Transcutaneous neuromuscular electrical stimulation (NMES) can be applied as a complementary intervention to regular exercise training programs. A distinction can be made between high-frequency (HF) NMES and low-frequency (LF) NMES. In order to increase understanding of the mechanisms of functional improvements following NMES, the purpose of this study was to systematically review changes in enzyme activity, muscle fiber type composition and muscle fiber size in human lower-limb skeletal muscles following only NMES.
Trials were collected up to march 2012 and were identified by searching the Medline/PubMed, EMBASE, Cochrane Central Register of Controlled Trials, CINAHL and The Physical Therapy Evidence Database (PEDro) databases and reference lists. 18 trials were reviewed in detail: 8 trials studied changes in enzyme activities, 7 trials studied changes in muscle fiber type composition and 14 trials studied changes in muscle fiber size following NMES.
The methodological quality generally was poor, and the heterogeneity in study design, study population, NMES features and outcome parameters prohibited the use of meta-analysis. Most of the LF-NMES studies reported significant increases in oxidative enzyme activity, while the results concerning changes in muscle fiber composition and muscle size were conflicting. HF-NMES significantly increased muscle size in 50% of the studies.
NMES seems to be a training modality resulting in changes in oxidative enzyme activity, skeletal muscle fiber type and skeletal muscle fiber size. However, considering the small sample sizes, the variance in study populations, the non-randomized controlled study designs, the variance in primary outcomes, and the large heterogeneity in NMES protocols, it is difficult to draw definitive conclusions about the effects of stimulation frequencies on muscular changes.
Citation: Sillen MJH, Franssen FME, Gosker HR, Wouters EFM, Spruit MA (2013) Metabolic and Structural Changes in Lower-Limb Skeletal Muscle Following Neuromuscular Electrical Stimulation: A Systematic Review. PLoS ONE 8(9): e69391. https://doi.org/10.1371/journal.pone.0069391
Editor: Stephen E. Always, West Virginia University School of Medicine, United States of America
Received: May 4, 2012; Accepted: June 13, 2013; Published: September 3, 2013
Copyright: © 2013 Sillen 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.
Funding: This research was supported by grants from The Netherlands Asthma Foundation, Leusden, The Netherlands, Grant 3.4.09.024 and the Weijerhorst Foundation, Maastricht, The Netherlands. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Regular exercise training programs consist of a combination of aerobic and strengthening exercises for developing and maintaining muscular endurance and strength, respectively . Indeed, combined training modalities result in improvements in body composition and cardiorespiratory fitness. These improvements can partially be explained by intramuscular changes, such as an increased enzyme activity and an increased muscle fiber size , .
These intramuscular changes are dependent on the type of exercise training. Generally, aerobic exercise training results in increased levels of oxidative enzymes  and only a marginal increase in percentage type I fibers ; whereas resistance training results in increased levels of glycolytic enzymes  and an increase in percentage and size of type II fibers –.
Neuromuscular electrical stimulation (NMES) can be applied as an complement intervention to voluntary exercise training . NMES involves the application of an electric current through electrodes placed on the skin over the targeted muscles, thereby depolarizing motor endplates via the motor nerve and, in turn, inducing skeletal muscle contractions , . NMES is composed of stimulation-rest cycles situated in regard to muscle motor points . In contrast to voluntary muscle actions, NMES activates the muscle to a greater extent under identical technical conditions . At identical levels of workload (10% of the quadriceps maximum isometric voluntary torque), the muscle reaches higher values in blood flow and oxygen consumption during NMES compared with voluntary contractions . Moreover, a single session of NMES is sufficient to stimulate molecular-level responses, which are indicative of the initiation of myogenic processes in skeletal muscle, while an additional NMES session (a total of 14 minutes spread over 2 days), was sufficient to induce an increase in the concentration of total ribonucleic acid (RNA) , most likely representing an increase in muscle protein synthesis. There is sufficient evidence that NMES induced contractions differ physiologically compared to voluntary contractions . In human studies contradictory findings on motor unit recruitment order have been found . Some studies suggest preferential or selective activation of fast motor units with NMES , , whereas others suggest that motor unit recruitment during NMES reflects a non-selective, spatially fixed, and temporally synchronous pattern rather than in a reversal of the physiological voluntary recruitment order . These diverse results could have been related to differences in protocols and stimulated muscles .
In daily clinical practice, lower-limb NMES improves skeletal muscle mass and function, exercise capacity and health status –, particularly in subjects who are unable to perform or complete volitional exercise training programs. Therefore, NMES may be valuable in dyspneic and deconditioned patients with chronic organ failure due to the low metabolic load on the impaired cardio-respiratory system , .
NMES training sessions generally last 10–30 minutes during a 4- to 5-week period that involves 20–25 sessions to increase peripheral muscle function . 2 types of NMES frequencies can be distinguished: high-frequency NMES (HF-NMES, >50 Hertz); and low-frequency NMES (LF-NMES, <20 Hertz) , , –. Frequencies of 50 Hertz and above induce a fused tetanus ,  and generate higher torques than low frequencies . The mechanisms by which NMES results in increased muscle strength or endurance are poorly understood. In isolated muscles in rats HF-NMES induces anabolic processes similar to resistance training (e.g. increased PKB-TSC2-mTor and protein synthesis) and LF-NMES similar to endurance training (AMPK-PG C1α activation) . In humans, it is unknown which stimulation frequency is involved in the specific physiological and biochemical processes .
