Studies have shown that the NMES parameters also affect the comfort and effectiveness of the stimulation (3, 7–9). Several parameters can be adjusted during NMES, such as frequency, pulse width, intensity, waveform, plateau time, on:off-time and ramp-up/ramp-down time (Figure 1).

While NMES aims to mimic voluntary muscle contraction, it differs from the contractions induced via the central nervous system in a number of ways. NMES activates muscle units simultaneously between the position of the electrodes, often targeting superficial muscles, and recruits them repetitively in a fixed spatial pattern, which leads to quicker fatigue compared to voluntary contractions (3, 7–9). In contrast, voluntary muscle contractions disperse the recruitment of motor units and vary their activation in numbers and across changing locations. NMES also primarily targets fast-twitch muscle fibers, which contribute to quicker fatigue but on the other hand is advantageous for rehabilitation, as these are the fibers predominantly weakened following injury or surgery (3).

In recent years, an increasing number of studies have indicated that improper electrical stimulation can have harmful effects (19). In addition to common muscle soreness lasting one to four days after treatment, over-treatment can result in muscle fiber damage, increased secretion of creatine kinase, and muscle breakdown (rhabdomyolysis). This can potentially lead to acute kidney failure, especially in individuals whose kidney function already is reduced (20). These injuries have been particularly noted with excessive muscle training in suits, i.e., whole-body electromyostimulation, containing many electrodes stimulating several muscle groups simultaneously (20). However, whole-body electromyostimulation has in recent reviews of controlled trials shown significant, moderate to large effect sizes on sarcopenia, muscle mass and strength parameters (21).

Other side effects or drawbacks of current NMES treatments are that many patients experience discomfort or pain during stimulation (3, 4), and difficulties in correctly setting up the NMES device without assistance, leading to low adherence (22, 23). Adherence to treatment is the most important factor in determining whether the treatment in clinical practice can achieve the effects shown in studies. This challenge has prompted researchers at Karolinska Institutet to focus on the development and optimization of NMES, including integrating the treatment into clothing, which has the potential to dramatically improve treatment adherence with NMES (Figure 2) (24).

Optimal NMES usage requires adapting the size, number, and placement of electrodes (Figure 2). Studies have shown that larger electrodes are more comfortable than smaller ones, but excessively large electrodes decrease the effectiveness of the treatment (15, 25). The optimal size also depends on the muscle being stimulated, with larger muscles generally requiring larger electrodes (15, 25). Placement of electrodes on so-called motor points has been shown to provide more comfortable and effective stimulation (3, 5). The electrophysiological definition of a motor point is the location on the skin which requires the lowest intensity of electrical stimulation to cause a muscle contraction (26). However, the time-consuming manual motor point search with a motor point pen requires training, and thus poses a problem in the daily use of NMES. Therefore, anatomical maps have been developed showing where on the body motor points are most likely to be found (5, 27, 28). However, there is significant individual variation in the location of motor points and thus normal users will experience problems in locating motor points, which will lead to a compliance problem with the therapy.

Several studies have demonstrated that combining NMES with voluntary muscle contractions yields superior training effects, both in younger and older individuals (3, 9, 29–31). For example, one study demonstrated that NMES combined with leg and gluteal strength training three times a week during for four weeks in older adults improved walking test times more than exercise alone (33). Another study in young, healthy and physically active individuals showed that a 6-week training program involving vertical jumps with added electrical stimulation increased jump height by 10% more than just jump training alone or no training at all (3). These findings suggest that NMES can stimulate parts of the muscle that regular exercise may not easily reach and/or provide a greater load the than typical training. Moreover, a recent study indicated that NMES and exercise can potentiate each other even when performed on opposite extremities (34). These observations suggest involvement of either systemic mediator mechanisms and/or effects mediated through the central nervous system.

Studies have shown that NMES alone can achieve a relatively high percentage of the maximum force generated during voluntary muscle activation, without any voluntary contraction (3, 9, 35, 36). To measure the force generated during knee extension exercises of the thigh muscles, a dynamometer (Biodex) is used, and the maximum force generated is referred to as the “maximum voluntary contraction” (MVC) (37). The degree of muscle activation during NMES can also be measured using this device (36), and the percentage of MVC achieved is reported as a percentage of MVC.

Research suggests that a stimulation level of at least 20% of MVC is required for muscle-strengthening effects (9). Muscle contractions induced by NMES generally produce lower force output than voluntary contractions, usually less than 50% of MVC at the highest tolerable intensity (38), which is attributed to the difference between how the muscles are activated (3, 8, 9). NMES may also activate more superficial muscle fibers, which could result in poorer training outcomes compared to regular exercise. This has led to further research aimed at improving NMES techniques (38), including optimizing the number, placement, and size of electrodes, NMES parameters, and training protocols (8, 15, 23, 39). Additionally, combining NMES with methods like blood flow restriction has shown potential for producing better training effects than NMES alone (38, 40).

