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Open Access

Peer-reviewed

Research Article

A scoping review of the contralateral effects of unilateral peripheral stimulation on neuromuscular function

  • Shi Zhou ,

    Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Writing – original draft, Writing – review & editing

    shi.zhou@scu.edu.au

    Affiliation Discipline of Sport and Exercise Science, Faculty of Health, Southern Cross University, Lismore, New South Wales, Australia

    ⨯
  • Shuang-Shuang Zhang,

    Roles Data curation, Formal analysis, Writing – review & editing

    Affiliations Discipline of Sport and Exercise Science, Faculty of Health, Southern Cross University, Lismore, New South Wales, Australia, School of Sport Science, Beijing Sport University, Beijing, China

    ⨯
  • Zachary J. Crowley-McHattan

    Roles Data curation, Formal analysis, Validation, Writing – review & editing

    Affiliation Discipline of Sport and Exercise Science, Faculty of Health, Southern Cross University, Lismore, New South Wales, Australia

    ⨯

Abstract

It is known that resistance exercise using one limb can affect motor function of both the exercised limb and the unexercised contralateral limb, a phenomenon termed cross-education. It has been suggested that cross-education has clinical implications, e.g. in rehabilitation for orthopaedic conditions or post-stroke paresis. Much of the research on the contralateral effect of unilateral intervention on motor output is based on voluntary exercise. This scoping review aimed to map the characteristics of current literature on the cross-education caused by three most frequently utilised peripheral neuromuscular stimulation modalities in this context: electrical stimulation, mechanical vibration and percutaneous needling, that may direct future research and translate to clinical practice. A systematic search of relevant databases (Ebsco, ProQuest, PubMed, Scopus, Web of Science) through to the end of 2020 was conducted following the PRISMA Extension for Scoping Review. Empirical studies on human participants that applied a unilateral peripheral neuromuscular stimulation and assessed neuromuscular function of the stimulated and/or the unstimulated side were selected. By reading the full text, the demographic characteristics, context, design, methods and major findings of the studies were synthesised. The results found that 83 studies were eligible for the review, with the majority (53) utilised electrical stimulation whilst those applied vibration (18) or needling (12) were emerging. Although the contralateral effects appeared to be robust, only 31 studies claimed to be in the context of cross-education, and 25 investigated on clinical patients. The underlying mechanism for the contralateral effects induced by unilateral peripheral stimulation remains unclear. The findings suggest a need to enhance the awareness of cross-education caused by peripheral stimulation, to help improve the translation of theoretical concepts to clinical practice, and aid in developing well-designed clinical trials to determine the efficacy of cross-education therapies.

Citation: Zhou S, Zhang S-S, Crowley-McHattan ZJ (2022) A scoping review of the contralateral effects of unilateral peripheral stimulation on neuromuscular function. PLoS ONE 17(2): e0263662. https://doi.org/10.1371/journal.pone.0263662

Editor: Emiliano Cè, Universita degli Studi di Milano, ITALY

Received: June 22, 2021; Accepted: January 21, 2022; Published: February 9, 2022

Copyright: © 2022 Zhou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: The authors received no specific funding for this work.

Competing interests: The authors have declared that no competing interests exist.

Introduction

It is known that motor practice using one limb can affect motor output in both the exercised muscle and the homologous muscle of the unexercised limb [1–3]. Several terms have been used in the literature to describe this phenomenon, such as cross education, cross training, cross transfer, or interlimb transfer, etc. However, a consensus has recently been reached among experts in this field through a Delphi survey, that “cross-education” should be used consistently in future reference to this phenomenon [3]. It should be noted that, cross-education is defined as “the increased motor output (i.e., force generation, skill) of the opposite, untrained limb following a period of unilateral exercise training” by the experts who participated in the Delphi survey [3]. This raises a question that whether the studies on the acute effect of a single bout of unilateral exercise or stimulation could be regarded as under the umbrella of cross-education. It is understandable that the adaptations to exercise training or intervention are based on the cumulative effects in response to repeated single stimulation sessions. It is important to examine and understand the acute responses and their contribution to the chronic adaptation. In this context, the definition of cross-education might be extendable to the investigations on the acute effect of a single bout unilateral exercise or stimulation. Therefore, studies that investigated either acute or chronic interventions were included in this review.