To date, narrative reviews have been published about the effects of NMES on gains in muscle performance, activation of motor units and/or muscle energetics , , , . However, there is a broad diversity in NMES programmes, populations and outcomes which makes it difficult to interpret the conclusions. The effects of NMES on intramuscular changes have not been systematically reviewed yet. The purpose of this study is to systematically review changes in enzyme activity, muscle fiber type composition and muscle fiber size in human lower-limbs following a NMES programme. A distinction will be made between HF-NMES and LF-NMES, as well as in healthy volunteers, patients with chronic organ failure or orthopedic problems. Our hypothesis is that LF-NMES (<20 Hz) will primarily induce endurance training-like adaptations such as increased oxidative enzyme capacity and fiber type I proportion, whereas HF-NMES (>50 Hz) will primarily induce adaptations comparable to resistance training such as an increased glycolytic capacity, fiber type II proportion and muscle fiber size. Safety and the methodological quality of the trials will also be assessed.
Data sources and searches
We followed the procedures described in the PRISMA statement for reporting systematic reviews (online supplement) . A broad computerized literature search was performed to identify relevant trials reported in the English language. We used the following databases: Medline/PubMed (from 1966), EMBASE (from 1974), Cochrane Central Register of Controlled Trials (from 1898), CINAHL (from 1982), and The Physical Therapy Evidence Database (PEDro) (from 1982). Trials were collected up to March 2012. Search terms were combinations of keywords related to neuromuscular electrical stimulation, lower-limb muscles, muscle mass and muscle metabolic profile. The exact search algorithm for Medline/PubMed can be found in Appendix 1. Similar search algorithms were used for the other databases. In addition, reference lists and citations of original articles were also scanned to identify additional articles that may contain information on the topic of interest.
A pre-designed data abstraction form was used to obtain data on trial design and relevant results. For each article, characteristics of the study subjects were noted: a) the condition of the study population (healthy or primary diagnosis), gender and age; b) study design and NMES features (i.e. pulse duration, pulse frequency, duty cycle and pulse amplitude of the used current, training intensity, session time and duration in weeks); c) outcome measures, such as muscle enzyme activity (i.e. changes in oxidative and glycolytic enzymes), changes in muscle fiber type, changes in muscle fiber size and d) safety.
Articles were used for further analyses when they met the following eligibility criteria:
Types of studies.
Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and clinical trials were included. A priori, congress abstracts, reviews, editorials and case reports were considered ineligible.
Included were trials in which human lower-limb muscles were electrically stimulated. Reasons for exclusion were studies with subjects suffering from neurological disorders (e.g., hemiplegia or lesion of the spine) or smooth muscle problems (e.g., period of bladder dysfunction)
Types of interventions.
Included were trials in which the muscles were stimulated transcutaneously at the muscle motor points with a stimulation frequency of <20 Hertz (LF-NMES) or >50 Hertz (HF-NMES), a minimum total session time of 120 minutes, a minimum of 3 sessions per week in a minimum of 4 weeks , , . Trials were not excluded based on pulse duration, pulse amplitude or training intensity.
Assessment of methodological quality
The methodological quality of the identified trials was scored using the PEDro scale and is based on the Delphi list and “expert consensus” . The PEDro scale consists of 11 criteria which receives either a “yes” or a “no”. Criterion 1 (‘Eligibility criteria’) is not used in the calculation of the PEDro score. All “yes” scores were summed resulting in a maximum score of 10 points . A κ coefficient was used to measure the level of interrater reliability, using a method for comparing the level of reliability with categorical data along with their respective 95% confidence intervals . Consensus was sought in case of disagreement. Trials with a PEDro score of ≥6 points were classified as “high-quality trials”, while trials with a PEDro score ≤5 points were classified as “low-quality trials” .
The use of meta-analytic techniques for data-pooling was not possible, because of the heterogeneity in study types, study populations, wide diversity in NMES protocols (e.g., frequency, pulse duration, session time, total number of sessions) and/or outcome parameters (e.g., activity of different enzymes). Also, the technique for measuring muscle fiber size differed among the included studies. Therefore, the present authors were only able to systematically review the available peer-reviewed literature and to critically appraise the methodological quality and the overall findings.
Search and selection
After removing duplicates, 1230 potentially relevant studies were identified by screening electronic databases. No trials were additionally identified by scanning reference lists. Of these trials, 1171 were excluded based on title and/or abstract. Of the remaining 59 trials, 41 trials were excluded after reading the full text based on type of intervention, outcome parameters and/or publication type. Finally, 18 – trials were included. 8 trials , , –, – studied changes in enzyme activity, 7 trials , , –, ,  studied changes in muscle fiber type composition, and 14 trials , –, –, ,  studied changes in muscle fiber size following NMES (figure 1).
A non-controlled experimental design was used in 6 studies, a controlled clinical trial was used in 3 studies and a randomized controlled design was used in 9 studies.
Methodological quality of the trials (table 1)
The interrater reliability for the reviewers (MJHS and FMEF) was 0.74 (95% confidence interval, 0.68 to 0.80; p<0.001).
