimulation; rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation; TMS, transcranial magnetic stimulation.

Eligibility criteria

The inclusion and exclusion criteria were set following the PICOS (population, intervention, comparisons, outcomes, and study design) principle, as shown in Table 2.

Table 2

Eligibility criteria following the PICOS principle

Subject Inclusion criteria Exclusion criteria
P-population Children diagnosed with CP who aged 18 years old or younger Animal or non-human experiments
Children were diagnosed with genetic or chromosomal disorders or congenital neurological illness
I-intervention NIBS, including tDCS or rTMS Studies using NIBS as diagnostic means
C-comparison Between-group comparison and/or within group comparison and/or pre-post comparison N/A
Intervention group and control group comparison
O-outcomes Measures outcomes related to upper limb function performance including the AHA, the COPM, BBT, MAS, HGS, MA, and ABILHAND-Kids N/A
S-study type RCTs Any articles that do not have full-text available
Non-English studies

AHA, Assisting Hand Assessment; BBT, Box and Block Test; COPM, Canadian Occupational Performance Measure; CP, cerebral palsy; HGS, Hand Grip Strength; MA, Melbourne Assessment; MAS, Modified Ashworth Scale; NIBS, non-invasive brain stimulation; N/A, not available; PICOS, population, intervention, comparisons, outcomes, and study design; RCT, randomized controlled trial; rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation.

The inclusion criteria were: (I) children diagnosed with CP who aged 18 years old or younger; (II) the intervention focus on NIBS including rTMS and tDCS; (III) between-group comparison, within-group comparison, pre-post comparison, and intervention group and control group comparison (including comparisons between the active and sham stimulation); (IV) measures outcomes related to upper extremity function performance including the Assisting Hand Assessment (AHA), the Canadian Occupational Performance Measure (COPM), Box and Block Test (BBT), Modified Ashworth Scale (MAS), Hand Grip Strength (HGS), Melbourne Assessment (MA), and ABILHAND-Kids; and (V) RCTs.

The exclusion criteria were: (I) animal or non-human experiments, and children diagnosed with genetic or chromosomal disorders or congenital neurological illness were excluded; (II) any articles not having full-text available or non-English studies were excluded; and (III) studies using NIBS as diagnostic means were excluded.

Study selection and data extraction

Study selection and data extraction were conducted independently by two reviewers (Y.Z. and M.Z.), and any disagreements between reviewers were resolved through discussion with the third person (K.X.) in the team. We first evaluated the retrieved studies based on the titles and abstracts of the literature, followed by full-text analyses and evaluation of all eligible studies to assess their compliance with the eligibility criteria. The following data were extracted: title, authors, publication year, study design, participants characteristics [sample size, age, type of CP, manual ability classification system (MACS) level], adverse events, stimulation parameters (intensity and frequency), stimulation site, duration, number of sessions, outcome measures, assessment time points (the time intervals from treatment to evaluation) and main conclusion, etc. Some RCTs provide raw data that can be obtained directly or calculated to derive mean and standard deviation, for data presented in graphs, WebPlotDigitizer version 3.10 was used to obtain data manually. Where necessary, the standard deviation was calculated from the mean standard by means of Cochrane handbooks and formulas.

Quality assessment

This study assessed the methodological quality of included studies using the Physiotherapy Evidence Database (PEDro) scale: https://pedro.org.au/english/resources/pedro-scale/. The PEDro scale is a valid and reliable measure of methodological quality of clinical trials (34). It contains eleven questions for scoring: (I) eligibility criteria were specified; (II) subjects were randomly allocated to groups; (III) allocation was concealed; (IV) the groups were similar at baseline regarding the most important prognostic indicators; (V) there was blinding of all subjects; (VI) there was blinding of all therapists who administered the therapy; (VII) there was blinding of all assessors who measured at least one key outcome; (VIII) measures of at least one key outcome were obtained from more than 85% of the subjects initially allocated to groups; (IX) all subjects for whom outcome measures were available received the treatment or control condition as allocated or, where this was not the case, data for at least one key outcome was analyzed by “intention to treat”; (X) the results of between-group statistical comparisons are reported for at least one key outcome; and (XI) the study provides both point measures and measures of variability for at least one key outcome (35). And it categorizes the quality of studies based on the scores assessed: studies with a score below 6 are considered low quality, studies with a score of 6–7 are considered good quality, and studies with a score greater than 7 are considered excellent quality (36,37).

GRADEprofiler software was used to assess the level of evidence quality for outcome measures. The quality included five downgrading factors: risk of bias, inconsistency, indirectness, imprecision, other considerations. The quality of evidence was divided into four levels: high, moderate, low, and very low.

Two reviewers (Y.Z. and M.Z.) independently assessed the quality of the included studies. If the results of the two authors differed, a third person (K.X.) participated in the discussion and decided on the final consensus.