Researchers and health practitioners have had a continued interest in the cross-education because it not only raises questions about the mechanisms of neural plasticity in response to unilateral exercise, but also has clinical implications, such as in rehabilitation for paresis post stroke, or after a single limb injury or surgical operation [4–9]. In respect to physiological mechanisms, the general consensus is that cross-education is mainly manifested by adaptations in the central nervous system (CNS). The viewpoint is supported by the common finding that no significant muscle hypertrophy is associated with increased strength in the unexercised contralateral limb after a short period of unilateral training [10–14]. It has been proposed that unilateral voluntary contractions can bring about complex changes in the cortical motor pathways controlling the contralateral homologous muscle [15]. Alternatively, the neural adaptations may reside in supraspinal areas that are predominantly involved in the control of the trained limb, and these modified neural circuits may be accessed during voluntary contractions of the untrained limb [15]. It has also been hypothesised that cross-education of strength may be best applied to clinical populations with asymmetries, such as neurological damage after stroke or unilateral orthopedic injury [5].

There have been reports on the clinical efficacy of cross-education in the treatment of, and rehabilitation after, an injury, surgical operation, or stroke [4, 16, 17]. For example, a systematic review that analysed the available cross-education evidence on muscle strength in post-stroke hemiplegic patients [4] presented two eligible research articles amongst the 53 screened. Both articles reported an improved strength performance in the untrained, more affected dorsiflexor muscle after training the less affected limb. In contrast, there are reports that cross-education does not accelerate the rehabilitation of neuromuscular functions after ACL reconstruction [17, 18].

Much of the evidence mentioned above results from unilateral resistance training and/or interventions using voluntary contractions exclusively. Interestingly, some alternative training methods, such as neuromuscular electrical stimulation (NMES) or electromyostimulation (EMS) [19, 20], mechanical vibration [21–23], and acupuncture or needling [24–26], have also exhibited cross-education benefits. These interventions are loosely termed “peripheral neuromuscular stimulation” in this article, to distinguish them from voluntary resistance training and interventions that apply stimulation directly to the CNS, such as transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), or similar.

It should be noted that the principle of unilateral or contralateral therapy has been applied clinically for centuries in traditional Chinese medicine. One example for the applications of this principle is acupuncture under a treatment strategy termed juci (contralateral meridian needling) or miaoci (contralateral collateral needling), that are also translated as opposing needling by some authors [27, 28]. Although such practices existed historically, only in the recent decades the efficacy of these opposing needling interventions and their potential mechanisms have been more rigorously examined in laboratory and clinical studies [29–31]. Furthermore, acupuncture and dry needling (DN) as a means of therapy has also been utilised in western countries [32, 33]. Researchers and practitioners have been critically examining the potential mechanisms and clinical efficacy of the DN, while recognising that their theoretical framework is not the same as that of acupuncture, for example, there are differences in how to determine the optimal sites and the techniques of needling between acupuncture and DN [30, 32–35].

From a health practice viewpoint, a unilateral intervention without voluntary muscle contraction, such as electrical stimulation, vibration, or needling, would have clinical implications, particularly for individuals with limited capacity in performing voluntary contractions using the affected limb. In respect to the underlying mechanisms, a compelling question is whether the contralateral effect of unilateral peripheral neuromuscular stimulation is manifested via the same or different neuromuscular mechanisms proposed for the cross-education resulting from voluntary contractions [36].

Scoping reviews are a way of knowledge synthesis that utilises a systematic approach to map evidence on a topic and identify the main concept, theories, sources, and knowledge gaps [37]. They may lead to further analysis of the evidence, such as systematic reviews and meta-analysis [37, 38]. The aim of this article was to provide a scoping review of the current literature on the contralateral effects of unilateral peripheral neuromuscular stimulations, following the recent guidelines for scoping reviews [37, 39], to summarise:

  1. the demographic characteristics of the eligible literature, including the number of research articles, year of publication, country and/or laboratory where the research was conducted, context of the studies, participants, setting, and types of research design;
  2. the intervention programs, including trials on acute and chronic effects, and the methods employed for peripheral stimulation and evaluation of the outcomes, including statistical analysis methods; and
  3. the research aims, major findings, and limitations for the studies that claimed to be in the context of cross-education.

After a preliminary search of the literature, we found that the major types of peripheral neuromuscular stimulation being electrical stimulation, vibration, and acupuncture or needling. Therefore, this review focused mainly on these three types of stimulation modalities. The terms of electrical stimulation, vibration, and acupuncture or needling, as used in this article, are defined below.