To better understand the effects of NMES on muscle, several studies have examined its effects at the gene and muscle fiber levels (13, 41–45). One study comparing a 30-min NMES session at the highest tolerable intensity with regular strength training found that both methods altered the expression of genes activated by exercise in the thigh muscle 24 h post-workout (13). While regular strength exercise regulated gene expression to a greater extent than NMES, NMES remains a good alternative when regular exercise is not possible (13).

A recent study conducted by our research group demonstrated that a single NMES session at 20% MVC, using NMES pants, regulated 4,448 differentially expressed genes (DEGs), with an 80% overlap with the 2,571 DEGs regulated by regular exercise. The genes regulated by NMES included well-known exercise-related genes such as PPARGC1A, ABRA, VEGFA, and GDNF. Only eight genes were regulated in opposite directions by NMES and exercise. The three genes upregulated by NMES and downregulated by exercise included genes involved in neurite outgrowth (MYLIP), cell proliferation and regulation of mTORC1 signaling (ICK) and negative regulation of cell proliferation (JARID2) (34). It was also demonstrated that the NMES-session at 20% of MVC could be applied with an acceptable level of discomfort, e.g., VAS below 4 (34).

In other studies, the effect of multiple NMES treatments (over 5 days to 10 weeks, with 3–6 sessions per week, lasting 18 min to 2 h per session) have been shown to affect gene and muscle fiber composition in both younger (41, 43) and older adults (41, 44). These effects have also been observed orthopedic contexts, aiding recovery of quadriceps strength after knee surgery, anterior cruciate ligament reconstruction and total knee arthroplasty (42, 46–48).

In summary, studies have concluded that NMES can preserve muscle mass, prevent muscle atrophy, and to some extent alter and improve gene expression. When compared to regular exercise, the effects of NMES are less pronounced, but it remains a valuable option for individuals unable to engage in regular exercise and as a complement to standard training for healthy individuals (41, 42).

For people over 65, there is a 30% risk of falling each year (57), and for those living in nursing homes, this rate increases to 50% (48). Falls in older adults can result in severe consequences, including fractures, immobilization, and even death (58). While regular physical activity reduces the risk of falls and related fractures (50), many older adults are unable to engage in such activities. NMES has, especially among older and/or untrained individuals, been shown to provide effective muscle activation, resulting in improved muscle strength and function (30, 31, 45, 54, 55, 59). For example, NMES treatment for 30 min, 2–3 times a week for 9 weeks has been shown to improve walking test time by 15%–20% (45).

In addition to the risk of falls, physical inactivity also increases the risk of type 2 diabetes and obesity (50). Globally, one in eleven adults has diabetes, and in 2019 more than four million people died due to diabetes or its complications, equating to one death every 8 s. In addition to those already diagnosed with diabetes, even more people have pre-diabetes with the risk of developing the disease but also with a great opportunity for prevention (60). Physical activity is crucial both for prevention and treatment of type 2 diabetes, but as mentioned above, many are unable to engage in regular exercise. For these individuals, NMES presents as a valuable alternative, offering similar effects as regular physical activity on blood sugar regulation (53, 61–64). One study demonstrated that patients with type 2 diabetes who performed 40-min quadriceps NMES sessions, 5 days per week for 8 weeks, significantly improved fasting glucose levels and reduced body fat (53). A systematic review has confirmed these effects (65). Moreover, patients with type 2 diabetes often suffer from peripheral artery disease, which causes ischemic pain in the lower limbs and impairs walking. NMES has been shown to increase peripheral arterial flow, reduce ischemic pain, and enhance walking distances (66). However, systematic reviews call for more high-quality trials to draw definitive conclusions (67).

Another significant risk posed by physical inactivity and extended immobilization is the development of blood clots in the legs or lungs (51). Between 1 and 4 out of 100 people will develop a blood clot requiring treatment during their lifetime (68). Anticoagulant treatments, while available, are not always effective (69), and for older adults who are prone to falls, they pose a bleeding risk (70). Mechanical compression therapy, such as intermittent pneumatic compression (IPC), is used in hospitals to increase blood flow, mimicking the muscle pump action that occurs during walking (71). However, IPC machines are too large and noisy for use outside of hospital environments, which is why NMES treatment, where electronics can be minimized, provides a quiet and mobile treatment option outside of hospitals. NMES treatment on the calf and quadriceps has been shown to improve venous blood flow in the leg vessels (12, 17, 18). Adding NMES treatment to drug therapy with anticoagulants during knee replacement surgery (72) and for patients undergoing major surgeries (73) reduces the risk of blood clots in the leg. While NMES alone can lower the risk of clots compared to no treatment during immobilization, it has not yet proven as effective as anticoagulants (18, 74). More research is needed to explore NMES as a sole treatment for preventing blood clots, as studies in this area are limited (18).