Risk of bias

Two reviewers (Y.Z. and M.Z.) completed the risk-of-bias assessment independently. Dispute between the reviewers was resolved through discussion, or referred to the third person (K.X.) when necessary. We used the version 2 of the Cochrane tool to access the risk of bias (RoB2) (38,39). Each study was assessed for five areas: randomization process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result. And the classifications of bias risk included low risk of bias, uncertain, and high risk of bias. If at least one of these five domains is rated as high risk, the overall score will be rated as high risk. If none of the domains are rated as high risk, but at least one domain is rated as some concern, the overall score will be rated as some concern. If all five domains are low risk, the overall score is low risk. Results were indicated by green, yellow and red color circles respectively.

Statistical analysis

The Review Manager 5.4 software was used for meta-analyses. As the outcome measures were continuous variables, the standardized mean differences (SMDs) of score changes were calculated as pool effect sizes, and the 95% confidence interval (CI) of the statistical results was reported. The Chi-squared test and I2 statistic were used to determine the heterogeneity of studies. And Z tests were used to compare differences in the subgroup’s overall effect sizes. A P value less than 0.05 indicates that the difference is statistically significant. The fixed-effect model was used when the heterogeneity test showed no statistically significant difference (I2<30%, P>0.05). When the heterogeneity test showed a statistically significant difference (I2>30%, P<0.05), a random-effects model was used (40). Subgroup analyses or sensitivity analyses is required if heterogeneity is large.

Results

Study selection

Initially, 708 studies were retrieved from five databases after searching. After removing duplicate studies, 492 studies were screened for titles and abstracts and 451 of them were removed for not being relevant, not having full texts or not meeting the eligibility criteria. As a result, 15 studies (41-55) were included in this review and 10 (44-47,50-55) of that were included in meta-analysis, and five of these RCTs were not included in the meta-analysis because data could not be extracted or outcome measures could not be combined. The PRISMA flow chart (Figure 1) described the screening and selection process of studies.

Figure 1 The PRISMA flow chart for study selection.

The studies included in this systematic review and meta-analysis were published between 2007 (49) and 2023 (42), covering several nations including America (48-50,54), Canada (41,43,55), Italy (53), China (44,52), Thailand (51), Korea (47), and India (42,45,46).

Participant characteristics

Table 3 summarizes the characteristics of participants included in this study. A total of 366 participants with CP (261 hemiplegic, 55 diplegic, 30 quadriplegic) were included in those fifteen studies. Thirteen studies (41-44,46-52,54,55) included 162 females and 176 males. Gender was not reported for 28 participants in two studies (45,53). The mean age of participants ranged from 2.5 to 22 years. One study (48) included four participants with CP older than 18 years but only in the sham stimulation group, and this study was not included in the meta-analysis, only included in the systematic review for descriptive analyses. And the level of MACS ranged from levels I to IV.

Table 3

Participants characteristics

Intervention type Study Nation Sample size (M/F) Treatment group, n Control group, n Age (years), range or mean ± SD Type of CP MACS level Adverse event
rTMS Kirton, 2016 Canada 23 (16/7) 12 11 11.96±3.9 Hemiparetic CP – 11% mild and self-limiting headache; tingling, nausea <3%
Wu, 2022 China 35 (14/21) 17 18 3.93±1.0 Hemiparetic CP Level I (n=19) Headache (n=1), relieved after
several minutes
Level II (n=16)
Valle, 2007 America 17 (8/9) 11 6 9.2±3.4 Spastic quadriplegia CP – No serious adverse events
Gillick, 2014 America 19 (9/10) 10 9 8–17 Hemiparetic CP Level I (n=4) Self-limiting headache; cast irritation
Level II (n=14)
Level III (n=1)
Gupta, 2019 India 20 (–/–) 10 10 2–15 Spastic CP – No report adverse events
Gupta, 2016 India 20 (16/4) 10 10 7.99±4.66/8.41±4.32 Hemiparetic CP (n=2) – No report adverse events
Spastic diplegic CP (n=11)
Quadriplegic CP (n=7)
Gupta, 2023 India 46 (30/16) 23 23 5–15 Hemiparetic CP Level I (n=1) No serious adverse events were seen
Level II (n=23)
Level III (n=22)
tDCS Inguaggiato, 2019 Italy 8 (–/–) 3 5 17.5±6.1 Hemiparetic CP Level I (n=2) Transient and slight discomfort (headache, neck pain, scalp pain, burning, tingling, drowsiness, and so on)
Level II (n=3)
Level III (n=3)
Carlson, 2018 Canada 15 (11/4) 7 8 12.1±3.0 Hemiparetic CP Level I–IV No report adverse events
Salazar Fajardo, 2022 Korea 24 (12/12) 14 10 5.25±2.1 Spastic unilateral (n=9) – No report adverse events
Spastic bilateral CP (n=15)
Nemanich, 2019 America 20 (9/11) 10 10 12.75±4.17 Hemiparetic CP Level I (n=2) Headache and itchiness
Level II (n=16)
Level III (n=1)
Level IV (n=1)
Aree-uea, 2014 Thailand 46 (24/22) 23 23 13.5±3.1 Spastic diplegia (n=29) – Erythematous rash (n=1)
Spastic hemiplegia (n=11)
Spastic quadriplegia CP (n=6)
He, 2022 China 30 (15/15) 15 15 3.96±0.94 Hemiparetic CP Level I (n=26) The proportion of dizziness (n=1), burning sensation (n=1), tingling (n=2), and itching (n=1)
Level II (n=4)
Gillick, 2018 America 20 (9/11) 10 10 12.75±4.17 Hemiparetic CP – Headache and itchiness
Kirton, 2017 Canada 23 (15/8) 12 11 11.8±2.7 Hemiparetic CP Level I (n=7) Itching (39%), headache (n=3), mild burning (n=3), or unpleasant tingling (n=1)
Level II (n=16)