In this review, electrical stimulation (ES) refers to the practice or methods that apply electrical impulses via surface electrodes over a peripheral nerve or a skeletal muscle [40], or through intramuscular electrodes such as in electroacupuncture [41], to evoke sensory inputs and/or motor activities, aiming to examine or improve neuromuscular function. Transcutaneous electrical stimulation has been referred to as EMS [12], NMES [40], or transcutaneous electrical nerve stimulation (TENS) [20], depending on the methodology and context. The intensity, pulse width and shape, frequency, and other stimulation parameters are controlled via an electrical stimulator [42].

Vibration (VB) refers to utilization of a vibration device to deliver forced mechanical oscillation to the human body or parts of it [43]. Small vibratory units can be placed directly on a muscle or tendon, and larger units that can elicit vibration through cables, belts, or platforms, and produce vertical sinusoidal or synchronous vibration when the participant uses or stands on the device [44].

Acupuncture or needling involves the use of sharp, thin (filiform) needles that are inserted into the body at specific points (e.g., acupoints or taut band) for the treatment of health conditions [45]. Electroacupuncture refers to applying electrical stimulation through the acupuncture needles [46]. Other practices also involve the insertion of needles to treat health conditions, such as DN [32, 47]. It is beyond the scope of this review to discuss the differences in the theoretical frameworks of the acupuncture and DN [33, 47]. From a practical viewpoint, ‘needling’ (ND) is used in this article for the practices that involve the insertion of needles percutaneously into tissues for the purpose of research, such as to examine the ergogenic effects of needling on athletes or healthy individuals, or for health interventions.

Materials and methods

A literature search protocol was constructed as described in Table 1. Databases relevant to health and exercise available at the University’s library, as the information source, were systematically searched through to 31st of December 2020. The literature search and appraisal were conducted in four steps.

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Table 1. Literature search protocol.

https://doi.org/10.1371/journal.pone.0263662.t001

Step 1—Searching databases

The following Booleans and search strings were used in the search: (“cross education” OR cross-education OR “cross transfer” OR cross-transfer OR cross training OR “cross-training” OR unilateral OR contralateral) AND (muscle OR muscular OR neuromuscular OR “motor function” OR “neural function”) AND (rehabilitation OR therapy OR treatment OR training) AND (“electrical stimulation” OR “electric stimulation” OR electromyostimulation OR “neuromuscular electrical stimulation” OR NMES). The last set of Booleans and search strings (after the AND in brackets) was replaced by (vibration OR vibratory) or (acupuncture OR electroacupuncture OR needling OR dry-needling) in the respective searches.

Table 1 shows the databases searched, the specific search strategies and limits, and the number of items found. The search outcomes were downloaded to EndNote (version X9.3.3) libraries and screened to remove duplicates, review articles, books and book sections, conference abstracts, and animal studies.

Step 2—Screening for eligible studies

The EndNote library was then screened for eligible items in “Any Field”, using the words (or a part of a key word) and Booleans and search strings in the sequence of (1) “electr” (or “vibrat”, or “acup” or “needl” in the respective libraries), (2) “unilateral” or “contralateral” or “local” or “focal” or “cross”, and (3) “strength” or “force” or “torque” or “power” or “function”. The search was performed by one author and verified by third-party assistants to ensure the reproducibility of the search outcomes, and a 100% match between repeated searches was achieved.

Step 3—Data charting and calibration

The eligible items identified in Step 2 were further screened against the following inclusion and exclusion criteria. The full text was reviewed if a decision could not be made from the title and abstract. One author screened all records. Another author also screened at least 50 randomly selected records in each of the ES, VB and ND areas, and compared the outcomes with the first author as a means of calibration. If there were discrepancies, they were verified by the authors to achieve 100% agreement.

Inclusion criteria.

Investigations on human participants; empirical research; applied a unilateral peripheral neuromuscular stimulation; and assessed neuromuscular function of the stimulated side and/or the unstimulated contralateral side of the body, are eligible for inclusion. Articles written in languages other than English but with an abstract (or translation of the text) in English that presented information required in this scoping review were also eligible for inclusion.

Exclusion criteria.

Studies using animal models; review articles; conference abstracts; stimulation was only applied directly to the brain or spinal cord; and peripheral stimulation was applied on both sides of the body simultaneously, were excluded. Fig 1 summarises the search and screening results, following the PRISMA Extension for Scoping Review [37, 48].

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Fig 1. PRISMA flow diagram for database search outcomes.

ES = electrical stimulation, VB = vibration, ND = needling.

https://doi.org/10.1371/journal.pone.0263662.g001

Step 4—Critical appraisal

The full text of each article eligible for inclusion was appraised according to the aim of the review.