PEDro scores ranged from 2 to 9 points in the trials concerning changes in enzyme activity (median: 5.5 points). 4 trials (50%) –,  scored >6 points on the PEDro scale. Of the trials studying muscle fiber type composition, PEDro scores ranged from 2 to 9 points (median: 6 points). 5 trials (71%) , –,  scored >6 points on the PEDro scale. In the trials concerning changes in muscle fiber size, PEDro scores ranged from 2 to 9 points (median: 4 points). 5 trials (36%) , , , ,  scored >6 points on the PEDro scale.
Overall, eligibility criteria , , , , , failure to conceal allocation, and blinding of the participants, therapists and outcome assessors were the most prevalent methodological shortcomings (table 1).
NMES Protocols (table 2)
There was a substantial heterogeneity in the studied populations and NMES features (table 2). For example, 6 studies enrolled patients with chronic organ failure, divided in 2 studies ,  including patients with chronic obstructive pulmonary disease (COPD) and 4 studies , , ,  including patients with chronic heart failure (CHF). In 3 studies , ,  the subjects had orthopedic problems of the lower limbs and in 9 studies –, , , , ,  healthy volunteers were enrolled.
Different lower-limb muscles were stimulated in the identified trials: quadriceps femoris muscles –, , –, , calf muscles , quadriceps femoris muscles combined with calf muscles , , , or quadriceps femoris muscles combined with hamstrings , , .
All trials used biphasic impulse current forms ranging from 8 to 20 and 50 to 120 Hertz. Pulse duration, not reported in 1 study , ranged between 200 and 700 µs. Duty cycle, not reported in 1 study , ranged between 3 seconds on, 30 seconds off to 55 seconds on, 2 seconds off. Pulse amplitude, not reported in 1 study , varied between 10 mA until the individual's maximum level of toleration. Session time varied between 10 minutes and 8 hours, 1 to 2 times a day. The total number of sessions varied between 12 and 140 (table 2) between 4 and 10 weeks. The total session time ranged from 2 to 384 hours.
Safety was not reported in 13 trials. In 3 trials , ,  no relevant side effects or adverse events were reported. Only once  a delayed onset muscle soreness was reported and one trial explicitly reported the absence of serious discomfort in the stimulated subjects . Finally, in 1 trial  1 study subject withdrew because of discomfort during NMES.
Changes in enzyme activity following NMES
5 trials studied changes in enzyme activity following LF-NMES , , , ,  and 3 trials following HF-NMES , ,  (tables 3 and 4). The study subjects consisted of healthy volunteers , , , , , , patients with severe CHF  or severe COPD . Enzyme activity was determined using muscle biopsies in the vastus lateralis of the quadriceps muscle in all studies.
Changes in oxidative enzymes in healthy volunteers
Citrate synthase (CS), a marker enzyme for the tricarboxylic acid cycle (Krebs cycle), was an outcome parameter in 4 LF-NMES trials , , , . In 3 trials , ,  CS increased compared to baseline (9 to 31%) and in 1 trial  CS increased compared to sham-stimulation.
Isocitrate dehydrogenase, another enzyme that participates in the tricarboxylic acid cycle, increased significantly following HF-NMES compared to baseline .
3-Hydroxylacyl-CoA dehydrogenase (HADH).
HADH, a key enzyme of ß-oxidation of fatty acids, increased significantly following LF-NMES compared to baseline in 2 trials in healthy volunteers (7–30%) , . Contradictionary, in a HF-NMES trial  HADH decreased.
Enoyl CoA hydratase.
Enoyl CoA hydratase, an enzyme that participates in the ß-oxidation of fatty acids, increased significantly following HF-NMES compared to baseline .
NADH-ubiquinone oxidoreductase, complex I of the electron transport chain, increased significantly following HF-NMES compared to baseline .
Succinate dehydrogenase, an enzyme that participates in both the tricarboxylic acid cycle and in complex II of the electron transport chain, increased significantly following HF-NMES compared to baseline and increased 16% compared to controls .
Ubiquinol-cytochrome c reductase.
Ubiquinol cyt C reductase, complex III of the electron transport chain, increased significantly following HF-NMES compared to baseline .
Cytochrome c oxidase.
Pyruvate dehydrogenase, an enzyme which contributes to linking the glycolysis metabolic pathway to the citric acid cycle and releasing energy via NADH, increased significantly following HF-NMES compared to baseline .
Changes in oxidative enzymes in patients with CHF or COPD
Levels of CS increased following LF-NMES (15 Hertz) compared to sham-stimulation in patients with severe CHF  and did not change following HF-NMES (50 Hertz) in patients with severe COPD .Levels of HADH did not change following HF-NMES (50 Hertz) in patients with severe COPD .
Changes in glycolytic enzymes in healthy volunteers
Levels of PFK, a glycolytic enzyme that catalyses the phosphorylation of fructose phosphate, decreased or did not change compared to baseline following LF-NMES or HF-NMES (variation from baseline was between −11 and 0%) , , .
Glyceraldehyde 3-phosphate dehydrogenase (GAPDH).
Concentrations of GAPDH, a marker enzyme of anaerobic energy metabolism by catalysing the sixth step of glycolysis, decreased significantly in 1 LF-NMES trial  compared with sham-stimulation (variation from baseline was -15%). Levels of GAPDH did not change in 2 LF-NMES trials ,  compared to baseline.
Hexokinase, a key glycolytic enzyme, increased significantly in females (36%) and did not change in males following LF-NMES compared to baseline .