CP, cerebral palsy; F, female; M, male; MACS, manual ability classification system; rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation; tDCS, transcranial direct current stimulation.

Characteristics of stimulation

Seven studies analyzed the effect of rTMS (41,42,44-46,49,50), while eight studies analyzed tDCS (43,47,48,51-55). As shown in Table 4, characteristics of NIBS included the content of intervention program, site of stimulation, stimulus parameters (intensity and frequency), total duration, duration of each session, number of sessions, outcome measures, and assessment time points.

Table 4

Characteristics of stimulation

Intervention type Study Content of intervention program Site of stimulation Stimulus parameter Duration Minutes (pulse)/session Number of NIBS sessions Outcomes measured Assessment time points
tDCS Inguaggiato, 2019 TG: active tDCS The M1 of the affected or more affected hemisphere Anodal tDCS, 1.5 mA – 20 minutes 2 BBT T0: baseline
CG: sham tDCS HGS T1: immediately
T2: 90 minutes
Carlson, 2018 TG: goal-directed motor learning therapy camp + real tDCS The contralesional primary motor cortex (M1) Cathodal tDCS,
1.0 mA,
0.04 mA/cm2		 2 weeks 20 minutes 10 COPM T0: baseline
AHA T1: 1 week post-intervention
CG: goal-directed motor learning therapy camp + sham tDCS MA T2: 8 weeks post-intervention
BBT
Salazar Fajardo, 2022 TG: tDCS + NDT The contralesional primary motor cortex (M1) Anodal tDCS, 1 mA 5 weeks 20 minutes 15 BBT T0: baseline
CG: the only NDT MAS T1: post-intervention
T2: 1 month follow-up
Nemanich, 2019 TG: active tDCS + CIMT The contralesional primary motor cortex (M1) Cathodal tDCS, 0.7 mA 10 days 20 minutes 10 AHA T0: 11 days prior to intervention
CG: sham tDCS + CIMT T1: 5 days after intervention
T2: 6 months after intervention
Aree-uea, 2014 TG: PT + active tDCS The M1 of the affected or more affected hemisphere Anodal tDCS, 1 mA 5 days 20 minutes 5 MAS T0: before treatment
CG: PT + sham tDCS ROM T1: immediately after treatment
T2: 24- and 48-hour follow-up
He, 2022 TG: active tDCS The M1 of the affected or more affected hemisphere Anodal tDCS, 1.5 mA 2 days 20 minutes 2 GMFCS T0: baseline
CG: sham tDCS BBT T1: immediately
MA 2 T2: 90 minutes
MAS T3: 24 hours
Gillick, 2018 TG: CIMT + active tDCS The contralesional primary motor cortex (M1) Cathodal tDCS, 0.7 mA 10 days 20 minutes 10 AHA T0: 2 weeks prior to intervention
CG: CIMT + sham tDCS COPM T1: 1 week after intervention
Grip strength T2: 6 months
Kirton, 2017 TG: active tDCS + motor learning therapy The contralesional primary motor cortex (M1) Cathodal tDCS, 1 mA, 0.04 mA/cm2 2 weeks 20 minutes 10 COPM T0: baseline
AHA T1: 1 week
CG: sham tDCS + motor learning therapy – – – – – MA T2: 2 months
BBT
ABILHAND-Kids
HGS
rTMS Kirton, 2016 TG: rTMS (+) + CIMT (+) The contralesional primary motor cortex (M1) Intensity 90% resting motor threshold frequency 1 Hz (1,200 stimuli) 2 weeks 20 minutes 10 AHA T0: baseline
CG: rTMS (−) + CIMT (+) COPM T1: 1 week postintervention
MA T2: 2 months postintervention
PedsQL T3: 6 months postintervention
BBT
Grip strength
ABILHAND-Kids
Wu, 2022 TG: CIMT + active TMS The contralesional primary motor cortex (M1) Intensity 90% resting motor threshold frequency 1 Hz 10 days 20 minutes 10 MACS T0: baseline
CG: CIMT + sham TMS COPM T1: 2 weeks post-intervention
MA 2 T2: 6 months post-intervention
MAS
SCUES
Valle, 2007 TG: 1 Hz/5 Hz active rTMS The motor cortex Intensity 90% resting motor threshold frequency 5 Hz/1 Hz 5 days 1,500 pulses 5 MAS T0: baseline
CG: sham rTMS ROM T1: the end of the treatment
Gillick, 2014 TG: CIMT + active rTMS The contralesional primary motor cortex (M1) Intensity 90% resting motor threshold frequency 1 Hz (6 Hz priming) 2 weeks 20 minutes 5 AHA T0: baseline
CG: CIMT + sham rTMS COPM T1: 2 days after the intervention
Gupta, 2019 TG: PT + rTMS The motor cortex Frequency 5 Hz 20 days 15 minutes 20 MAS T0: baseline
CG: only PT T1: post-intervention
Gupta, 2016 TG: standard therapy + rTMS The motor cortex Frequency 5 Hz/10 Hz (1,500 pulses) 4 weeks 15 minutes 20 MAS T0: baseline
CG: only standard therapy T1: post-intervention
Gupta, 2023 TG: mCIMT + real rTMS The contralesional primary motor cortex (M1) Intensity 90% resting motor threshold frequency 1 Hz (6 Hz priming) 4 weeks 20 minutes 10 QUEST T0: baseline
CG: mCIMT + sham rTMS CP-QOL T1: post-intervention
Speed and strength measures T2: 12 weeks
post-intervention