Results

The literature search resulted in a total of 5,005 items, of which 83 articles were identified as eligible for the scoping review, with 53 on ES, 18 on VB, and 12 on ND (Fig 1). Among these studies, there was one study [23] that included an ES and a VB group, three studies [24, 25, 41] that included both manual needling and electrical stimulation via needling groups, and one study [49] that included a manual needling and a vibration group.

The demographic information (year of publication, country and laboratory), contexts, participants, setting, and design of the reviewed articles are presented in Table 2 [12, 19–26, 41, 49–121].

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Table 2. Demographic characteristics of the reviewed articles.

https://doi.org/10.1371/journal.pone.0263662.t002

Context of the studies

Amongst the 83 articles reviewed, 31 (37.3%) claimed that their studies examined cross-education, 13 (15.7%) investigated the effects of unilateral stimulation with the contralateral side as control, 24 (28.9%) examined the effects of unilateral stimulation on CNS activities or plasticity (e.g. assessment by fMRI, fNIRs, TMS, MEP or EEG, etc.), and 15 (18.1%) examined clinical efficacy of unilateral interventions. Nine (10.8%) applied peripheral stimulation in combination with other types of interventions, and 35 (42.2%) applied unilateral stimulation but did not mention cross-education at all (Table 2).

Participants

The majority of the articles (58/83, 69.9%) reported effects of various interventions on healthy participants, 25 (30.1%) studies were on patients, including those with stroke (10, 12.0%), pain (3, 3.6%), injuries or surgeries (5, 6.0%), arthritis or muscle dystrophy (4, 4.8%), Parkinson’s disease (2, 2.4%) or critically ill (1, 1.2%) (Table 2).

Design of the studies

Thirty (30/83, 36.1%) studies claimed that they utilised a randomised, controlled design; and among them six studies investigated on patients [68, 74, 75, 93, 99, 121], whilst only one study claimed to be in the context of cross-education [99]. There were 12 (14.5%) studies utilised non-randomised or case-matched controls, with eight were on patients [56, 80, 83, 88, 94, 111, 112, 115]. There were 40 (48.2%) studies used a single group, self-controlled design, with nine investigated on patients [55, 58, 59, 63, 85, 98, 106, 117, 120]; while there was one (1.2%) single case study on a patient [82]. Sixteen (16, 19.3%) studies were conducted in clinical settings and 67 (80.7%) were in laboratory settings (Table 2).

The intervention protocols, including the muscles and nerves stimulated, outcome measures (muscle strength, neuromuscular function, muscle activation, muscle size, and CNS responses), and statistical analyses used in the studies are presented in Table 3.

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Table 3. Intervention protocols and outcome measures.

https://doi.org/10.1371/journal.pone.0263662.t003

Muscles and/or nerves stimulated

Many of the 83 studies involved stimulation of more than one muscle, or stimulation on nerves. For those stimulating one or more muscles, each muscle was recorded to one count. For the studies that applied needling to multiply points on a limb, each arm or leg was recorded as one count. There was a total of 104 counts of muscles or limbs. The knee extensors were most frequently investigated with 30 counts (30/104 = 28.8%), followed by 13 (12.5%) studies on ankle dorsiflexors, 10 (9.6%) on ankle plantar flexors, nine (8.7%) on each of the wrist flexors, wrist extensors and hand muscles, five (4.8%) on each of the arm and leg, four (4.2%) on the elbow flexors, two (1.9%) on each of the elbow extensors, deltoid, and knee flexors, three (2.9%) on paraspinal or neck muscles, and one (1.0%) on hip flexors. There were 11 (11/83 = 13.3%) studies that applied stimulation to nerves, including four on the peroneal nerve, three on the ulnar nerve, one each on the median nerve, radial nerve, tibia nerve, and accessory spinal nerve. Five of the 12 needling studies included one or more groups that applied electrical stimulation via the needles.

There were 21 studies (21/83, 25.3%) applied stimulation on the affected or weaker side in patients, 14 studies (16.9%) stated that the stimulation was on the dominant side, two (2.4%) on the non-dominant side, 28 (33.7%) on the right side (28, 33.7%), six (7.2%) on the left side, three (3.6%) on the right and left side alternately, and four (4.8%) did not state the side of stimulation (Table 3).

Duration of the intervention

There were 40 articles (48.2%) that reported the effects of chronic peripheral stimulation (training), with 31, six and three applying ES, VB or ND, respectively; and 43 (51.8%) that investigated the acute effects, with 22, 12 and nine applying ES, VB or ND, respectively. Among the 40 studies that used chronic stimulation, the typical protocols involved 2–5 sessions per week (except for one ES study [80] that applied 10 sessions per week, and three ES studies [51, 92, 98] and one VB study [111] that trained for seven sessions per week), for 1–12 weeks with a total of 9–36 training sessions (with exception of one ES study [55] that lasted 56 weeks and involved 280 sessions) (Table 3).