Β-enolase, which catalyses the glycolysis of 2-phosphoglycerate to phosphoenolpyruvate, did not change in a sedentary group of healthy young men following HF-NMES compared to baseline, but increased in an active group of healthy young men following HF-NMES compared to baseline .
Changes in glycolytic enzymes in patients with CHF
In patients with severe CHF levels of GAPDH decreased significantly in 1 LF-NMES trial  compared with sham-stimulation (variation from baseline was −15%).
Skeletal muscle fiber type composition following NMES
3 trials , ,  studied skeletal muscle fiber type composition following LF-NMES and 4 trials , , ,  following HF-NMES (table 5). The study subjects consisted of healthy volunteers , , , , patients with severe CHF  and patients with severe COPD , .
Type I fibers.
Proportion of type I fibers increased in 1 LF-NMES trial (15%)  and 1 HF-NMES trial (active group 20% and sedentary group 96%) , and did not change in 1 LF-NMES trial . This fiber type decreased in 1 trial following HF-NMES (−15%) .
Type II fibers.
Type IIa fibers proportions increased following LF-NMES (19%)  and HF-NMES (63%) . In another HF-NMES trial this fiber type increased in the sedentary group (42%) and decreased in the active group (9%) .
Patients with CHF or COPD
Type IIa proportions did not change in patients with CHF following LF-NMES  and these fiber type proportions remained unchanged compared to controls in patients with COPD following HF-NMES . Type IIx fibers decreased following LF-NMES (19%)  and did not change following HF-NMES compared to a control group .
Changes in muscle size following NMES
Different techniques were used to determine changes in whole muscle cross-sectional area (CSA) or muscle fiber CSA following NMES (tables 6, 7 and 8). Muscle fiber CSA was measured by percutaneous needle biopsy of the vastus lateralis muscle , , , , . Whole muscle CSA was measured by computed tomography , , , magnetic resonance imaging (MRI) , , , , ultrasonography  or circumference and skinfold measurements . Maillefert and colleagues determined the total volume of the soleus muscles and gastrocnemius muscles by calculated muscle volume from serial CSAs measured by MRI .3 trials used LF-NMES , ,  and 11 trials used HF-NMES , –, , –, , .
Muscle fiber CSA did not change following 1 LF-NMES trial  and 1 HF-NMES trial . Following another HF-NMES trial muscle fiber CSA increased, in both type I and type II fibers  (table 6). Whole muscle CSA was studied in 3 HF-NMES trials , ,  and did not change in 1 trial  and increased in 2 trials , .
Patients with CHF or COPD.
Following HF-NMES muscle fiber CSA did not change in one trial  and increased compared to sham stimulation in another trial  (table 7). Whole muscle CSA increased following LF-NMES ,  and HF-NMES  (table 7).
This is the first systematic review on the effects of lower-limb NMES on intramuscular changes in the human lower-limb muscles. Most of the studies reported a significant increase in oxidative enzymes following LF-NMES. There are obvious changes in skeletal muscle fiber type composition following NMES. Indeed, LF-NMES seems to increase percentage of type I and IIa fibers, whereas fiber type composition following HF-NMES shows conflicting results. Both NMES protocols showed conflicting results in changes in muscle fiber size and total muscle volume. Heterogeneity in study design, study population, NMES features and outcome parameters prohibits the use of meta-analysis.
Overall, the methodological quality of the included trials was poor (median score 4 points). None of the 18 included trials had a perfect score on the PEDro scale (table 2). In fact, only 7 trials (39%) were of high-quality. Eligibility criteria were not specified in 4 trials (22%) and a control group was lacking in 6 trials (33%). Other methodological considerations were the limited number of study subjects (n = 8 to n = 40), the low mean age (38 years) and the fact that most subjects studied were men. Elderly subjects may respond differently on anabolic training stimulus compared to younger subjects . Moreover, gender-differences exist in fiber type distribution and mean CSA . So, the internal and external validity of the findings of the reviewed trials were limited.
NMES protocols varied tremendously among the included trials. Pulse duration, if reported, ranged between 200 and 700 µs. Pulse duration of 300–400 µs is recommended for large muscle groups, such as the quadriceps muscles and calf muscles . It remains currently unknown which duty cycle is optimal for effective treatment.
While throughout the literature a wide variety of protocols are used, there seems to be at least some agreement on the use of biphasic symmetrical pulses that last between 100 and 500 µs and are delivered at a pulse rate of 10–100 Hertz. Pulse rates between 10–50 Hz are used in patients with CHF and in patients with COPD with positive improvements in exercise capacity and health status , whereas pulse rates between 50–100 Hz are mostly recommended for gains in muscle performance , . Such pulses are widely accepted as being well tolerated.
The stimulus intensity varied among the included trials, from a comfortable stimulus till maximum tolerance level. These diverse results could have been related to differences in protocols and stimulated muscles. It is strongly recommended that pulses are delivered at the highest tolerable pulse amplitude . Another common procedure is to quantify isometric maximal voluntary contraction (MVC) force at the beginning of a NMES session, and subsequently express the level of each electrically elicited contraction as a percentage of the MVC force .
The duration of the NMES programmes varied between 10 minutes to 8 hours/day, 1 to 2 sessions/day, 3 to 7 days/week for 4 to10 weeks. The minimum total duration of the NMES in the included studies are in line with the studies which show significant improvements in peripheral muscle function ,.