AHA, Assisting Hand Assessment; BBT, Box and Block Test; CG, control group; CIMT, constraint-induced movement therapy; COPM, Canadian Occupational Performance Measure; CP-QOL, Cerebral Palsy Quality of Life; GMFCS, gross motor function classification system; HGS, Hand Grip Strength; MACS, manual ability classification system; MA, Melbourne Assessment; MAS, Modified Ashworth Scale; mCIMT, modified CIMT; NDT, neurodevelopmental treatment; PedsQL, pediatric quality of life inventory; PT, physiotherapy; QUEST, Quality of Upper Extremity Skills Test; rTMS, repetitive transcranial magnetic stimulation; ROM, range of motion; SCUES, the selective control of the upper extremity scale; tDCS, transcranial direct current stimulation; TG, treatment group; TMS, transcranial magnetic stimulation.

For the site of stimulation, 10 studies (41-44,47,48,50,51,54,55) targeted the contralesional hemisphere primary motor cortex, two (52,53) focused on the affected or more affected hemisphere primary motor cortex, and three studies (45,46,49) did not specify beyond the motor cortex. Intensity of rTMS is 90% resting motor threshold with frequency of 1 or 5 Hz. And intensity of tDCS are 0.7 mA (48,54), 1 mA (43,47,51,55), and 1.5 mA (52,53). Four studies (47,51-53) used anodal tDCS for the affected or more affected hemisphere and four (43,48,54,55) used cathodic tDCS for the contralesional hemisphere. One study (49) used 1500 pulses as the session length, two studies (45,46) conducted each session for 15 minutes, and the remaining studies lasted 20 minutes per session.

A variety of outcome measures were used in the included studies. Six studies (41,43,48,50,54,55) used AHA to evaluate the function of the affected hand during collaborative movement of hands (56,57), six (41,43,44,50,54,55) used COPM to evaluate performance and satisfaction in occupational activities, five (41,43,44,52,55) used MA [two studies (44,52) used MA 2] to evaluate function and quality of upper extremity, six (41,43,47,52,53,55) used BBT to evaluate hands flexibility, seven (44-47,49,51,52) used MAS to assess the muscle tone of upper extremity, two (49,51) used range of motion (ROM) to evaluate the joint function of upper extremity, two (41,55) used ABILHAND-Kids to evaluate hands-on ability, three (41,53,55) used grip strength to evaluate muscle strength, and one (42) used Quality of Upper Extremity Skills Test (QUEST) to evaluate the quality of upper extremity function and movement patterns in children with CP.

The intervals from treatment to follow-up evaluation included immediately (45-47,49,51-53), 90 minutes (52,53), 24 hours (51,52), 48 hours (51), 1 week (41,43,54,55), 2 weeks (44), 1 month (47), 2 months (41,43,55), 12 weeks (42), and 6 months (41,44,48,54).

Assessment of quality

The PEDro scale was used in this systematic review and meta-analysis for assessment of quality. The PEDro scores of the included studies is listed in Table 5. Six studies (41,42,48,51,54,55) had excellent quality, six studies (45,46,49,50,52,53) had good quality, and three studies (43,44,47) had low quality.