Types of muscle activity

Among the 83 studies, 51 (61.4%) induced or performed isometric contraction or participants held a static position during the intervention (28 under ES, 13 under VB, and 10 under ND); 21 (25.3%) induced or performed dynamic contraction (isotonic, concentric, eccentric, or joint movement; 16 under ES, five under VB), with one of them utilising both static and dynamic contractions [85]; and 12 (14.5%) did not specify the type of contraction or was deemed irrelevant (10 under ES and two under ND). There were 10 (12.0%) studies that employed peripheral stimulation combined with other types of interventions (e.g. voluntary muscle contraction) (Table 3).

Stimulation properties

Most of the studies adequately described the stimulation parameters, while some did not describe the methods in detail. For example, among the 53 ES studies, 15 did not report the wave shape of the stimulation pulse, and one did not report stimulation frequency. Typically, ES studies employed stimulation frequencies between 20 and 300 Hz (with exception of two studies that used 2000 Hz and 2500 Hz respectively, and two studies used under 10 Hz), pulse width 50–500 μS (with exception of nine studies that reported 1.0–2.5 ms), biphasic symmetrical rectangular waves (13), rectangular/square waves (8), biphasic waves (8), monophasic wave (4), sine/alternate waves (3) or mixed wave types (1). For the 18 vibration studies, vibration frequency of 8–300 Hz and amplitude of 0.5–6.0 mm were used. For the 12 needling studies, nine reported regular hand manipulation of the needles during a session, and seven reported the depth of needle insertion.

Assessments of intervention outcomes

Just under one-half of the studies (39, 47.0%) assessed muscle strength changes in response to the interventions for both the stimulated and unstimulated sides. In contrast, five studies (6.0%) only reported muscle strength changes for the contralateral (not directly stimulated) side of the body. There were 34 (41.0%) studies that did not use muscle strength as the major outcome measure but assessed other neuromuscular functions, such as CNS responses (31 used EEG, fMRI, TMS, fNIRs, or reflexes, etc.) or other functional responses. Thirty-five studies measured EMG changes, with most combined with other measurements such as strength, while five studies measured EMG only as the major outcome indicator [105, 108, 115]. Five studies assessed muscle activation using the twitch interpolation technique [23, 25, 71, 74, 91]. One study measured muscle girth change [52], seven studies utilised medical imaging methods, such as MRI, CT or ultrasound [12, 21, 51, 87, 98] or muscle fibre typing [56, 75] to determine muscle morphological changes (Table 3).

Statistical analysis

The majority of the studies (82, 98.8%) employed statistical analyses that were P value based, and 12 studies (14.5%) reported the effect size (but did not necessarily employ a magnitude-based assessment). Among the 82 studies, 13 (15.8%) reported statistical justification for the sample size in their studies; and among the 45 studies that employed ANOVA or GLM analysis, 30 (30/45, 66.7%) reported assessment of sample normality against the assumptions of the method. Most of the studies that reported sample distribution (28/30) or justification of sample size (12/13) were publish after year 2010.

Major findings from the studies on cross-education

Among the 83 studies, 31 (37.3%) claimed that their aim was to examine the cross-education effects, with 10 studies examining acute effects of unilateral stimulation and 21 studies investigating the chronic effects of repeated unilateral stimulation. The aims, major findings, strength of the research design, and limitations as stated by the authors are summarised in Table 4 [12, 19–21, 23–25, 41, 52, 54, 57, 62, 64, 69–71, 77, 80, 91, 96, 97, 99, 100, 103, 105, 107–110, 113, 114].

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Table 4. The major characteristics of the studies on cross-education.

https://doi.org/10.1371/journal.pone.0263662.t004

Discussion

There were five major findings from this scoping review.

Research that addresses the effect of unilateral peripheral stimulation should consider the potential cross-education

Although there appears to be a broad research interest in investigating the effects of unilateral peripheral stimulation, there were only 31 out of the 83 studies reviewed (37.3%) claiming that their studies were primarily within the context of cross-education (Table 4). Other studies investigated the effects of unilateral stimulation while using the contralateral side as a control (13, 15.7%), examined the impact of unilateral stimulation on cortex activities or plasticity (24, 28.9%), or examined the clinical efficacy of unilateral interventions (15, 18.1%) (Table 2). This indicates that many researchers may not be aware of the phenomenon of cross-education induced by peripheral stimulation, while investigating the effects of unilateral interventions. Therefore, the cross-education phenomenon should be introduced to the broader research community. Particularly, investigators who would use the contralateral side as a within-subject control for unilateral interventions should consider the potential cross-education effect in future studies.