Changes in enzyme activity following NMES
Activity of oxidative enzymes generally increased significantly following 6 weeks of LF-NMES. The increase in oxidative enzyme activity was accompanied with an improved resistance to fatigue ,  and an improvement in functional exercise capacity . Compared with a minimum of 6 weeks of endurance cycling training , , the absolute and relative improvement in CS activity after NMES is lower.
Levels of glycolytic enzymes did not change or decreased following LF-NMES. These results are comparable with endurance training in healthy young men  and in patients with COPD . In healthy volunteers levels of oxidative enzymes increased following HF-NMES , . These adaptations are more endurance-specific. Collins and colleagues recently showed that the use of a wide pulse (1 ms), high frequency (80–100 Hertz) and a low intensity might favour the recruitment of fatigue-resistant motor units (according to the Henneman's size principle) . This combination of stimulation parameters could also be relevant for increasing oxidative capacity. However, they used a wide pulse and low stimulation intensity whereas the included trials in the present review ,  used narrow pulses and intensities at the maximum toleration level. As the consequence, the corresponding increase of oxidative enzymes is likely due to the non-selective recruitment of both type IIx and type I fibers during HF-NMES . Another study limitation is that only one study (in healthy volunteers) with a very small sample size  studied glycolytic enzymes following HF-NMES. In the sedentary group the downregulation of glycolytic enzymes is highly consistent with the fast-to-slow MHC isoform shift as slow fibers mostly have an oxidative metabolism and type IIx fibers mostly have a glycolytic metabolism. Additionally, glycolytic enzyme content is known to increase in the order of slow oxidative, fast oxidative, glycolytic, fast glycolytic fibers . However, the small sample size is too limited (n = 10) to provide an answer on the hypothesis that HF-NMES increases glycolytic capacity.
Changes in skeletal muscle fiber type composition following NMES
Changes in type I and IIa fiber proportion were variable following HF-NMES. Resistance training resulted in no changes in type I fibers and an increase of type II fibers , . However, based on the results of the present systematic review changes in type IIa and type IIx fibers following regular resistance training programs  cannot be compared with HF-NMES. Following LF-NMES type I and IIa fibers increased. Endurance training programs also resulted in an increase of type I and type IIa fibers and a decrease of type IIx fibers , , . However, considering the small number of studies and heterogeneity in NMES protocols and study populations it is difficult to draw relations between LF-NMES and endurance training.
Changes in muscle size following NMES
In 50% of the HF-NMES studies muscle fiber size increased significantly. The increased CSA was accompanied with an increased muscle strength –, . Changes in total muscle fiber size following LF-NMES are conflicting. Differences in the LF-NMES studies which could possible explain the conflicting results are the study population (age, healthy volunteers versus patients with chronic organ failure), measurement of muscle fiber size or intensity of NMES.
These results are in line with previous studies concluding that muscle fiber size increased less in subjects who performed endurance training than in strength training , . Conflicting results for the changes in muscle fiber size in HF-NMES could be related to the intensity of the training. In two trials ,  reporting no changes in muscle fiber size, the stimulus intensity varied from “a comfortable stimulus”  to 25 mA  compared with a stimulus at the maximum tolerable level in the trials with an increased muscle fiber size –, . Moreover, Vivodtzev and colleagues showed that gains in muscle strength were proportional to the increase in pulse amplitude during the training program and to the final pulse amplitude of training . The impact of NMES is also dependent on the training duration. It is well known that long training duration is needed to induce muscle hypertrophy , however the total duration time in the HF-NMES trials ranged from 2  to 54 hours .
Overall, LF-NMES seems to improve oxidative phenotype (oxidative enzyme capacities, type I/IIa fibers). However, some of the results of the included trials are difficult to compare and cannot be generalized. Besides the heterogeneity in NMES protocols and study designs, the number of study populations is limited and varies among the trials, from well-trained healthy volunteers  to patients with severe chronic organ failure ,  or severe orthopedic problems , . Stimulation variables (i.e. pulse amplitude, session time and number of sessions) might have influenced the number of muscle fibers recruited during NMES, the motor unit recruitment order and the types of the recruited muscle fibers , .
Therefore, future trials are needed to determine the optimal settings of NMES, such as stimulation frequency (HF-NMES or LF-NMES), session time, pulse amplitude and electrodes (number, size and location) in healthy (i.e. athletes) and in diseased people (i.e. COPD, CHF, orthopedic problems). These trials should not only study the effects of NMES versus volitional training, but also study the superimposed effects of NMES on volitional training.
Based on the results of the present systematic review, randomized controlled trials using concealed allocation, blinded therapists, blinded participants and blinded outcome assessors are recommended. Additionally, studies should focus on larger study populations, including both genders and a broad range in age. These studies should not include only healthy people but also people who are unable to perform or complete volitional exercise training programs. Finally, safety should be added to new randomized controlled trials as secondary outcome.
NMES seems to be a training modality resulting in changes in oxidative enzyme activity, skeletal muscle fiber type and skeletal muscle fiber size. A more formal meta-analysis would be a more rigorous way to analyze the current data, but is not possible at this time. Indeed, the small sample sizes, the variance in study populations, the non-randomized controlled study designs, the variance in primary outcomes and the large heterogeneity in NMES protocols are major methodological limitations which may limit the external validity of the current findings. Therefore, it is difficult to draw definitive conclusions about the effects of stimulation frequencies on muscular changes. This systematic review, however, will help generate discussion in the field that would lead to a consensus in study design that would permit a meta-analysis in the future.