Table 5

PEDro scores

Study Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Q11 Total score
rTMS
   Kirton et al. Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes 9
   Wu et al. Yes Yes No Yes No No Yes Yes No No Yes 5
   Valle et al. Yes Yes No No Yes No Yes Yes No Yes Yes 6
   Gillick et al. Yes Yes No No Yes Yes Yes Yes No Yes Yes 7
   Gupta et al., 2019 Yes Yes No Yes No No Yes Yes Yes No Yes 6
   Gupta et al., 2016 Yes Yes No Yes No No Yes Yes Yes No Yes 6
   Gupta et al., 2023 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10
tDCS
   Inguaggiato et al. Yes Yes No No Yes Yes Yes Yes No No Yes 6
   Carlson et al. Yes Yes No Yes Yes Yes Yes No No No Yes 6
   Salazar Fajardo et al. Yes Yes No Yes No No Yes Yes No No Yes 5
   Nemanich et al. Yes Yes No Yes Yes Yes Yes Yes No Yes Yes 8
   Aree-uea et al. Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes 10
   He et al. Yes Yes No Yes Yes No No Yes No Yes Yes 6
   Gillick et al. Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes 9
   Kirton et al. Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes 9

The PEDro scale includes 11 items, but only Q2–Q11 (10 items) contribute to the total score (range, 0–10). Q1 serves solely as a screening criterion for study validity and does not contribute to the total score. PEDro, Physiotherapy Evidence Database; Q, question; rTMS, repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation.

The quality of the evidence for the outcome measures of the included studies was assessed using the GRADEprofiler software. A total of eight outcome measures (three for rTMS and five for tDCS) were included. Among them, there was one low-quality measure and two very low-quality outcome measures of rTMS. There were four low-quality outcome measures and one very low-quality outcome measures for tDCS, as shown in Figure 2.

Figure 2 The quality of evidence for the included study outcome indicators. AHA, Assisting Hand Assessment; BBT, Box and Block Test; CI, confidence interval; COPM, Canadian Occupational Performance Measure; HGS, Hand Grip Strength; MAS, Modified Ashworth Scale; MD, mean difference; NIBS, non-invasive brain stimulation; rTMS, repetitive transcranial magnetic stimulation; SMD, standardized mean difference; tDCS, transcranial direct current stimulation.

Risk of bias assessment

The version 2 of the Cochrane tool was used to access the risk of bias. The results are shown in Figure 3. Five studies (44-48) were at high risk of bias during randomization, five (41,43,49,52,53) at some concern, and five (42,50,51,54,55) at low risk. One study (47) was at high risk of the bias from the established intervention, seven (43-46,49,52,53) at some concern, and the rest (41,42,48,50,51,54,55) at low risk. Bias for missing outcome data were at low risk in all fifteen studies. Two (45,46) were at some concern of bias for outcome measures and the rest at low risk. Two (41,48) were at high risk of bias for selective reporting of results, eight (43-47,49,51,53) at some concern, and the remaining five (42,50,52,54,55) at low risk. The overall risk of bias was five (41,45-48) at high risk, six (43,44,49,51-53) at some concern, and four (42,50,54,55) at low risk.

Figure 3 Risk of bias. (A) Summary of study bias risk; (B) risk of bias graph.

Effectiveness of NIBS: meta-analysis

NIBS including rTMS and tDCS were used in 10 studies (44-47,50-55) for meta-analysis. These studies using rTMS as a stimulation intervention assessed upper extremity function in 76 participants, and tDCS as a stimulation intervention evaluated upper extremity function and spasticity in 181 participants.

COPM

In two studies of tDCS, COPM was used to assess the post and follow-up effects in the occupational activities including two components: performance and satisfaction. Heterogeneity existed (SMD =0.73; 95% CI: 0.14 to 1.32; P=0.01; I2=70%), and we divided the groups into two subgroups: performance and satisfaction. For the performance subgroup, we selected a random-effects model (SMD =0.71; 95% CI: −0.17 to 1.60; P=0.12; I2=73%). For the satisfaction subgroup, we chose a random-effects model (SMD =0.76; 95% CI: −0.15 to 1.66; P=0.10; I2=74%). The results of the analysis were not statistically significant for both subgroups, as shown in Figure 4.

Figure 4 Meta-analysis results of using the COPM to assess the effects of NIBS. (A) The result of meta-analysis using COPM to assess the performance and satisfaction effects of tDCS on occupational performance in patients with CP; (B) the result of meta-analysis using COPM to assess the performance and satisfaction effects of rTMS on occupational performance in patients with CP. CI, confidence interval; COPM, Canadian Occupational Performance Measure; CP, cerebral palsy; NIBS, non-invasive brain stimulation; rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation; tDCS, transcranial direct current stimulation.

COPM was also used to assess occupational performance related to daily activities in three studies of rTMS. There were no significant changes in performance (SMD =−0.22; 95% CI: −0.73 to 0.30; P=0.41; I2=0%) or satisfaction (SMD =−0.11; 95% CI: −0.62 to 0.40; P=0.67; I2=0%) scores using a fixed-effects model, as shown in Figure 4.

BBT

BBT was used to assess the effects of different time point in two studies of tDCS in the coordination of affected hand or unaffected hand, as shown in Figure 5.

Figure 5 Meta-analysis results of using the BBT to assess the effects of tDCS. (A) The result of using BBT to assess the effect of tDCS at different time points on the affected hand; (B) the result of using BBT to assess the effect of tDCS at different time points on the unaffected hand. BBT, Box and Block Test; CI, confidence interval; SD, standard deviation; tDCS, transcranial direct current stimulation.