It should also be noted that few studies aimed to investigate the cross-education effect induced by peripheral stimulation on motor skills. This might be due to the involuntary nature of the peripheral neuromuscular stimulation, or the search terms used in this review that did not specifically focus on motor skill aspects, that is a limitation of this scoping review. A pertinent question of interest is whether unilateral peripheral neuromuscular stimulation should be hypothesised as affecting the contralateral side’s skill performance. This also underscores the recommendation from the recent Delphi survey that the context of a study, e.g. transfer of strength or skill, should be clearly presented in future reports [3].

Chronic unilateral peripheral neuromuscular stimulation appears to cause robust cross-education effect on motor performance

A thorough analysis of the outcomes of the above-mentioned 31 studies on cross-education is beyond the scope of this review and may be addressed in a separate systematic review or meta-analysis. Briefly, 21 studies investigated chronic effects of unilateral peripheral stimulation (Table 4), of which all demonstrated a significant increase in motor performance of the contralateral limb. In contrast, among the 10 investigations on the acute effects, two studies reported no significant changes in strength or EMG in the unstimulated contralateral side [109, 114], whist another study [100] reported a reduction in MVC in both limbs but no change in EMG after a short period of vibration. Therefore, the chronic effects of unilateral peripheral stimulation on motor performance of the contralateral side appear to be robust, while the acute effects might be inconsistent (particularly in response to vibration) possibly due to the differences in research design and outcome measures (Table 4).

The majority of the 83 studies investigated healthy participants (58, 69.9%). In contrast, the studies on patients were limited, with 12 (14.5%) on CNS disorders such as post-stroke recovery, and 13 (15.7%) on patients post surgical operation or injuries, with one studying both patients and healthy individuals. Only 16 studies (15.7%) were conducted in clinical settings, and only two of these studies investigated the cross-education effect in patients. This finding is similar to that from a recent meta-analysis that identified only six studies on patient populations out of 96 studies reviewed (including unilateral voluntary or ES interventions) [6], indicating a lack of clinical studies on the application and efficacy of cross-education interventions. Therefore, studies on the translation of the cross-education effects found in healthy populations to clinical practice should be enhanced.

The physiological mechanisms underlying the cross-education induced by peripheral neuromuscular stimulation are unclear

It has been speculated that the sensory inputs would play a major role in manifesting the contralateral changes in response to peripheral neuromuscular stimulation [1, 36]. The cross-education caused by peripheral neuromuscular stimulation possibly cannot be explained by the hypothesised mechanisms for unilateral voluntary resistance training [15], and the exact pathway/s and mechanism/s remain to be elucidated.

There have been numerous studies that investigated the CNS responses or plasticity to unilateral peripheral stimulation, utilising a variety of methods and techniques, including EEG (2), EMG (35), fMRI (7), fNIR (2), MEG (1), reflexes (11), TMS-MEP (9), and central activation (twitch interpolation, 5). Bilateral cortical activation and/or changes in neural plasticity and muscle activation were reported in several studies but they only investigated acute effects, e.g. [65, 73, 76]. Few studies have attempted to identify what and how sensory inputs are involved in the manifestation of the contralateral effect [96], possibly due to the lack of a suitable methodology.

It is hypothesised that the mechanism of the cross-education, induced by the peripheral neuromuscular stimulation, is based on adaptations in the CNS [12, 21] because there is no significant change in muscle size of the unstimulated contralateral side. This review found nine studies that measured muscle morphological changes, such as limb girth (1), muscle cross sectional area or thickness (1 CT, 1 MRI, 4 ultrasound), or muscle fibre cross-sectional area and fibre type composition (2 histochemistry) (Table 3). However, among the studies that claimed to examine the cross-education effect, there was only one study that measured changes in muscle cross-sectional area using MRI in response to a training program with EMS superimposed on voluntary exercise [12], and one study assessed CNS activity together with muscle thickness measured by ultrasound in response to a vibration training program [21]. Therefore, there has been no sufficient evidence on whether the unilateral peripheral neuromuscular stimulation would affect muscle size in the unstimulated contralateral side comparing with the stimulated side, although it may be predictable that muscle hypertrophy would not occur in the unstimulated limb in response to a short period of intervention.