A better understanding of metabolic and structural changes following NMES is of particular clinical interest as it will increase its applicability in specific populations who are not able to perform regular exercise training. Therefore, future well-designed, randomized controlled trials with larger study samples are needed to determine the optimal NMES settings (i.e. electrode placement, stimulation frequency and pulse amplitude) to achieve endurance or resistance training-like adaptations. The actual stimulation parameters, session time, total time and changes in NMES pulse intensity over time should be reported to enable comparisons between studies and to facilitate the further development and implementation of NMES.
Searchstring Medline/PubMed 02-03-2012.
Conceived and designed the experiments: MJHS EFMW MAS. Performed the experiments: MJHS FMEF. Analyzed the data: MJHS FMEF HRG MAS. Contributed reagents/materials/analysis tools: MJHS FMEF HRG. Wrote the paper: MJHS. Revised the manuscript: MJHS FMEF HRG EFMW MAS.
- 1. American College of Sports Medicine, Position Stand (1998) The recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness, and flexibility in healthy adults. Med Sci Sports Exerc 30: 975–991.
- 2. Bell GJ, Syrotuik D, Martin TP, Burnham R, Quinney HA (2000) Effect of concurrent strength and endurance training on skeletal muscle properties and hormone concentrations in humans. Eur J Appl Physiol 81: 418–427.
- 3. Hakkinen K, Alen M, Kraemer WJ, Gorostiaga E, Izquierdo M, et al. (2003) Neuromuscular adaptations during concurrent strength and endurance training versus strength training. Eur J Appl Physiol 89: 42–52.
- 4. Carter SL, Rennie CD, Hamilton SJ (2001) Tarnopolsky (2001) Changes in skeletal muscle in males and females following endurance training. Can J Physiol Pharmacol 79: 386–392.
- 5. Trappe SW, Costill DL, Fink WJ, Pearson DR (1995) Skeletal muscle characteristics among distance runners: a 20-yr follow-up study. J Appl Physiol 78: 823–829.
- 6. Tesch PA, Thorsson A, Essen-Gustavsson B (1989) Enzyme activities of FT and ST muscle fibers in heavy-resistance trained athletes. J Appl Physiol 67: 83–87.
- 7. Kryger AI, Andersen JL (2007) Resistance training in the oldest old: consequences for muscle strength, fiber types, fiber size, and MHC isoforms. Scand J Med Sci Sports 17: 422–430.
- 8. Andersen JL, Aagaard P (2000) Myosin heavy chain IIX overshoot in human skeletal muscle. Muscle Nerve 23: 1095–1104.
- 9. Farup J, Kjolhede T, Sorensen H, Dalgas U, Moller AB, et al. (2012) Muscle morphological and strength adaptations to endurance vs. resistance training. J Strength Cond Res 26: 398–407.
- 10. Verdijk LB, Gleeson BG, Jonkers RA, Meijer K, Savelberg HH, et al. (2009) Skeletal muscle hypertrophy following resistance training is accompanied by a fiber type-specific increase in satellite cell content in elderly men. J Gerontol A Biol Sci Med Sci 64: 332–339.
- 11. Hainaut K, Duchateau J (1992) Neuromuscular electrical stimulation and voluntary exercise. Sports Med 14: 100–113.
- 12. Vanderthommen M, Crielaard JM (2001) [Muscle electric stimulation in sports medicine]. Rev Med Liege 56: 391–395.
- 13. Vivodtzev I, Lacasse Y, Maltais F (2008) Neuromuscular electrical stimulation of the lower limbs in patients with chronic obstructive pulmonary disease. J Cardiopulm Rehabil Prev 28: 79–91.
- 14. Vanderthommen M, Duchateau J (2007) Electrical stimulation as a modality to improve performance of the neuromuscular system. Exerc Sport Sci Rev 35: 180–185.
- 15. Vanderthommen M, Duteil S, Wary C, Raynaud JS, Leroy-Willig A, et al. (2003) A comparison of voluntary and electrically induced contractions by interleaved 1H- and 31P-NMRS in humans. J Appl Physiol 94: 1012–1024.
- 16. Bickel CS, Slade J, Mahoney E, Haddad F, Dudley GA, et al. (2005) Time course of molecular responses of human skeletal muscle to acute bouts of resistance exercise. J Appl Physiol 98: 482–488.
- 17. Bickel CS, Gregory CM, Dean JC (2011) Motor unit recruitment during neuromuscular electrical stimulation: a critical appraisal. Eur J Appl Physiol 111: 2399–2407.
- 18. Maffiuletti NA (2010) Physiological and methodological considerations for the use of neuromuscular electrical stimulation. Eur J Appl Physiol 110: 223–234.
- 19. Cabric M, Appell HJ, Resic A (1988) Fine structural changes in electrostimulated human skeletal muscle. Evidence for predominant effects on fast muscle fibres. Eur J Appl Physiol Occup Physiol 57: 1–5.
- 20. Trimble MH, Enoka RM (1991) Mechanisms underlying the training effects associated with neuromuscular electrical stimulation. Phys Ther 71: 273–280; discussion 280–272.
- 21. Gerovasili V, Stefanidis K, Vitzilaios K, Karatzanos E, Politis P, et al. (2009) Electrical muscle stimulation preserves the muscle mass of critically ill patients: a randomized study. Crit Care 13: R161.