The BBT scores of the affected hand changed significantly in overall effect using a fixed-effect model (SMD =0.50; 95% CI: 0.19 to 0.81; P=0.002; I2=0%). The BBT scores of the affected hand changed significantly in post (SMD =0.68; 95% CI: 0.02 to 1.34; P=0.044; I2=0%) and 90-minute effect (SMD =0.69; 95% CI: 0.02 to 1.36; P=0.04; I2=0%); There was no significant changes at short-term (SMD =0.44; 95% CI: −0.15 to 1.02; P=0.14; I2=0%) and long-term follow-up effect (SMD =0.29; 95% CI: −0.29 to 0.87; P=0.33; I2=0%).

However, there was no significant change in the BBT score of the unaffected hand at post (SMD =0.07; 95% CI: −0.57 to 0.71; P=0.83; I2=0%), 90-minute (SMD =0.04; 95% CI: −0.60 to 0.68; P=0.90; I2=0%), short-term (SMD =0.25; 95% CI: −0.33 to 0.83; P=0.40; I2=0%), and long-term follow-up effect (SMD =0.31; 95% CI: −0.27 to 0.89; P=0.30; I2=0%) using a fixed-effect model.

MAS

MAS was used to assess improvement of muscle tone in two studies of tDCS, as shown in Figure 6. There was a significant change in MAS scores (SMD =−0.51; 95% CI: −0.99 to −0.03; P=0.04; I2=0%).

Figure 6 Meta-analysis results of using the MAS to assess the effect of NIBS in children with CP. (A) The result of using MAS to assess the effect of tDCS on improving spasticity in patients with CP; (B) the result of the effect of rTMS on improving spasticity of biceps and wrist extensors in patients with CP. CI, confidence interval; CP, cerebral palsy; MAS, Modified Ashworth Scale; NIBS, non-invasive brain stimulation; rTMS, repetitive transcranial magnetic stimulation; SD, standard deviation; tDCS, transcranial direct current stimulation.

MAS was used to assess muscle tone of biceps and wrist extensor in two studies of rTMS, as shown in Figure 6. There were no significant changes in MAS scores in biceps (SMD =0.16; 95% CI: −0.46 to 0.78; P=0.61; I2=0%) or wrist extensor (SMD =−0.13; 95% CI: −0.75 to 0.49; P=0.67; I2=0%).

AHA

AHA was used to assess the post and follow-up effects in two studies of tDCS in the improvement of upper extremity function on the affected side during collaborative movement of hands, as shown in Figure 7. There was no significant change in AHA scores, either post (SMD =0.23; 95% CI: −0.37 to 0.83; P=0.46; I2=0%) or follow-up effect (SMD =0.12; 95% CI: −0.48 to 0.72; P=0.69; I2=0%) using a fixed-effect model.

Figure 7 Results of meta-analysis of the AHA and HGS. (A) The result of using AHA to assess the effect of tDCS; (B) the result of using HGS to assess the effects of tDCS on improving muscle strength in patients with CP. AHA, Assisting Hand Assessment; CI, confidence interval; CP, cerebral palsy; HGS, Hand Grip Strength; SD, standard deviation; tDCS, transcranial direct current stimulation.

HGS

HGS was used to assess improvement of muscle strength in two studies of tDCS, as shown in Figure 7. There was no significant change in HGS scores at overall (SMD =−0.06; 95% CI: −0.60 to 0.48; P=0.83; I2=0%) and post effect (SMD =0.03; 95% CI: −0.73 to 0.79; P=0.94; I2=0%) using a fixed-effect model.

Safety and adverse events

We evaluated the safety and tolerability of NIBS by analyzing adverse events and dropouts, as shown in Figure 8. We performed a meta-analysis of all fifteen studies, and there is no difference in dropouts between active and sham stimulation groups, with only three dropouts in each group. The reasons for dropouts were botulinum toxin injection, disease progression, and distance.

Figure 8 Forest plot of dropouts in NIBS trials. The diamond at the bottom of the plot summarizes the best estimate results of the meta-analysis with the width representing the corresponding 95% CI. CI, confidence interval; NIBS, non-invasive brain stimulation.

All studies discussed adverse events that occurred during the trials, with the exception of three studies (43,45,47) that no information on adverse events was provided. None of the fifteen studies observed serious adverse effects, instead, all reported adverse event were mild and transient discomfort. Headache was the most common adverse event, with about 8% patients experienced headaches in three studies (41,44,55) in total. There were also patients with headache in Gillick et al.’s 2014 (50) and 2018 (54) studies, as well as in the studies of Inguaggiato et al. (53), Nemanich et al. (48), and Gupta et al. (42), but the incidence was not reported. Tingling was the second most common symptom, reported in multiple studies. About 5% patients experienced tingling in three studies (41,52,55); In Inguaggiato et al.’s study (53), patients also experienced tingling. There were also cases with itching (48,52,54,55), burning sensation (52,53,55), dizziness (42,52), nausea (41), etc. reported. In Aree-uea et al.’s study (51), one participant developed an erythematous rash and mild skin burn, but there was no pain, peeling, or infection. The rash resolved spontaneously within 2 hours, and the skin burn resolved within 3 days without scar. Notably, in Gupta et al.’s study (42), one child who had a history of epilepsy developed vacant stare lasting for a few seconds, within a few hours after the intervention, though this occurred in the sham rTMS group.