Unilateral intramuscular needling can affect muscle strength of the contralateral limb

The concept of contralateral treatment for ipsilateral health conditions using needling has historical roots. More recently, an increased number of investigations utilising randomised and controlled trial designs to examine its clinical efficacy and or mechanisms have emerged [30, 31]. However, much of the research in this area is not published in English. This scoping review has identified 12 studies on the effect of unilateral needling with three specifically addressing the cross-education effect on muscle function [24, 25, 41]. The Tianjin University of Sport and Southern Cross University research group has applied unilateral needling to the tibialis anterior muscle in three trials on healthy young men, with intervention durations from 4 to 8 weeks. These trials reported robust and similar bilateral strength gains, regardless of whether the needles were applied on known acupoints or sham points, or whether the needles were manually operated or electrical stimulation was delivered through them [24, 25, 41]. Other laboratories are encouraged to undertake similar investigations to confirm the phenomenon and conduct trials on clinical populations to evaluate the clinical efficacy of unilateral needling. There have been systematic reviews and meta-analyses on the effects of unilateral needling therapy for various patient groups, such as post stroke or injury [30, 31]. However, due to the language barrier, most of these studies are not indexed by the English-based databases. The physiological mechanisms for the effects of needling remain unclear [32, 33], particularly for the needling without electrical stimulation. It has been reported that unilateral manual needling on limb muscles resulted in modulatory effects in human brain as shown in functional MRI [122], and electroacupuncture caused bilateral changes in the insulin-like growth factor (IGF-1) mRNA and protein in rat brain of an ischemic stroke model [123]. However, it has also been reported in a study on rats that unilateral ES significantly increased the level of IGF-mRNA in the stimulated muscle but not in the unstimulated muscle of the contralateral side [124]. Obviously, further research is required to explore the neural or other mechanisms underlying the effects of needling interventions on motor performance. This area of investigation would benefit from cross institutional collaboration to replicate and translate (to clinical practice) past findings, examine clinical efficacy, and elucidate potential mechanisms of cross-education caused by needling.

Demographic characteristics of the research

Research design.

Although it is beyond the scope of a scoping review to evaluate the quality of the included studies [37], a few important aspects should be briefly discussed. Various designs were employed in the 83 studies, with 30 utilising a randomised, controlled design and 40 utilising a single group for pre vs post intervention comparison. The use of a single group for within-subject comparison may be very well justifiable according to the study’s objective. However, more randomised, controlled clinical trials on patients or specific populations would be required to confirm the clinical efficacy or implications of unilateral/contralateral intervention/therapy in the context of cross-education.

It was also noted that 82 out of 83 studies employed P-value-based statistics (one other study was a single case report), with 12 studies reported the effect size (although not necessarily for magnitude-based assessment). However, only 13 studies presented a statistical justification for the sample size, and 30 studies reported justifications for the use of the statistical analysis against the method’s assumptions (e.g. ANOVA). These statistical issues should be carefully considered when designing future studies to minimise ambiguous findings. It is noted that the majority of the studies that reported the justification of sample size and against the assumptions of the method was published from 2010 onwards (Table 3), reflecting the trend of increased rigor in research reports.

Location of the study.

Of the 83 studies reviewed, 50 (60.2% were published within the past 10 years, indicating an increased research interest in this area (Table 2). Studies were undertaken by researchers/research groups from all continents (except Antarctica), with 13 studies coming from the United States (15.7%), 11 from China (mainland, 13.3%), 6 (7.2%) from each of France and Spain, and 5 (6.0%) from each of Australia, Brazil, Canada and Turkey (Table 2). The remaining articles were from other 15 countries or regions, with each having one to four publications. Although these counts were based only on the first author’s first affiliation, it indicates a wide spread interest from researchers worldwide.

The participants.

The studies included in this review recruited participants from a wide age range (14–89 years), with approximately 70% of participants being males. A majority of the investigations recruited young adult participants (approximately 50 studies focused on participants under 35 years of age); while a relatively small number of studies investigated on specific populations, e.g. 24 studies involved participants over 60 years of age, and two recruited female participants only (Table 2). Thirteen (13) studies did not specify gender profile, and one study did not report participants’ age (Table 2). The reporting of demographic information should be considered to be essential in future studies for an accurate and clearer description of the participants or the population concerned. It is known that the neuromuscular function changes with ageing (e.g., muscle strength, fatiguability, mass and fibre type composition), as well as in response to various health conditions, diseases and interventions [125–128]. Whether there is an age- or gender-related difference in peripheral neuromuscular stimulation induced cross-education cannot be determined from the current literature due to the limited evidence available. Further studies in these aspects would advance our understanding on cross-education and may inform clinical implications as well.