- 22. Lake DA (1992) Neuromuscular electrical stimulation. An overview and its application in the treatment of sports injuries. Sports Med 13: 320–336.
- 23. Sillen MJ, Speksnijder CM, Eterman RM, Janssen, Wagers SS, et al. (2009) Effects of neuromuscular electrical stimulation of muscles of ambulation in patients with chronic heart failure or COPD: a systematic review of the English-language literature. Chest 136: 44–61.
- 24. Sillen MJ, Janssen., Akkermans MA, Wouters EF, Spruit MA (2008) The metabolic response during resistance training and neuromuscular electrical stimulation (NMES) in patients with COPD, a pilot study. Respir Med 102: 786–789.
- 25. Chan Kwan Kit-Lan P (1991/1992) Contemporary trends in electrical stimulation: “The frequency-specificity theory”. Hong-Kong Physiother J 13: 23–27.
- 26. Maffiuletti NA (2010) Physiological and methodological considerations for the use of neuromuscular electrical stimulation. Eur J Appl Physiol.
- 27. Grimby L, Hannerz J (1977) Firing rate and recruitment order of toe extensor motor units in different modes of voluntary conraction. J Physiol 264: 865–879.
- 28. Taylor A, Stephens JA (1976) Study of human motor unit contractions by controlled intramuscular microstimulation. Brain Res 117: 331–335.
- 29. Edwards RH, Young A, Hosking GP, Jones DA (1977) Human skeletal muscle function: description of tests and normal values. Clin Sci Mol Med 52: 283–290.
- 30. Kramer JF (1987) Effect of electrical stimulation current frequencies on isometric knee extension torque. Phys Ther 67: 31–38.
- 31. Atherton PJ, Babraj J, Smith K, Singh J, Rennie MJ, et al. (2005) Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J 19: 786–788.
- 32. Gregory CM, Bickel CS (2005) Recruitment patterns in human skeletal muscle during electrical stimulation. Phys Ther 85: 358–364.
- 33. Gondin J, Cozzone PJ, Bendahan D (2011) Is high-frequency neuromuscular electrical stimulation a suitable tool for muscle performance improvement in both healthy humans and athletes? Eur J Appl Physiol 111: 2473–2487.
- 34. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, et al. (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339: b2700.
- 35. Sherrington C, Herbert RD, Maher CG, Moseley AM (2000) PEDro. A database of randomized trials and systematic reviews in physiotherapy. Man Ther 5: 223–226.
- 36. Brennan P, Silman A (1992) Statistical methods for assessing observer variability in clinical measures. BMJ 304: 1491–1494.
- 37. Foley NC, Bhogal SK, Teasell RW, Bureau Y, Speechley MR (2006) Estimates of quality and reliability with the physiotherapy evidence-based database scale to assess the methodology of randomized controlled trials of pharmacological and nonpharmacological interventions. Phys Ther 86: 817–824.
- 38. Dal Corso S, Napolis L, Malaguti C, Gimenes AC, Albuquerque A, et al. (2007) Skeletal muscle structure and function in response to electrical stimulation in moderately impaired COPD patients. Respir Med 101: 1236–1243.
- 39. Gauthier JM, Theriault R, Theriault G, Gelinas Y, Simoneau JA (1992) Electrical stimulation-induced changes in skeletal muscle enzymes of men and women. Med Sci Sports Exerc 24: 1252–1256.
- 40. Gondin J, Brocca L, Bellinzona E, D'Antona G, Maffiuletti NA, et al. (2011) Neuromuscular electrical stimulation training induces atypical adaptations of the human skeletal muscle phenotype: a functional and proteomic analysis. J Appl Physiol 110: 433–450.
- 41. Gondin J, Guette M, Ballay Y, Martin A (2005) Electromyostimulation training effects on neural drive and muscle architecture. Med Sci Sports Exerc 37: 1291–1299.
- 42. Herrero JA, Izquierdo M, Maffiuletti NA, Garcia-Lopez J (2006) Electromyostimulation and plyometric training effects on jumping and sprint time. Int J Sports Med 27: 533–539.
- 43. Jancik J, Siegelova J, Homolka P, Svacinova H, Placheta P, et al. (2002) Low-frequency electrical stimulation of skeletal muscles in patients with chronic heart failure.. Scripta Medica Facultatis Medicae Universitatis Brunensis Masarykianae 75: 203–208.
- 44. Maillefert JF, Eicher JC, Walker P, Dulieu V, Rouhier-Marcer I, et al. (1998) Effects of low-frequency electrical stimulation of quadriceps and calf muscles in patients with chronic heart failure. J Cardiopulm Rehabil 18: 277–282.
- 45. Martin L, Cometti G, Pousson M, Morlon B (1994) The influence of electrostimulation on mechanical and morphological characteristics of the triceps surae. J Sports Sci 12: 377–381.
- 46. Nuhr M, Crevenna R, Gohlsch B, Bittner C, Pleiner J, et al. (2003) Functional and biochemical properties of chronically stimulated human skeletal muscle. Eur J Appl Physiol 89: 202–208.
- 47. Nuhr MJ, Pette D, Berger R, Quittan M, Crevenna R, et al. (2004) Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Eur Heart J 25: 136–143.
- 48. Perez M, Lucia A, Rivero JL, Serrano AL, Calbet JA, et al. (2002) Effects of transcutaneous short-term electrical stimulation on M. vastus lateralis characteristics of healthy young men. Pflugers Arch 443: 866–874.