Discussion

NIBS regulates brain activity and neuroplasticity by regulating cerebral cortical excitability (58,59), thereby affecting the function innervated by the corresponding brain region. The novelty of our study lies in searching and summarizing the effectiveness and safety of NIBS for improving upper extremity function in children with CP, along with conducting a quantitative meta-analysis which had not been done in previous related studies. Our findings suggest for the first time that tDCS is effective in improving spasticity (MAS), and hand fine motor function, especially hand dexterity in children with CP. Meanwhile, our results have certain clinical and practical significance for relevant healthcare professionals. First, the results provide evidence for the safety of NIBS in children with CP, which is very important for professionals to apply NIBS in clinical practice; second, the effectiveness of tDCS provides professionals with an evidence-based auxiliary treatment method, and medical professionals should regard it as part of a comprehensive rehabilitation plan rather than a single treatment; finally, the results cautiously show that different stimulation parameters could be targeted to treat different dysfunction.

Improvement of upper extremity function

Seven studies analyzed the effect of rTMS in this systematic review (41,42,44-46,49,50). These articles used assessment tools such as AHA, COPM, MA, BBT, MAS, etc. Two of the studies used COPM and two used MAS for outcome assessment in meta-analysis, but neither showed statistically significant score changes. This is consistent with the results of Metelski et al.’s systematic review (27), which reported little or no significant impact for upper extremity dysfunction outcomes after using rTMS. On the one hand, the number of studies retrieved for the particular research question—improving upper extremity function in CP children through rTMS—was relatively small. Consequently, the number of studies that could be incorporated into the systematic review and meta-analysis was limited. On the other hand, COPM mainly evaluates the ability of occupational activities, which place relatively higher requirements for upper extremity and hand function (60,61), and scores may be influenced by the parents and patients’ own subjective judgment. Remarkably, changes in upper extremity may be different in body structure and function outcomes after rTMS. As mentioned in Metelski et al.’s review (27), there was improvement in the ROM of the thumb, wrist, and elbow of children with CP after using rTMS in some RCTs, but these changes in body structure and function did not necessarily translate into improvements in upper extremity function without supplementary interventions.

Eight studies analyzed the effect of tDCS (43,47,48,51-55). Six studies using AHA, COPM, BBT, HGS, MAS as assessment instruments were included in meta-analysis. Among them, score changes of BBT on affected hand, MAS were statistically significant. The results of meta-analysis of MAS suggested that tDCS had some effectiveness in improving spasticity. This is inconsistent with the results of Metelski et al.’s systematic review (27), which found little or no statistically significant improvement in the outcome of upper extremity dysfunction after using tDCS. This discrepancy may stem from differences in the articles included in the analyses between the two studies, as well as differences in supplementary interventions, study design, and tDCS parameters. One study (62) suggested that tDCS combined with sensorimotor training significantly activated the motor cortex. Most of the non-significant results in our meta-analysis may be due to the fact that the effectiveness of NIBS is not generalized to the improvement of functional tasks, and the effectiveness of NIBS in combination with other interventions need to be further explored.

In our study, tDCS did not significantly improve hand muscle strength and occupational activity in children with CP, but it was different in adults. Significant improvement in score on outcome measures of related upper extremity occupational activity after tDCS was reported in a meta-analysis (63) of adult stroke. And another study (64) in adults with stroke reported significant improvement in hand muscle strength after tDCS. This disparity may be due to the differential impact of tDCS on the developing brain of children compared to the mature brain of adults (65).

In addition, rTMS and tDCS exhibit different effects, which may be due to differences in their mechanisms of action. And different stimulation parameters may affect the effectiveness of tDCS and rTMS. We hypothesize that the optimal parameters for each modality may vary depending on clinical experience, different functional impairments, and that future studies should explore these parameters in more detail to improve the effectiveness of NIBS interventions.

Stimulation parameters

Seven studies used rTMS (41,42,44-46,49,50). The study by Valle et al. showed that there was no statistically significant improvement in spasticity after low-frequency or sham rTMS, while there was a statistically significant improvement in spasticity after high-frequency rTMS (49). It indicated that the high frequency (5 Hz) is better than the low frequency (1 Hz) in improving spasticity in some degree. The advantage of low-frequency rTMS is that it directly stimulates the unaffected cortex and indirectly acts on the affected cortex, which is a good choice when there is some organic damage to the affected cortex and the risk of direct stimulation is high (66,67). And one study (68) showed that although both high- and low-frequency rTMS had a positive effect on motor recovery and promote the reorganization of the motor network in stroke patients, high-frequency rTMS may be more conductive to the functional connectivity reorganization of the motor network and have greater benefit to the motor recovery.