The ipsi- and contra-lateral side investigated.

Previously there have been debates on whether a cross-education effect is influenced by limb dominancy or asymmetry in response to voluntary interventions [5, 129–131]. Such debates have not principally focused on the effects of unilateral peripheral stimulation. However, it is of note to find in this scoping review that more studies had stimulated the dominant side (14) compared to the non-dominant side (2), had investigated the affected or weaker side (21, mainly for patients) than the less affected side (2), or had utilised the right side (28, that may or may not be the dominant side) than the left side (6); there were three studies that stimulated the right and left side alternately, and four studies did not indicate how/why one side was chosen to be stimulated (Table 3). Whether the cross-education effects induced by peripheral neuromuscular stimulation are influenced by limb dominancy or asymmetry would be an interesting topic for future studies.

Furthermore, considering the potential clinical implications of the contralateral effect caused by unilateral intervention as repeatedly suggested in the literature, it would be necessary to evaluate the efficacy of unilateral interventions on the less affected limb in the treatment or rehabilitation of the more affected side. However, most (21/25) of the studies on patients included in this review applied the stimulation on the more affected limb, whilst only one study that applied chronic ES on the nonparetic limb in patients with subacute stroke [99] to investigate cross-education effect. Therefore, further studies are needed to determine the efficacy of unilateral interventions on the less affected side, with cross-education being used as the theoretical framework in specific and clinical populations.

The subject muscles.

In respect to muscle groups examined, 104 muscles or limbs were tested in the studies reviewed. Among them, 61 (58.7%) stimulated muscles were in leg with 30 on knee extensors, 16 on ankle dorsiflexors, and 10 on plantar flexors; 40 (38.5%) stimulated muscles in arm; and other studies stimulated the paraspinal, neck or hip muscles (4), or on one or more points on a limb (10, such as needling or vibration) (Table 3). Over one-half of the 83 studies (48, 57.8%) assessed the effect on the homologous muscles contralateral to the stimulated side. In contrast, most of the remaining studies (31, 37.3%) examined the CNS responses (Table 3), and a small number of studies also assessed the responses in clinical functional assessments [68, 93, 99], spasticity [59], sympathetic nervous system function [61] or cutaneous thermal regulation [97]. Among the 31 studies that claimed to investigate cross-education, 15 were on knee extensors, six on ankle dorsiflexors, six on forearm muscles, three on plantar flexors, and one on elbow flexors. The accessibility of the muscles might be a major factor for such a distribution. However, whether the homologous muscles in the arms and legs, and/or muscles with different functionality (e.g. muscles in hands vs those in legs, with different motor unit sizes or types) would respond to unilateral peripheral stimulation differently are unknown and require further investigation.

It is interesting to note that some studies have examined the effect of unilateral stimulation on the function of the autonomic nervous system, for example, thermal regulation [97], blood pressure and heart rate [61], or pain [74, 86]. However, these measurements do not fit in the definition of cross-education (on motor outputs or skill).

Summary and recommendations for future studies

An increased research interest in cross-education is seen over the past decades in the area of contralateral effects of unilateral peripheral neuromuscular stimulation, such as neuromuscular electrical stimulation, focal or whole-body vibration, and needling. However, only one-third of the studies were designed to examine cross-education specifically, and many studies utilised the contralateral (unstimulated) limb as a within-subject control. Considering the strong evidence for the cross-education phenomenon, a potential methodological flaw may exist when using a within-subject (contralateral) control design. Therefore, it is important that the broader neuromuscular physiology research community be made aware of the contralateral effect of unilateral stimulation.

Few studies on patients included in this review applied stimulation on the less affected side to investigate the clinical implications or applications of cross-education. Future research with randomised, controlled clinical trials on patients and/or specific populations is required to determine the clinical efficacy for applying unilateral peripheral stimulation as a means of intervention.

The majority of the studies employed electrical stimulation, while other types of stimulation (such as vibration and needling) are emerging and demonstrate detectable cross-education effects. In respect of the underlying mechanisms, it has been speculated that peripheral sensory inputs play a major role in the manifestation of the contralateral effect. However, the current literature has not clearly identified, or hypothesised, which sensory pathway/s is/are most relevant and effective to cause central plasticity and/or the contralateral effect on motor performance in response to acute and chronic peripheral neuromuscular stimulation.

Supporting information

S1 Checklist. PRISMA-ScR-checklist.

https://doi.org/10.1371/journal.pone.0263662.s001

(DOCX)

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