- 49. Quittan M, Wiesinger GF, Sturm B, Puig S, Mayr W, et al.. (2001) Improvement of thigh muscles by neuromuscular electrical stimulation in patients with refractory heart failure: a single-blind, randomized, controlled trial. Am J Phys Med Rehabil 80: 206–214; quiz 215–206, 224.
- 50. Rebai H, Barra V, Laborde A, Bonny JM, Poumarat G, et al. (2002) Effects of two electrical stimulation frequencies in thigh muscle after knee surgery. Int J Sports Med 23: 604–609.
- 51. Singer K (1986) The influence of unilataral electrical stimulation on motor unit activity patterns in atrophic human quadriceps. The Australian Journal of Physiotherapy 32: 31–37.
- 52. Theriault R, Boulay MR, Theriault G, Simoneau JA (1996) Electrical stimulation-induced changes in performance and fiber type proportion of human knee extensor muscles. Eur J Appl Physiol Occup Physiol 74: 311–317.
- 53. Theriault R, Theriault G, Simoneau JA (1994) Human skeletal muscle adaptation in response to chronic low-frequency electrical stimulation. J Appl Physiol 77: 1885–1889.
- 54. Vivodtzev I, Debigare R, Gagnon P, Mainguy V, Saey D, et al. (2012) Functional and muscular effects of neuromuscular electrical stimulation in patients with severe COPD: a randomized clinical trial. Chest 141: 716–725.
- 55. Walls RJ, McHugh G, O'Gorman DJ, Moyna NM, O'Byrne JM (2010) Effects of preoperative neuromuscular electrical stimulation on quadriceps strength and functional recovery in total knee arthroplasty. A pilot study. BMC Musculoskelet Disord 11: 119.
- 56. Canepari M, Rossi R, Pellegrino MA, Orrell RW, Cobbold M, et al. (2005) Effects of resistance training on myosin function studied by the in vitro motility assay in young and older men. J Appl Physiol 98: 2390–2395.
- 57. Simoneau JA, Bouchard C (1989) Human variation in skeletal muscle fiber-type proportion and enzyme activities. Am J Physiol 257: E567–572.
- 58. Bowman BR, Baker LL (1985) Effects of waveform parameters on comfort during transcutaneous neuromuscular electrical stimulation. Ann Biomed Eng 13: 59–74.
- 59. Smart NA, Dieberg G, Giallauria F (2012) Functional electrical stimulation for chronic heart failure: A meta-analysis. Int J Cardiol.
- 60. Fernstrom M, Tonkonogi M, Sahlin K (2004) Effects of acute and chronic endurance exercise on mitochondrial uncoupling in human skeletal muscle. J Physiol 554: 755–763.
- 61. Howarth KR, LeBlanc PJ, Heigenhauser GJ, Gibala MJ (2004) Effect of endurance training on muscle TCA cycle metabolism during exercise in humans. J Appl Physiol 97: 579–584.
- 62. Tremblay A, Simoneau JA, Bouchard C (1994) Impact of exercise intensity on body fatness and skeletal muscle metabolism. Metabolism 43: 814–818.
- 63. Maltais F, LeBlanc P, Simard C, Jobin J, Berube C, et al. (1996) Skeletal muscle adaptation to endurance training in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 154: 442–447.
- 64. Collins DF, Burke D, Gandevia SC (2002) Sustained contractions produced by plateau-like behaviour in human motoneurones. J Physiol 538: 289–301.
- 65. Takekura H, Yoshioka T (1987) Determination of metabolic profiles on single muscle fibres of different types. J Muscle Res Cell Motil 8: 342–348.
- 66. Hakkinen K, Newton RU, Gordon SE, McCormick M, Volek JS, et al. (1998) Changes in muscle morphology, electromyographic activity, and force production characteristics during progressive strength training in young and older men. J Gerontol A Biol Sci Med Sci 53: B415–423.
- 67. Holm L, Reitelseder S, Pedersen TG, Doessing S, Petersen SG, et al. (2008) Changes in muscle size and MHC composition in response to resistance exercise with heavy and light loading intensity. J Appl Physiol 105: 1454–1461.
- 68. Short KR, Vittone JL, Bigelow ML, Proctor DN, Coenen-Schimke JM, et al. (2005) Changes in myosin heavy chain mRNA and protein expression in human skeletal muscle with age and endurance exercise training. J Appl Physiol 99: 95–102.
- 69. Hakkinen K, Keskinen KL (1989) Muscle cross-sectional area and voluntary force production characteristics in elite strength- and endurance-trained athletes and sprinters. Eur J Appl Physiol Occup Physiol 59: 215–220.
- 70. Putman CT, Xu X, Gillies E, MacLean IM, Bell GJ (2004) Effects of strength, endurance and combined training on myosin heavy chain content and fibre-type distribution in humans. Eur J Appl Physiol 92: 376–384.
- 71. American College of Sports Medicine position stand (2009) Progression models in resistance training for healthy adults. Med Sci Sports Exerc 41: 687–708.
- 72. Bergquist AJ, Clair JM, Lagerquist O, Mang CS, Okuma Y, et al. (2011) Neuromuscular electrical stimulation: implications of the electrically evoked sensory volley. Eur J Appl Physiol 111: 2409–2426.