Eight studies used tDCS, most of which use the stimulation intensity of 1 mA (43,47,48,51-55). For anodal tDCS, the stimulation was consistently applied over the primary motor cortex (M1) of the affected or more affected hemisphere. Conversely, cathodal tDCS targeted the contralesional primary motor cortex (M1). One study (69) reported that cathodal tDCS is superior to anodal or bilateral stimulation in improving ADL after stroke. The relative advantage of cathodal tDCS may be due to insufficient inter-hemisphere inhibition, leading to downregulation of the overactive unaffected brain hemispheres, thereby restoring the balance of excitatory and inhibitory interactions between both hemispheres (70-72). However, due to the insufficient number of studies included in this review, it was not possible to compare the effects of anodal stimulation with cathodal stimulation.

According to our meta-analysis, several parameters could be summarized to target different dysfunction. In children with CP, 1 mA anodal tDCS of at least five sessions of 20 minutes per session may be effective in improving spasticity; 1.5 mA anodal tDCS of two sessions of 20 minutes per session may be effective in improving the fine motor function, especially flexibility of hands. Thus, different stimulation parameters need to be used for children with CP in different conditions, and knowing these parameters could enhance the clinical application of NIBS as an adjunctive therapy of CP in children.

Safety and tolerability

As shown in the results, there were only three dropouts in each group. The low number of dropouts and loss to follow-up may be due to small sample sizes and strict adherence to inclusion and exclusion criteria. And there were no serious adverse events reported in either rTMS or tDCS. The most serious adverse events mentioned in this study were erythematous rash and mild skin burns, all of which healed quickly. The other adverse events such as headache, tingling, itching, burning sensation, dizziness, and nausea were transient and mild.

Among all the included RCTs, some studies excluded unstable (41,43,55) or uncontrolled epilepsy (44,49,52), some (48,50,54) excluded people who had history of epilepsy in the past 2 years, and some (47,51,53) considered only patients with no history of epilepsy. After the end of the trials, none of the patients experienced adverse effects of epilepsy. Therefore, there is not enough evidence to suggest that NIBS induces epilepsy in patients without a history of epilepsy or in stable epilepsy when safety guidelines (30,73) are followed. Overall, our results demonstrated that NIBS is tolerable for children when adhere to safety guidelines (30,73).

Limitations

The RCTs in this meta-analysis had small sample sizes, which may limit the strength of our conclusions and the applicability of our findings to a wider population or setting, so the interpretation of the results needs to be more rigorous. We emphasize the need for further research on a larger and more diverse sample. Also, due to the limited number of articles included, we were unable to quantitatively analyze and compare the effects of NIBS in combination with other interventions. In addition, this systematic review analyzed only a subset of outcomes, and analyses of improvements in upper extremity function was not comprehensive enough. Potential bias exists as only English-language articles were included in this systematic review and full texts were not available for some article when searching databases and selecting studies. Finally, only RCTs were included in this systematic review and meta-analysis, with case reports and non-RCTs being excluded.

Conclusions

This systematic review and meta-analysis showed that rTMS and tDCS are safe and tolerable for children with CP. Current evidence suggests that when safety guidelines are followed, NIBS does not induce seizures in pediatric patients with no history of epilepsy or stable epilepsy. And tDCS is effective in improving upper extremity dysfunction such as fine motor function especially hand dexterity, and in reducing upper extremity spasticity in children with CP. However, the effectiveness of rTMS remains uncertain due to the limited number of RCTs included in this meta-analysis. In conclusion, NIBS seems safe for use in children with CP and could be used as an adjunct to the clinic rehabilitation in children with CP. Nevertheless, given the paucity of studies on NIBS for upper extremity dysfunction in children with CP, further high-quality RCTs are needed to establish robust evidence and treatment parameters.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-488/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-488/prf

Funding: The work was supported by the Featured Clinical Technique of Guangzhou (No. 2023C-TS59), the Guangzhou Municipal Science and Technology Project (No. 2024A03J01274), and the Plan on Enhancing Scientific Research in Guangzhou Medical University (No. GMUCR2024-02020).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-488/coif). All authors report funding from the Featured Clinical Technique of Guangzhou (No. 2023C-TS59), the Guangzhou Municipal Science and Technology Project (No. 2024A03J01274), and the Plan on Enhancing Scientific Research in Guangzhou Medical University (No. GMUCR2024-02020). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Cite this article as: Zhang Y, Zhong M, Peng T, Chen T, Cai S, Chen Z, Xu K. Non-invasive brain stimulation for upper extremity dysfunction in children with cerebral palsy: a systematic review and meta-analysis. Transl Pediatr 2025;14(2):262-285. doi: 10.21037/tp-24-488

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